Abstract
AFAP1-AS1 is a long non-coding RNA which partakes in the pathoetiology of several cancers. The sense protein coding gene from this locus partakes in the regulation of cytophagy, cell motility, invasive characteristics of cells and metastatic ability. In addition to acting in concert with AFAP1, AFAP1-AS1 can sequester a number of cancer-related miRNAs, thus affecting activity of signaling pathways involved in cancer progression. Most of animal studies have confirmed that AFAP1-AS1 silencing can reduce tumor volume and invasive behavior of tumor cells in the xenograft models. Moreover, statistical analyses in the human subjects have shown strong correlation between expression levels of this lncRNA and clinical outcomes. In the present work, we review the impact of AFAP1-AS1 in the carcinogenesis.
Keywords: AFAP1-AS1, cancer, biomarker, expression, ncRNA
Introduction
Actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1, NC_000004.12) is a long non-coding RNA (lncRNA) which contributes in the pathoetiology of several cancers (1). It is transcribed from AFAP1 gene locus on 4p16.1. It has two alternatively spliced variants. Its second exon overlaps with exons 14-16 of AFAP1 gene. The motor fiber-associated protein encoded by AFAP1 has been shown to organize a platform for joining a number of tumor-related proteins such as SRC and protein kinase C (2). This platform can influence the organization and activity of actin filaments, therefore participating in cytophagy, cell motility, invasive characteristics of cells and metastatic ability (3). Both AFAP1 and FAP1-AS1 participate in the carcinogenesis through modulation of related signaling pathways. AFAP1 has acknowledged roles in the pathogenesis of a number of cancers, namely breast (4) and prostate cancer (5), yet its expression has been found to decreased in gastric cancer samples (6). AFAP1-AS1 is mainly regarded as an oncogenic lncRNA (1). However, the oncogenic effect of this lncRNA is not necessarily exerted through AFAP1-dependent routes. A number of deletion type copy-number variants (CNVs) have been identified in AFAP1-AS1 coding gene through application of whole genome sequencing (7). AFAP1-AS1 has been shown to affect several aspects of carcinogenesis through modulation of expression of cancer-related miRNAs. Since it has been shown to be dysregulated in diverse types of cancer, this lncRNA is a putative marker for a wide variety of cancers. Functional impacts of AFAP1-AS1 in the carcinogenesis have been appraised through knock-down and over-expression studies in cell lines and animal models. Moreover, the impact of AFAP1-AS1 deregulation has been assessed in human samples. In the present review, we discuss the role of AFAP1-AS1 in the carcinogenesis based on the evidence from these three types of studies.
Cell Line Studies
Lung Cancer
AFAP1-AS1 has been found to be over-expressed in non-small cell lung cancer (NSCLC) cells H1975, PC-9, A549, and SPCA-1 compared with the human non-tumorigenic lung epithelial cell line BEAS-2B. Functional studies in these cells have confirmed the ability of this lncRNA in binding with and sequestering miR-139-5p, a down-regulated miRNA in NSCLC samples. AFAP1-AS1 silencing and miR-139-5p up-regulation could similarly inhibit proliferation, colony forming ability and chemoresistance of NSCLC cells, while increasing their apoptosis. The sequestering impact of AFAP1-AS1 on miR-139-5p leads to up-regulation of RRM2, a protein which has been demonstrated to increase chemoresistance of NSCLC cells via activation of EGFR/AKT pathway (8). Another study in NSCLC has shown up-regulation of FAP1-AS1 parallel with down-regulation of IL-12 and up-regulation of IL-10 and IFN-γ. Functionally, AFAP1-AS1 has been shown to induce activity of IRF7, RIG-I-like receptor signals and Bcl-2. Cumulatively, AFAP1-AS1 enhances migration and invasive properties of NSCLC cells through activating IRF7 and the RIG-I-like receptor signaling pathway (9). Moreover, the interaction between AFAP1-AS1 and EZH2 and subsequent recruitment of EZH2 to the promoter of p21 has been shown to repress expression of p21 in this type of cancer (10). AFAP1-AS1 has also been shown to enhance expression of AFAP1 in lung cancer cells. Expression of AFAP1-AS1 in lung cancer cells is regulated through CpG methylation marks in its promoter, since the DNA methyltransferase inhibitor agent decitabine has been demonstrated to activate AFAP1-AS1 expression. AFAP1-AS1 has been reported to increase expression levels of pro-invasive genes PPP1R13L, VASP and SPTAN1, while decreasing expression levels of a number of anti-metastatic genes such as STAT1, NF1, and FBN2 (11). Figure 1 summarizes the mentioned routes of participation of AFAP1-As1 in the pathogenesis of lung cancer.
Figure 1.
The oncogenic role of AFAP1-AS1 in lung cancer through modulation of expressions of RRM2, IRF7, p21 and PPP1R13L. The effects of AFAP1-AS1 on RRM2 expression is mediated through sponging miR-139-5p. This mode of action results in enhancement of cell proliferation, migration and invasiveness.
AFAP1-AS1 can also affect lung cancer through a variety of other mechanisms being summarized in Figure 2 . For instance, AFAP1-AS1 has been shown to regulate expression of numerous members of the small GTPase proteins as well as those participating in the actin cytokeratin signaling. Thus, the promoting effect of AFAP1-AS1 on cancer metastasis is most probably exerted through modulation of actin filament integrity (12). GTPases harmonize several cellular processes, such as cell polarity, migration, and cell cycle transition, thus they can participate in the pathogenies of cancer (13). Moreover, cytokeratins as members of intermediate filament protein family have been shown to affect carcinogenesis. They can also been used as cancer biomarkers (14).
Figure 2.
The oncogenic role of AFAP1-AS1 in lung cancer metastasis.
AFAP1-AS1 can also enhance expression of HDGF through decreasing miR-545-3p levels in lung cancer cells. Thus, AFAP1-AS1 silencing could inhibit progression of lung cancer through influencing activity of miR-545-3p/HDGF axis (15). Finally, AFAP1-AS1 can interact with Smad nuclear interacting protein 1 (SNIP1), a protein which suppresses ubiquitination and subsequent destruction of c-Myc. This function of AFAP1-AS1 leads to over-expression of c-Myc, increase in ZEB1, ZEB2, and SNAIL levels, and enhancement of epithelial to mesenchymal transition (EMT) (16).
Breast Cancer
In breast cancer cells, AFAP1-AS1 silencing could decrease proliferation and migratory potential, and increase cell apoptosis. miR-497-5p has been recognized as a target of AFAP1-AS1 in breast cancer cells. Since this miRNA targets SEPT2, AFAP1-AS1 up-regulation results in up-regulation of SEPT2 (17). miR-145 is another target of AFAP1-AS1 in triple negative breast cancer cells (TNBC) MDA-MB-231 breast cancer cells. According to the results of luciferase reporter assay, miR-145 can directly target MTH1. Thus, the effects of AFAP1-AS1 in enhancement of proliferation and invasiveness of TNBC are exerted through miR-145/MTH1 axis (18). Moreover, in this type of cancer, AFAP1-AS1 can sequester miR-2110 to enhance expression of Sp1 (19). AFAP1-AS1 has also been shown to enhance EMT of TNBC cells via influencing Wnt/β-catenin signaling (20). Finally, AFAP1-AS1 has been found to have significant over-expression in trastuzumab-resistant breast cancer cells versus responsive cells. Expression of this lncRNA has been enhanced by H3K27ac at its promoter. Most notably, trastuzumab resistant cells have been shown to secrete AFAP1-AS1 into exosomes, thus disseminating trastuzumab resistance in other cells. The impact of exosomal AFAP1-AS1 in induction of trastuzumab resistance is exerted via its interaction with AUF1 and subsequent induction of ERBB2 translation (21). Figure 3 depicts the impact of AFAP1-AS1 in carcinogenesis and therapy resistance of breast cancer cells.
Figure 3.
The impact of AFAP1-AS1 in breast cancer progression and resistance to therapy. In addition to increasing cell proliferation and invasion, this lncRNA can increase expression of Her-2 protein, thus increasing resistance to trastuzumab.
Osteosarcoma
In MNNG/HOS and U2OS osteosarcoma cells, AFAP1-AS1 has been found to promote tumorigenesis via influencing RhoC/ROCK1/p38MAPK/Twist1 cascade (22). The AFAP1-AS1-mediated increase in Twist1 can enhance expression of N-cadherin and Vimentin, while diminishing E-cadherin levels, thus promoting EMT of osteosarcoma cells (22). Moreover, AFAP1-AS1 can sequester miR-497 and miR-4695-5p in these cells, therefore increasing expressions of IGF1R and TCF4, respectively (23, 24). The latter can activate Wnt-β catenin pathway and increase both proliferation and invasive abilities of osteosarcoma cells (24). Figure 4 depicts the oncogenic role of AFAP1-AS1 in osteosarcoma.
Figure 4.
The oncogenic role of AFAP1-AS1 in osteosarcoma is exerted through modulation of RhoC/ROCK1/p38MAPK/Twist1 cascade as well as sponging miR-497 and miR-4695-5p.
Gastric Cancer
Similarly, AFAP1-AS1 has an oncogenic role in gastric cancer. AFAP1-AS1 silencing has significantly suppressed proliferation and cell cycle transition in this kind of cancer. Besides, reduction in the levels of this lncRNA can inhibit invasive capacity through affecting EMT (25). Down-regulation of KLF2 is another mechanism by which AFAP1-AS1 enhances proliferative and migratory aptitudes of gastric cancer cells (26). AFAP1-AS1 silencing in gastric cancer cells has led to a significant increase in the levels of Bax, cleaved PARP, Caspase 3, and Caspase 9, while decreasing Bcl-2 level. AFAP1-AS1 silencing has also reduced p-AKT levels and enhanced expression of PTEN in gastric cancer cells. Taken together, AFAP1-AS1 regulates proliferation and apoptotic processes in gastric cancer cell through PTEN/p-AKT cascade (27). AFAP1-AS1 can also promote proliferation and metastatic ability of gastric cancer cell through sequestering miR-155-5p and enhancing expression of FGF7 (28). Figure 5 shows the oncogenic role of AFAP1-AS1 in gastric cancer.
Figure 5.
The oncogenic role of AFAP1-AS1 in gastric cancer is exerted through repression of KLF2, sponging miR-155-5p and enhancing activity of PTEN/p-AKT pathway.
Esophageal Cancer
AFAP1-AS1 have also been shown to bind with miR-26a, therefore influencing expression of its target gene, i.e. ATF2. Exosomes originated from M2 macrophages have higher expression of AFAP1-AS1 and ATF2 and reduced expression of miR-26a, compared with M1 macrophages. These exosomes could transfer AFAP1-AS1 to esophageal cancer cells, thus downregulating miR-26a and enhancing ATF2 levels in the recipeint cells. These expression changes affect phenotype of esophageal cancer cells (29). The regulatory role of AFAP1-AS1 on miR-498/VEGFA axis is another mechanism of participation of this lncRNA in the pathetiology of esophageal cancer (30).
Other Types of Cancers
In prostate cancer cells, AFAP1-AS1 has been shown to promote sequester miR-195-5p (31) and miR-512-3p (32), thus affecting malignnat behavious of these cells.
A number of other miRNAs, namely miR-423-5p (33), miR-320a (34), miR-107 (35) and miR-384 (36) have been found to be sequestered by AFAP1-AS1 in different cancer tissues ( Figure 6 ).
Figure 6.
The oncogenic role of AFAP1-AS1 in nasopharyngeal carcinoma, laryngeal carcinoma, ovarian cancer and pancreatic cancer. In all types of mentioned cancers, AFAP1-AS1 can act as molecular sponge for tumor suppressor miRNAs.
Table 1 summarizes the results of studies which appraised oncogenic roles of AFAP1-AS1 in different tissues.
Table 1.
Outlines of papers which judged expression of AFAP1-AS1 in cell lines.
| Tumor type | Interactions | Cell lines | Effects | Reference |
|---|---|---|---|---|
| Non-small Cell Lung Cancer | miR-139-5p, RRM2, EGFR/AKT signaling pathway | H1975, PC-9, A549, SPCA-1, BEAS-2B | Δ AFAP1-AS1: ↓ proliferation, ↓ chemo-resistance, ↑ apoptosis | (8) |
| _ | A549, H1975, H1650, H1395, H12994 | Δ AFAP1-AS1: ↓ proliferation ↑ AFAP1-AS1: ↑ invasion, ↑ migration, ↓ apoptosis | (9) | |
| p21, EZH2 | 16HBE, A549, SPC-A, H1299 | Δ AFAP1-AS1: ↓ proliferation, ↑ cell cycle arrest | (10) | |
| PPP1R13L, VASP, SPTAN1, STAT1, NF1, FBN2, AFAP1 | H1299, PC9, H1975, 293T | Δ AFAP1-AS1: ↓ invasion, ↓ migration ↑ AFAP1-AS1: ↑ invasion, ↑ migration | (11) | |
| HBP1 | 16HBE, A549, SPC‐A1, PC‐9, H1299, H1975 | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↑ G0/G1 cell cycle arrest, ↑ apoptosis | (37) | |
| Lung cancer | AFAP1, KRT1 | A549, H1299 and H460, 95-D, 16HBE | Δ AFAP1-AS1: ↓ proliferation, ↓ migration | (38) |
| RhoA, Rac2, Rab10, Rab11a, Rhogdi proteins, Pfn1, RhoC, Rab11b, LIM, Lasp1 | A549 | Δ AFAP1-AS1: ↓ invasion, ↓ migration, ↓ metastasis | (12) | |
| miR-545-3p, HDGF | _ | Δ AFAP1-AS1: ↓ proliferation ↓ invasion, ↓ migration, ↑ apoptosis | (15) | |
| SNIP1, c-Myc, ZEB1, ZEB2, SNAIL | A549, PC9 | Δ AFAP1-AS1: ↓ invasion, ↓ migration, ↓ EMT process | (16) | |
| _ | H1915, HCC827 | Δ AFAP1-AS1: ↓ invasion, ↓ growth, ↑ apoptosis | (39) | |
| Breast cancer (BC) | _ | MCF-10A, MCF-7, SK-RB-3, MDA-MB231, MDA-MB-468 | Δ AFAP1-AS1: ↓ proliferation, ↓ colony formation, ↓ metastasis ↑ apoptosis, did not affect AFAP1 expression, did not affect actin filament integrity | (40) |
| miR-497-5p | HCC70, BT-549, MCF-7, MDA-MB-231, MCF-10A | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↑ apoptosis | (17) | |
| miR-145, MTH1, ATF6 | MDA-MB-231, MDA-MB-468, MDA-MB-435S, and HCC1937, MCF-10A | Δ AFAP1-AS1: ↓ viability, ↓ colony formation, ↓ invasion | (18) | |
| Wnt/β-catenin signaling pathway, C-myc, SLUG, SNAIL, vimentin, fibronectin, N-cadherin, E-cadherin | 184A1, MCF-10A, BT474, MCF-7, T47D, BT483, BT20, MDA-MB-468, BT549, MDA-MB-231 | Δ AFAP1-AS1: ↓ proliferation ↓ invasion, ↓ migration, ↓ EMT process, ↑ apoptosis | (20) | |
| miR-2110, Sp1 | MCF-10A, BT-549, MDA–MB-468 | Δ AFAP1-AS1: ↓ proliferation ↓ invasion, ↓ migration | (19) | |
| ERBB2, AUF1 | KBR-3, BT474, | Δ AFAP1-AS1: ↓ trastuzumab resistance | (21) | |
| Osteosarcoma | Twist1, N-cadherin and Vimentin, E-cadherin, RhoC/ROCK1/p38MAPK signaling pathway | MNNG/HOS, MG63, SaOS-2, hFOB 1.19 | Δ AFAP1-AS1: ↓ proliferation, ↓ invasion, ↓ migration, ↓ actin filament integrity, ↓ EMT process, ↓ VM formation capacity, ↑ apoptosis, ↑ G0/G1 cycle arrest | (22) |
| miR-497, IGF1R | MG-63, 143B, U2OS, Saos-2, hFOB 1.19 | Δ AFAP1-AS1: ↓ proliferation ↓ invasion, ↓ migration, ↑ apoptosis, | (23) | |
| miR-4695-5p, TCF4, Wnt/β-catenin pathway | hFOB 1.19, Saos-2, U2OS, MG-63, 143B | Δ AFAP1-AS1: ↓ proliferation ↓ invasion | (24) | |
| Esophageal cancer (EC) | miR-26a, ATF2 | PBMCs, KYSE410 | Δ AFAP1-AS1 in M2 Macrophage-Derived Exosomes: ↓ invasion, ↓ migration, ↓ metastasis | (29) |
| miR-498, VEGFA | HET-1A, Eca109, KYSE-30 | Δ AFAP1-AS1: ↓ proliferation, ↓ Migration, ↑ apoptosis | (30) | |
| _ | ECA‐109, TE‐1, HEEC | Δ AFAP1-AS1: ↓ proliferation, ↑ apoptosis | (41) | |
| _ | OE-33, SK-GT-4, FLO-1, HEEpic | Δ AFAP1-AS1: ↓ proliferation, ↓ invasion, ↓ anchorage-dependent growth did not affect the expression level of AFAP1 | (42) | |
| Gastric cancer (GC) | KLF2, EZH2 | GES-1, AGS and SGC-7901 | Δ AFAP1-AS1: ↓ proliferation, ↓ invasion, ↓ viability, ↑ apoptosis | (26) |
| intrinsic pathway, PTEN/p-AKT Pathway | AGS, MGC-803, SGC-7901, BGC-823, GES-1 | Δ AFAP1-AS1: ↓ proliferation, ↑ apoptosis | (27) | |
| _ | MKN-45, MGC-803 and AGS | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↓ invasion, ↑ G0/G1 phase arrest, ↑ apoptosis | (43) | |
| _ | AGS, BGC823, MGC-803, SGC-7901, GES-1 | Δ AFAP1-AS1: ↓ proliferation, ↓ invasion, ↓ EMT process, ↓ cell cycle progress | (25) | |
| miR-155-5p, FGF7 | MKN-28, BGC-823, MGC-803, SGC-7901, GES-1 | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↓ invasion | (28) | |
| _ | GES-1, HGC-27, MGC-803, BGC-823, SGC-7901 | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↓ invasion | (44) | |
| _ | GES-1, AGS, BGC-823, MKN-45, SGC-7901 | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↓ invasion, ↓ EMT process | (45) | |
| Prostate cancer | miR-195-5p, FKBP1A | PC3, DU145 | Δ AFAP1-AS1: ↑ PTX sensitivity, ↑ apoptosis, ↓ migration, ↓ invasion | (31) |
| miR-512-3p | 22RV1 | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↓ invasion, ↑ G0/G1 phase arrest | (32) | |
| Nasopharyngeal carcinoma (NPC) | YAP, KAT2B, RBM3 | HNE-1, C666-1, SUNE-1, CNE-1, CNE-2, NP69 | Δ AFAP1-AS1: ↓ proliferation | (46) |
| miR-423-5p, Rho/Rac signaling, FOSL2, LASP1 | 5-8F, HNE2 | ↑ AFAP1-AS1: ↑ migration, ↑ invasion | (33) | |
| AFAP1, RhoA, Rac2, Rab10, Rab11a, Rhogdi, Pfn1, RhoC, Rab11b, Lasp1 | 5-8F, HNE2 and HK-1 | Δ AFAP1-AS1: ↓ migration, ↓ invasion, ↓ stress filament integrity | (47) | |
| Endometrial carcinoma (EC) | miR-545-3p, VEGFA | Ishikawa, HEC-1-B, HEC1-A, AN3-CA, hEEC, | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↓ invasion, ↓ angiogenesis | (48) |
| Cholangiocarcinoma (CCA) | AFAP1 | HuCCT1, TFK-1, HIBEpic | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↓ invasion, ↓ stress filament integrity | (49) |
| MMP-2, MMP-9 | QBC939, CCLP1, HuCC-T1 and RBE, BEC, 293T | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↓ invasion, ↑ G0/G1 phase arrest | (50) | |
| Colorectal cancer (CRC) | GAS8-AS1 | CR4 (Sigma-Aldrich, USA), RKO (ATCC, USA) | ↑ AFAP1-AS1: ↑ proliferation | (51) |
| _ | HCT116, SW480 | Δ AFAP1-AS1: ↓ proliferation, ↑ G0/G1 phase arrest | (52) | |
| AFAP1 | HCT116, SW480 | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↓ invasion | (53) | |
| EZH2 | LOVO, SW1116, SW480, HCT116, SW620, HT29 | Δ AFAP1-AS1: ↓ proliferation, ↑ cell-cycle arrest | (54) | |
| Colon cancer | actin-cytokeratin signaling pathway, E-cadherin, vimentin, MMP9, ZEB1, ZO-1, β-catenin | SW480, SW620, HCT116, HT-29 | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↓ invasion | (55) |
| Hepatocellular carcinoma (HCC) | N-cadherin, vimentin, E-cadherin, CRKL, Ras, MEK, c-Jun | Huh7, HepG2, HCCLM3, LO2 | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↓ invasion, ↓ EMT process | (56) |
| RhoA/Rac2 signaling | SMCC7721 and HepG2 | Δ AFAP1-AS1: ↓ proliferation, ↓ invasion, ↑ S phase arrest, ↑ apoptosis | (57) | |
| _ | LO2, SMMC-7721, Bel-7402, MHCC-97 L, MHCC-97H | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↓ invasion | (58) | |
| Cervical cancer (CC) | RhoA/Rac2 signaling, Vimentin, β-catenin, ZO-1 | ATCC no. CCL-2, | Δ AFAP1-AS1: ↓ migration, ↓ invasion, ↓ EMT process | (59) |
| Laryngeal carcinoma | miR‐320a, RBPJ | HEp‐2 | Δ AFAP1-AS1: ↓ stemness, ↓ cisplatin resistance, ↑ apoptosis | (34) |
| Thyroid cancer | _ | K-1, TPC-1, SW579, FTC133, XTC-1, l Nthy-ori3-1 | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↓ EMT process, ↑ apoptosis | (60) |
| Glioma | _ | U87MG, U251, SHG-44, A172 | Δ AFAP1-AS1: ↓ invasion | (61) |
| Ovarian cancer (OC) | _ | SKOV3, OV90, TOV112D, ES2 | Δ AFAP1-AS1: ↓ proliferation, ↑ apoptosis ↑ AFAP1-AS1: ↑ proliferation | (62) |
| miR-107, PDK4 | IOSE80, COV504, OVISE, OV90 and SKOV3 | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↓ invasion | (35) | |
| Pancreatic cancer (PC) | miR-384, ACVR1 | SW1990, Capan-1, AsPC-1, MIAPaCa-2, PANC-1, HPC-Y5 | Δ AFAP1-AS1: ↓ stemness | (36) |
| ZEB1, N-cadherin, E-cadherin, MMP-2, MMP-9, Slug, Snail | BxPC-3, PANC-1 | Oridonin-induced Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↓ EMT process, ↑ apoptosis, ↑ cell cycle arrest | (63) | |
| miR-133a, IGF1R | AsPC-1, BxPC-3, PANC-1, PaCa-2 and SW1990 | Δ AFAP1-AS1: ↓ proliferation, ↓ invasion, ↓ metastasis, ↑ apoptosis | (64) | |
| EGFR/Akt signaling, miR‐146b‐5p | ASPC‐1, BxPC‐3, HPAC, MiaPaCa‐2, HPDE6‐C7 | CUB-induced Δ AFAP1-AS1: ↓ proliferation, ↑ cell cycle arrest | (65) | |
| Pancreatic ductal adenocarcinoma (PDAC) | _ | Panc1, MIAPaCa-2, Capan2, SW1990, BXPC-3, HPDE6 | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↓ invasion | (66) |
| Renal cell carcinoma (RCC) | PTEN/AKT signaling | HK2, 786-O, Caki-1, ACHN, A498 | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↓ invasion, ↓ EMT process | (67) |
| Gallbladder cancer (GBC) | _ | NOZ, H69, GBC-SD, SGC-996 | Δ AFAP1-AS1: ↓ proliferation, ↓ invasion, ↓ epithelial phenotype to mesenchymal phenotype | (68) |
| Pituitary adenoma | miR-103a-3p, PI3K/AKT Signaling Pathway | GH3 and MMQ | Δ AFAP1-AS1 + miR-103a-3p inhibitor: ↑ proliferation, ↑ cell cycle progression, ↓ apoptosis | (69) |
| PTEN/PI3K/AKT signaling pathway | GH3, MMQ | Δ AFAP1-AS1: ↓ proliferation, ↑ cell cycle arrest, ↑ apoptosis | (70) | |
| Melanoma | miR-653-5p, RAI14, E-cadherin, N-cadherin, Ki67 | HEMa-LP, A375, M21, B16F10, SK-MEL-2 | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↓ invasion | (71) |
| Retinoblastoma | _ | Weri-Rb1 and Y79, ARPE-19, HRMECs | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↓ invasion | (72) |
| Tongue squamous cell carcinoma (TSCC) | Wnt/β-catenin, SLUG, SNAIL1, VIM, CADN, ZEB1, ZEB2, and TWIST1 | SCC-15, Tca8113, SCC-4, SCC-9, CAL-27 | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↓ invasion, ↑ G0/G1 cell cycle arrest | (73) |
| Oral squamous cell carcinoma (OSCC) | miR-145, HOXA1 | SCC9, SCC15, SCC25, HOKs | Δ AFAP1-AS1: ↓ proliferation, ↓ migration, ↓ invasion | (74) |
(Δ: knock-down, CuB: Cucurbitacin B).
Animal Studies
Investigations, particularly those conducted in BALB/c nude mice models have verified the oncogenic roles of AFAP1-AS1 in different types of cancers. AFAP1-AS1 knock-down has consistently led to significant reduction in tumor size/weight, attenuation of tumor growth rate and enhancement of response of cancer cells to therapeutic modalities ( Table 2 ). In NSCLC, AFAP1-As1 silencing not only reduces tumorigenicity, but also confers chemosensitivity (8). Moreover, its silencing can affect IRF7 and RIG-I-like receptor signals (9). In breast cancer, AFAP1-AS1 down-regulation can affect trastuzumab resistance (21).
Table 2.
Outlines of studies which tested function of AFAP1-AS1 in xenografts.
| Tumor Type | Animal models | Results | Reference |
|---|---|---|---|
| Non-small Cell Lung Cancer | male athymic nude BALB/c mice | Δ AFAP1-AS1: ↓ tumorigenicity, ↓ chemo-resistance | (8) |
| _ | Δ AFAP1-AS1: ↓ mRNA and protein of IRF7 and RIG-I-like receptor signals | (9) | |
| ↑ AFAP1-AS1: ↑ mRNA and protein of IRF7 and RIG-I-like receptor signals | |||
| male BALB/c nude mice | Δ AFAP1-AS1: ↓ tumor volume, ↓ tumor weight | (10) | |
| BALB/c nude mice | Δ AFAP1-AS1: ↓ tumor weight, ↓ tumor size | (37) | |
| Lung cancer | BALB/c nude mice | Δ AFAP1-AS1: ↓ tumor volume, ↓ tumor weight, ↓ tumor growth | (38) |
| murine xenograft mice | Δ AFAP1-AS1: ↓ tumor growth | (15) | |
| female nude mice | Δ AFAP1-AS1: ↓ metastatic nodules | (16) | |
| Breast cancer (BC) | female nude mice | Δ AFAP1-AS1: ↓ tumor growth | (17) |
| Female BALB/c nude mice | Δ AFAP1-AS1: ↓ tumor growth | (18) | |
| female nude mice | Δ AFAP1-AS1: ↓ tumor growth, ↓ tumor weight | (20) | |
| BALB/C specific-pathogen-free nude mice | Δ AFAP1-AS1: ↓ tumor volume, ↓ tumor weight, ↓ tumor growth | (19) | |
| male BALB/c nude mice | Δ AFAP1-AS1: ↓ tumor resistance, ↓ metastasis | (21) | |
| Osteosarcoma | female BALB/c nude mice | Δ AFAP1-AS1: ↓ tumor growth, ↓ invasion | (22) |
| male athymic BALB/c nude mice | Δ AFAP1-AS1: ↓ tumor volume, ↓ tumor weight, ↓ tumor growth | (23) | |
| female BALB/c nude mice | Δ AFAP1-AS1: ↓ tumor size, ↓ tumor weight | (24) | |
| Esophageal cancer (EC) | _ | Δ AFAP1-AS1: ↓ATF2, ↑ miR-26a | (29) |
| Gastric cancer (GC) | male BALB/c nude mice | Δ AFAP1-AS1: ↓ tumor volume, ↓ tumor weight, ↓ tumor growth | (44) |
| Prostate cancer | nude mice | Δ AFAP1-AS1: ↓ tumor volume, ↓ tumor weight, ↑ C-caspase 3 | (31) |
| Nasopharyngeal carcinoma (NPC) | male BALB/C nude mice | ↑ AFAP1-AS1: ↑ metastasis | (33) |
| nude mice | Δ AFAP1-AS1: ↓ number and size of the metastatic foci | (47) | |
| Endometrial carcinoma (EC) | male BALB/c nude mice | Δ AFAP1-AS1: ↓ tumor volume, ↓ tumor weight | (48) |
| Cholangiocarcinoma (CCA) | female BALB/c/nu nude mice | Δ AFAP1-AS1: ↓ tumor volume, ↓ tumor weight, ↓ number and size of the metastatic foci | (49) |
| female BALB/c athymic nude mice | Δ AFAP1-AS1: ↓ tumor volume, ↓ tumor weight | (50) | |
| Colorectal cancer (CRC) | male C57BL/6 nude mice | Δ AFAP1-AS1: ↓ tumor volume, ↓ tumor weight | (53) |
| female BALB/c-nude mice | Δ AFAP1-AS1: ↓ tumor growth | (54) | |
| Hepatocellular carcinoma (HCC) | female immune-deficient BALB/c-nu nude mice | Δ AFAP1-AS1: ↓ tumor weight | (57) |
| nude mice | Δ AFAP1-AS1: ↓ tumor weight, ↓ tumor growth, ↓ Ki-67 expression | (58) | |
| Pancreatic cancer (PC) | nude mice | Δ AFAP1-AS1: ↓ tumor volume, ↓ tumor weight | (36) |
| male/female BALB/C nude mice | Δ AFAP1-AS1: ↓ tumorigenicity, ↓ EMT process | (63) | |
| female BALB/c nude mice | CUB-induced Δ AFAP1-AS1: ↓ tumor volume, ↓ tumor weight, ↓ tumor growth | (65) | |
| Pancreatic ductal adenocarcinoma (PDAC) | nude mice | Δ AFAP1-AS1: ↓ tumor volume, ↓ tumor weight | (66) |
| Renal cell carcinoma (RCC) | female BALB/c athymic nude mice | Δ AFAP1-AS1: ↓ tumor volume, ↓ tumor weight | (67) |
| Melanoma | male BALB/c nude mice | Δ AFAP1-AS1: ↓ tumor volume, ↓ tumor weight, ↓ tumor size | (71) |
| Tongue squamous cell carcinoma (TSCC) | female BALB/c athymic nude mice | Δ AFAP1-AS1: ↓ tumor growth, ↓ tumor weight, ↓ tumor size | (73) |
| Oral squamous cell carcinoma (OSCC) | male BALB/c nude mice | Δ AFAP1-AS1: ↓ tumor volume, ↓ tumor weight | (74) |
(Δ: knock down or deletion).
Clinical Studies
Except from a single low-sample size study in gastric cancer which reported down-regulation of AFAP1-AS1 in tumoral tissues versus nearby samples (6), other studies consistently reported over-expression of AFAP1-AS1 in different neoplastic tissues compared with non-neoplastic tissues of the same origin ( Table 3 ). Even in the mentioned study, levels of AFAP1-AS1 were higher in patients who showed lymphatic or vascular invasion in comparison with those without these properties (6). Moreover, different statistical methods have been applied to assess correlations between expression level of AFAP1-AS1 and clinical outcomes, all of them reporting significant impact of up-regulation of this lncRNA on increasing malignant behaviors of tumors and decreasing patients’ survival. In pancreatic cancer, up-regulation of AFAP1-AS1 has been associated with lymph node involvement, perineural invasion, and poor clinical outcome. An in silico analysis of TCGA data of breast cancer patients has revealed AFAP1-AS1, as a differentially expressed lncRNA in basal tumors whose expression levels are associated with poor survival. Expression of this lncRNA has also been associated with hormone receptors status, HER2 expression, and PAM50 classification (81).
Table 3.
Outlines of studies that appraised levels of AFAP1- AS1 in clinical setting.
| Tumor type | Numbers of clinical samples | Expression (Tumor vs. Normal) | Kaplan-Meier analysis | Univariate cox regression | Multivariate cox regression | Clinicopathologic characteristics of patients | Reference |
|---|---|---|---|---|---|---|---|
| Non-small Cell Lung Cancer (NSCLC) | 44 NSCLC patient tissues and ANCTs | high | _ | _ | _ | _ | (8) |
| 165 NSCLC patients, 118 benign lung tumor tissues, and 173 healthy samples | high | _ | _ | _ | Paired t test: AFAP1- AS1 was correlated with pathological grade, TNM staging and metastatic ability. | (9) | |
| GEO analysis | high | _ | _ | – | _ | ||
| 92 pairs of NSCLC tissues and ANCTs | high | Patients with high levels of AFAP1-AS1 had poorer OS. | Histological grade, TNM stage, and AFAP1-AS1 expression were identified as three prognostic factors. | Histological grade, TNM stage, and AFAP1-AS1 expression were independent predictors for OS in NSCLC patients. | Chi-square test: Relative levels of AFAP1-AS1 were associated with tumor burden. | (10) | |
| 7 NSCLC tumor tissues and ANCTs | high | _ | _ | _ | _ | (11) | |
| 126 NSCLC patients and 60 healthy controls | high | _ | _ | _ | Mann–Whitney U test: High serum levels of AFAP1-AS1 were strongly associated with DM, LNM, poor clinical stage, and larger tumor size. | (75) | |
| 82 pairs of NSCLC tissue and ANCTs | high | _ | _ | _ | _ | (76) | |
| 52 NSCLC patients | high | AFAP1-AS1 down-regulation was correlated with improved survival time. | _ | High expression level of ASAP1-S1 was an indicator of poor survival. | _ | ||
| Non-small Cell Lung Cancer (NSCLC) | 96 pairs of lung cancer tissues and ANCTs | high | AFAP1‐AS1 over-expression was related with short OS and PFS. | _ | _ | _ | (37) |
| GEO and TCGA analysis: _ | high | _ | _ | _ | _ | ||
| 121 NSCLC patients and 79 healthy controls | high | AFAP1‐AS1 over-expression was related with short OS. | _ | AFAP1-AS1 was an independent prognostic indicator for NSCLC patients. | Chi-square test: AFAP1-AS1 expression was influenced by clinical stage, smoking history, infiltration extent, LNM and distant metastasis. | (77) | |
| 36 studies: 6267 NSCLC patients | high | _ | _ | _ | _. | (78) | |
| TCGA analysis: 465 LUAD patients and 49 ANCTs | high | _ | _ | _ | _ | (79) | |
| 53 newly diagnosed LUAD tissues and ANCTs | high | _ | _ | _ | _ | ||
| 20 pairs of LUAD and LUSC tumor tissues and ANCTs | high | _ | _ | _ | _ | (80) | |
| TCGA analysis: 57 paired LUAD and normal samples and 16 paired LUSC and normal samples | high | _ | _ | _ | _ | ||
| Lung cancer | 98 pairs of lung cancer tissues and ANCTs | high | _ | _ | _ | Patients with high levels of AFAP1-AS1 had poor histology type, great tumor size, LNM, distant metastasis, and advanced TNM stage. | (38) |
| GSE31210 analysis: 226 primary lung cancer samples and 20 normal lung samples | high | High levels of were associated with poor OS. | _ | _ | _ | (12) | |
| GSE19804 analysis: 60 pairs of lung cancer tissues and ANCTs | high | _ | _ | _ | _ | ||
| GSE27262 analysis: 25 pairs of tumor tissues and ANCTs | high | _ | _ | _ | _ | ||
| GSE18842 analysis: 46 pairs of tumor tissues and ANCTs | high | _ | _ | _ | _ | ||
| GSE37745 analysis: 106 lung cancer biopsies | high | High levels of were associated with poor OS. | _ | _ | _ | ||
| 187 paraffin-embedded lung cancer tissues and 36 normal lung specimens | high | High AFAP1-AS1 expression was tightly correlated with poorer OS. | _ | _ | _ | (16) | |
| Lung cancer | 36 lung adenocarcinoma tissue samples and ANCTs | high | High levels of AFAP1-AS1 were associated with shorter DFS. | _ | _ | _ | (39) |
| Breast cancer (BC) | 160 pairs of breast cancer tissues and ANCTs | high | The 3-years OS of patients with high AFAP1-AS1 expression was lower. | AFAP1-AS1 expression, tumor grade, TNM stage, and LNM were Significant factors. | High level of AFAP1-AS1 was correlated with the malignant features. | _ | (40) |
| 20 pairs of breast cancer tissues and ANCTs | high | _ | _ | _ | _ | (17) | |
| TCGA analysis: _ | high | _ | _ | _ | _ | (18) | |
| 31 pairs of TNBC tissues and ANCTs | high | High levels of AFAP1-AS1 were correlated with poorer DFS and OS. | _ | AFAP1-AS1 could be regarded as an independent prognostic factor in TNBC. | _ | (20) | |
| TCGA analysis: _ | high | High expression of AFAP1 was correlated with short surviavl in patients with Luminal B, HER2 +, and basal tumors and worse OS Luminal A and HER2 + tumor subtypes. | _ | _ | _ | (81) | |
| 8 pairs of TNBC tissues and ANCTs | high | _ | _ | _ | _ | (19) | |
| 64 HER-2 positive patients and 40 HER-2 negative patients | Higher in HER-2 positive than HER-2 negative | _ | _ | _ | _ | (21) | |
| 51 pairs of tumor tissues and ANCTs | high | _ | _ | _ | Its expression was low in ki-67 negative tumor tissues. | (82) | |
| Osteosarcoma | 8 pairs of Osteosarcoma tissues and ANCTs | high | _ | _ | _ | _ | (22) |
| 45 OS tissues and ANCTs | high | Patients who had high AFAP1-AS1 expression level indicated poor OS rate than those who had low AFAP1-AS1 expression level. | _ | _ | _ | (23) | |
| 49 pairs of OS tissues and ANCTs | high | Patients with higher expression of AFAP1-AS1 showed lower OS and PFS rates. | _ | _ | _ | (24) | |
| Esophageal cancer (EC) | 42 ESCC tissues and 35 ANCTs | high | _ | _ | _ | _ | (30) |
| 65 pairs of tissues and ANCTs | high | _ | _ | _ | Chi‐squared test: high level of AFAP1‐AS1 was correlated with tumor size and advanced TNM stage. | (41) | |
| 48 pairs of ESCC tissues and ANCTs | high | _ | _ | _ | _ | (83) | |
| 162 pairs of ESCC tissues and ANCTs | high | High levels of AFAP1‐AS1 were strongly associated with shorter PFS. | Tumor depth, LNM, TNM stage, dCRT response, and AFAP1‐AS1 expression were associated with PFS and OS. | Tumor depth, dCRT response, and AFAP1‐AS1 expression were independent prognostic factors for PFS. Moreover, high levels of AFAP1‐AS1 indicated unfavorable OS. | Chi‐squared test: higher expression of AFAP1‐AS1 was strongly correlated with LNM, distant metastasis, advanced clinical stage, and lack of response to dCRT. | ||
| Gastric cancer (GC) | 20 pairs of GC tissues and ANCTs | high | _ | _ | _ | _ | (27) |
| 52 pairs of GC tissues and ANCTs | high | _ | _ | _ | _ | (43) | |
| 91 pairs of primary gastric cancer tissues and their ANCTs | high | Patients with high levels of AFAP1-AS1 showed poor OS than those with low levels. | _ | Lymph node metastasis, TNM stage, and AFAP1-AS1 expression levels were independent prognostic factors for OS time. | X2 test: expression of AFAP1-AS1 was associated with LNM and TNM stage. | (25) | |
| 52 pairs of GC tissues and ANCTs | high | Patients with high expression of AFAP1-AS1 had a significantly poorer OS compared to those with low-expression of AFAP1-AS1. | _ | _ | _ | (28) | |
| 30 tumor tissues and ANCTs | down | _ | _ | _ | Levels of AFAP1-AS1 were higher in patients who showed lymphatic or vascular invasion in comparison with those who did not. | (6) | |
| 66 pairs of GC tissues and ANCTs | high | _ | _ | Expression of AFAP1-AS1, clinical stage, and tumor differentiation could be regarded as the factors that were independently correlated with OS. | Higher expression level of AFAP1-AS1 was correlated with tumor mass, clinical stage, and tumor differentiation. | (44) | |
| 89 GC patients, 55 benign gastric lesion groups, 73 age-matched healthy volunteers | high | _ | _ | _ | Logistic regression analysis: high level of AFAP1-AS1 was significantly correlated with tumor size, TNM stage and LNM. | (45) | |
| 80 pairs of GC tissues and ANCTs | high | Patients with high levels of AFAP1-AS1 had shorter OS than those with low levels of AFAP1-AS1. | _ | _ | _ | (84) | |
| Prostate cancer | 30 PCa tissues and corresponding nearby healthy tissues | high | _ | _ | _ | _ | (31) |
| 38 pairs of prostate cancer tissues and ANCTs | high | Patients with high expression of AFAP1-AS1 had lower OS. | _ | _ | Chi-Square test: AFAP1-AS1 expression was associated with histological grade and distant metastasis. | (32) | |
| Nasopharyngeal carcinoma (NPC) | 10 pairs of freshly frozen samples and ANCTs | high | Patients with high expression of AFAP1-AS1 showed lower OS. | _ | _ | _ | (46) |
| 100 pairs of paraffin-embedded samples and ANCTs | |||||||
| 96 paraffin-embedded NPC samples | high | Patients with high expression of AFAP1-AS1 had a poor prognosis, with shorter OS. | _ | _ | Patients with high expression of AFAP1-AS1 were showed distant metastasis when they relapsed. | (85) | |
| 32 nasopharyngeal carcinoma samples and 13 non tumor nasopharyngeal epithelium tissues | high | _ | _ | _ | High expression of AFAP1-AS1 was highly correlated with clinical TNM stages, neck LNM, and T stages of the patients. | (33) | |
| 101 NPC patients and 101 healthy controls | high | _ | _ | _ | _ | (86) | |
| 101 NPC patients and 20 chronic nasopharyngitis patients | |||||||
| 101 NPC patients and 20 asymptomatic EBV carriers | |||||||
| 23 NPC samples and 7 non-tumor nasopharyngeal epithelium samples | high | _ | _ | _ | _ | (47) | |
| 112 paraffin-embedded NPC and 10 NPE tissue samples | high | High expression of AFAP1-AS1 was correlated with poor OS and poor RFS. | _ | _ | Expression of AFAP1-AS1 was associated with distant tumor metastasis. | ||
| Endometrial carcinoma (EC) | 73 pairs of EC tissues and ANCTs | high | _ | _ | _ | _ | (48) |
| Cholangiocarcinoma (CCA) | 20 pairs of CCA tissues and ANCTs | high | _ | _ | _ | _ | (49) |
| 56 pairs of tumor tissues and ANCTs | high | Patients with high expression of AFAP1-AS1showed shorter OS. | _ | _ | High expression of AFAP1-AS1 had positive association with tumor size, vascular invasion, and advance TNM stage. | (50) | |
| Colorectal cancer (CRC) | 68 CRC patients and 60 healthy volunteers | high | _ | _ | _ | Chi-squared test: plasma levels of AFAP1-AS1 were correlated with clinical stage. | (51) |
| 52 pairs of CRC tissues and ANCTs | high | Patients with up-regulation of AFAP1-AS1 had a significantly poorer prognosis. | AFAP1-AS1 expression, tumor size, TNM stage, and distant metastasis were significantly correlated with OS and DFS. | AFAP1- AS1 expression, TNM stage, and distant metastasis were strongly correlated with OS and DFS. | High levels of AFAP1-AS1 were associated with tumor size, TNM stage and remote metastasis. | (52) | |
| 15 pairs of CRC tissues and ANCTs | high | _ | _ | _ | _ | (53) | |
| TCGA analysis: 50 pairs of clinical colorectal cancer tumors and the peritumoral tissues | |||||||
| 80 CRC tissues and 10 normal colon tissues | high | Patients who had high AFAP1-AS1 mRNA levels indicated worse prognosis compared with those with low. | _ | _ | _ | (54) | |
| Colon Cancer | GEO analysis: _ | high | _ | _ | _ | _ | (55) |
| TCGA-COAD analysis | high | Patients with high expression of AFAP1-AS1 indicated shorter OS and DFS. | _ | _ | _ | ||
| Hepatocellular carcinoma | 17 pairs of tumor tissues and ANCTs | high | _ | _ | _ | _ | (56) |
| 17 pairs of HCC tissues and ANCTs | high | Patients with high levels of AFAP1-AS1 showed a shorter median survival time. | _ | AFAP1-AS1 expression could be regarded as an independent prognostic factor for OS in HCC patients. | High levels of AFAP1-AS1 were correlated with pathological staging and lymph-vascular space invasion. | (57) | |
| 156 pairs of HCC tissues and ANCTs | high | Patients with low levels of AFAP1-AS1 showed better OS and DFS. | _ | _ | High levels of AFAP1-AS1 were correlated with tumor size, vascular invasion, and TNM stage. | (58) | |
| Cervical cancer (CC) | TCGA analysis: _ | high | Patients with high expression of AFAP1-AS1 expression had a short OS. | _ | _ | High levels of AFAP1-AS1 were correlated with TNM stage. | (59) |
| Laryngeal carcinoma | 24 pairs of tumor tissues and ANCTs | high | _ | _ | _ | _ | (34) |
| Thyroid cancer | 36 pairs of tumor tissues and ANCTs | high | Patients with high expression of AFAP1-AS1 expression had a short OS | _ | AFAP1-AS1 expression might be a positive, independent prognostic factor. | _ | (60) |
| Glioma | 52 glioma cases and 5 non-tumor control cases | high | High expression of AFAP1-AS1 predicted worse prognosis in glioma patients. | _ | _ | Expression of AFAP1-AS1 was closely correlated with glioma grading and KPS scores. | (61) |
| Ovarian cancer (OC) | 65 pairs of OC tissues and ANCTs | high | _ | _ | _ | Upregulation of AFAP1-AS1 was correlated with high FIGO stage and resistance response. | (62) |
| 39 pairs of OC tissues and ANCTs | high | Patients with low expression of AFAP1-AS1 showed greater survival probability. | _ | _ | Chi-square analysis: Upregulation of AFAP1-AS1 was correlated with FIGO stage. | (35) | |
| Pancreatic cancer (PC) | 75 pairs of PC tissues and ANCTs | high | _ | _ | _ | Upregulation of AFAP1-AS1 was positively associated with TNM stage, LNM, and tumor size. | (36) |
| GEO analysis: _ | high | _ | – | _ | _ | (64) | |
| 63 pairs of PC tissues and ANCTs | high | Patients with high AFAP1-AS1 expression showed a shorter 5-year OS rate. | _ | _ | Upregulation of AFAP1-AS1 was positively associated with advanced TNM stage, tumor size and LNM. | ||
| Pancreatic ductal adenocarcinoma (PDAC) | 8 cases of PDAC tissues and 4 cases of CP tissues | high | _ | _ | _ | _ | (66) |
| 90 pairs of PDAC tissues and ANCTs | high | Patients with high expression of AFAP1-AS1 showed worse OS and PFS. | _ | _ | Upregulation of AFAP1-AS1 was positively associated with LNM and perineural invasion. | ||
| Renal cell carcinoma (RCC) | 60 ccRCC tissues and 20 ANCTs | high | Patients with high expression of AFAP1-AS1 showed worse OS. | _ | _ | Upregulation of AFAP1-AS1 was positively associated with LNM and TNM stage. | (67) |
| Gallbladder cancer (GBC) | 40 pairs of GBC tissues and ANCTs | high | Upregulation of AFAP1-AS1 indicated a poor prognosis in gallbladder cancer. | _ | _ | Upregulation of AFAP1-AS1 was positively associated with tumor size. | (68) |
| Pituitary adenoma | 60 pairs of pituitary adenomas tissues and ANCTs | high | _ | _ | _ | _ | (70) |
| Retinoblastoma | 58 freshly frozen retinoblastoma tissue samples and 10 non-cancerous retina samples | high | Patients with high expression of AFAP1-AS1 had shorter OS. | High-expression of AFAP1-AS1 was found to be an unfavorable prognostic factor. | High-expression of AFAP1-AS1 was found to be an independent unfavorable prognostic factor. | Upregulation of AFAP1-AS1 was positively associated with tumor bulk as well as choroidal or optic nerve invasion. | (72) |
| Tongue squamous cell carcinoma | 103 pairs of tumor tissues and ANCTs | high | High AFAP1-AS1 expression was related to poor survival. | _ | _ | Expression level of AFAP1-AS1 was associated with tumor differentiation, T classification, clinical stage, invasion depth, and relapse. | (73) |
| Oral squamous cell carcinoma (OSCC) | 48 pairs of OSCC tissues and ANCTs | high | Patients with high AFAP1-AS1 expression had a poor OS. | _ | _ | Expression level of AFAP1-AS1 was associated with an advanced clinical stage and LNM. | (74) |
(ANCTs, adjacent non-cancerous tissues; OS, Overall survival; DFS, Disease-free survival; PFS, progression free survival; TNM, tumor‐node‐metastasis; dCRT, definitive chemoradiotherapy; DM, distant metastasis; LNM, lymph node metastasis; TCGA, The Cancer Genome Atlas; GEO, Gene Expression Omnibus; KPS, Karnofsky Performance Status; CP, chronic pancreatitis tissues).
Tissue levels of AFAP1-AS1 could be used as a prognostic biomarker with the areas under ROC curves values of 0.86 and 0.93 for forecasting cancer progression in the periods of 6 and 12 months, respectively (66).
The ability of tissue levels of AFAP1-AS1 or its circulatory levels in differentiation of patients’ samples from control samples has been appraised in different types of cancers ( Table 4 ). For instance, Li et al. have shown that over-expression of AFAP1-AS1 in serum samples of patients with NSCLC compared with normal controls can be used to distinguish these two sets of samples with an area under the curve (AUC) of 0.759. Combination of expression levels of this lncRNA with those of cyfra21-1 has increased AUC value to 0.860. Moreover, AFAP1-AS1 over-expression has been more prominent in patients with distant or lymph node metastasis, advanced clinical stage, and greater tumor burden (75). Serum levels of AFAP1-AS1 have also been shown to separate gastric cancer patients from controls with higher AUC value compared with conventional markers, i.e. CEA and CA19-9. Notably, serum levels of AFAP1-AS1 have been shown to be reduced following surgical treatment of patients (45).
Table 4.
Diagnostic value of AFAP1-AS1 in different cancers.
| Tumor Type | Numbers of clinical samples | Distinguish between | Area Under Curve | Sensitivity | Specificity | Accuracy | Reference |
|---|---|---|---|---|---|---|---|
| Non-small Cell Lung Cancer (NSCLC) | 126 NSCLC patients and 60 healthy controls | patients with NSCLC vs. healthy controls | 0.759 | 0.693 | 0.883 | 0.759 | (75) |
| Breast cancer | 160 pairs of breast cancer tissues and ANCTs | Cancer tissues vs. ANCTs | 0.736 | 74% | 69% | _ | (40) |
| Esophageal cancer (EC) | 162 pairs of ESCC tissues and ANCTs | Cancer tissues vs. ANCTs | 0.802 | 73.3% | 79.4% | _ | (83) |
| Gastric cancer (GC) | 30 tumor tissues and ANCTs | Cancer tissues vs. ANCTs | 0.67 | 70% | 63.3% | _ | (6) |
| 89 GC patients and 73 healthy controls | patients with GC vs. healthy controls | 0.820 | 76.4% | 56.2% | 67.3% | (45) | |
| 80 pairs of GC tissues and ANCTs | Cancer tissues vs. ANCTs | 0.8802 | 81.25% | 83.75% | _ | (84) | |
| Nasopharyngeal carcinoma (NPC) | 101 NPC patients and 101 healthy controls | patients with NPC vs. healthy controls | 0.665 | 0.640 | 0.838 | _ | (86) |
| 101 NPC patients and 20 chronic nasopharyngitis patients | patients with NPC vs. chronic nasopharyngitis patients | 0.625 | 0.590 | 0.822 | _ | ||
| 101 NPC patients and 20 asymptomatic EBV carriers | patients with NPC vs. asymptomatic EBV carriers | 0.620 | 0.592 | 0.819 | _ |
ANCTs, adjacent non-cancerous tissues; ESCC, esophageal squamous cell carcinoma.
Discussion
AFAP1-AS1 has been found to be up-regulated in almost all kinds of malignant tissues. This lncRNA has multiple effects in the carcinogenesis process, most of them being exerted through AFAP1-independent manners. Most notably, AFAP1-AS1 can sequester a number of tumor suppressor miRNAs, thus releasing the targets of these miRNAs from inhibitory effects of miRNAs. miR-139-5p, miR-545-3p, miR-497-5p, miR-145, miR-2110, miR-4695-5p, miR-26a, miR-498, miR-155-5p, miR-195-5p, miR-512-3p, miR-423-5p, miR-545-3p, miR‐320a, miR-107, miR-384, miR-133a, miR‐146b‐5p, miR-103a-3p and miR-653-5p are among miRNAs which have been found to be sequestered by AFAP1-AS1 through functional studies in different types of cancer cells. Notably, the interaction between AFAP1-AS1 and miR-497 has been verified in breast cancer and osteosarcoma. Moreover, similar interaction has been verified between this lncRNA and miR-145 in breast cancer and oral squamous cell carcinoma.
In fact, AFAP1-AS1 has multiple binding sites for miRNAs, thus regulating expression of a wide array of miRNAs. It is not clear whether binding of this lncRNA with a certain miRNA affects its interactions with other miRNAs. The crosstalk between AFAP1-AS1 and miRNAs can regulate activity of signaling pathways, angiogenic processes as well as EMT.
AFAP1-AS1 can indirectly influence activity of some cancer-related pathways such as EGFR/AKT, Wnt/β-catenin, PTEN/p-AKT, RhoA/Rac2 and PI3K/AKT. The effects of this lncRNA on Wnt/β-catenin, EGF/AKT and PI3K/AKT are mediated through sponging miR-4695-5p, miR-139-5p and miR-103a-3p, respectively. However, its effects on other pathways might be exerted in an independent manner from miRNAs sponging.
Lung cancer, nasopharyngeal carcinoma, colorectal cancer and cholangiocarcinoma are among cancers in which the interaction between AFAP1-AS1 and AFAP1 has been verified. However, the results of these studies are conflicting. For instance, AFAP1-AS1 silencing has been shown to increase expression of AFAP1 in a single study in lung cancer cells (12), while another study in this type of cancer has shown its effect on enhancement of expression of AFAP1 (11). Moreover, in a single study in MCF-7 breast cancer cells, AFAP1-AS1 silencing has not affected AFAP1 levels or actin filament integrity (40). Therefore, future studies are needed to elaborate the mechanistical impacts of AFAP1/AFAP1-AS1 interactions.
AFAP1-AS1 can affect response of cancer cells to a variety of anti-cancer modalities ranging from conventional chemotherapeutics to targeted therapeutics such as trastuzumab. Therefore, measurement of expression levels of this lncRNA can guide clinical oncologists to find the most appropriate therapeutic option for each patient. AFAP1-AS1 can also affect EMT and stemness of cancer cells, thus promoting their metastatic ability and increasing the propensity to tumor recurrence.
From a prognostic point of view, AFAP1-AS1 levels have been associated with tumor depth, tumor differentiation, TNM stage and other determinants of patients’ survival, thus could be used as markers for prediction of clinical outcomes of patients with a variety of malignant conditions. Diagnostic application of AFAP1-AS1 has been appraised in several types of cancers, with the best results being obtained from studies in gastric and esophageal cancers.
Cumulatively, AFAP1-AS1 is a prototype of cancer-related lncRNAs that regulates carcinogenesis not only through modification of expression of its sense transcript, but also through a variety of other methods such as miRNA sequestering and epigenetically affecting expression of tumor suppressor genes.
Author Contributions
SG-F and BH wrote the draft and revised it. MT designed and supervised the study. TK and MM collected the data and designed the figures and tables. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
- 1. Ji D, Zhong X, Jiang X, Leng K, Xu Y, Li Z, et al. The Role of Long Non-Coding RNA AFAP1-AS1 in Human Malignant Tumors. Pathol Res Pract (2018) 214(10):1524–31. doi: 10.1016/j.prp.2018.08.014 [DOI] [PubMed] [Google Scholar]
- 2. Baisden JM, Qian Y, Zot HM, Flynn DC. The Actin Filament-Associated Protein AFAP-110 Is an Adaptor Protein That Modulates Changes in Actin Filament Integrity. Oncogene (2001) 20(44):6435–47. doi: 10.1038/sj.onc.1204784 [DOI] [PubMed] [Google Scholar]
- 3. Liu F-T, Xue Q-Z, Zhu P-Q, Luo H-L, Zhang Y, Hao T. Long Noncoding RNA AFAP1-AS1, a Potential Novel Biomarker to Predict the Clinical Outcome of Cancer Patients: A Meta-Analysis. OncoTargets Ther (2016) 9:4247. doi: 10.2147/OTT.S107188 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Dorfleutner A, Stehlik C, Zhang J, Gallick GE, Flynn DC. AFAP-110 Is Required for Actin Stress Fiber Formation and Cell Adhesion in MDA-MB-231 Breast Cancer Cells. J Cell Physiol (2007) 213(3):740–9. doi: 10.1002/jcp.21143 [DOI] [PubMed] [Google Scholar]
- 5. Zhang J, Park SI, Artime MC, Summy JM, Shah AN, Bomser JA, et al. AFAP-110 Is Overexpressed in Prostate Cancer and Contributes to Tumorigenic Growth by Regulating Focal Contacts. J Clin Invest (2007) 117(10):2962–73. doi: 10.1172/JCI30710 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Esfandi F, Taheri M, Namvar A, Kholghi Oskooei V, Ghafouri−Fard S. AFAP1 and its Naturally Occurring Antisense RNA Are Downregulated in Gastric Cancer Samples. Biomed Rep (2019) 10(5):296–302. doi: 10.3892/br.2019.1207 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Wong L-P, Ong RT-H, Poh W-T, Liu X, Chen P, Li R, et al. Deep Whole-Genome Sequencing of 100 Southeast Asian Malays. Am J Hum Genet (2013) 92(1):52–66. doi: 10.1016/j.ajhg.2012.12.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Huang N, Guo W, Ren K, Li W, Jiang Y, Sun J, et al. LncRNA AFAP1-AS1 Supresses miR-139-5p and Promotes Cell Proliferation and Chemotherapy Resistance of Non-Small Cell Lung Cancer by Competitively Upregulating RRM2. Front Oncol (2019) 9:1103. doi: 10.3389/fonc.2019.01103 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Tang X-D, Zhang D-D, Jia L, Ji W, Zhao Y-S. lncRNA AFAP1-AS1 Promotes Migration and Invasion of Non-Small Cell Lung Cancer via Up-Regulating IRF7 and the RIG-I-Like Receptor Signaling Pathway. Cell Physiol Biochem (2018) 50(1):179–95. doi: 10.1159/000493967 [DOI] [PubMed] [Google Scholar]
- 10. Yin D, Lu X, Su J, He X, De W, Yang J, et al. Long Noncoding RNA AFAP1-AS1 Predicts a Poor Prognosis and Regulates Non–Small Cell Lung Cancer Cell Proliferation by Epigenetically Repressing P21 Expression. Mol Cancer (2018) 17(1):1–12. doi: 10.1186/s12943-018-0836-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. He J, Wu K, Guo C, Zhou J-K, Pu W, Deng Y, et al. Long Non-Coding RNA AFAP1-AS1 Plays an Oncogenic Role in Promoting Cell Migration in Non-Small Cell Lung Cancer. Cell Mol Life Sci (2018) 75(24):4667–81. doi: 10.1007/s00018-018-2923-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Zeng Z, Bo H, Gong Z, Lian Y, Li X, Li X, et al. AFAP1-AS1, a Long Noncoding RNA Upregulated in Lung Cancer and Promotes Invasion and Metastasis. Tumor Biol (2016) 37(1):729–37. doi: 10.1007/s13277-015-3860-x [DOI] [PubMed] [Google Scholar]
- 13. Clayton NS, Ridley AJ. Targeting Rho GTPase Signaling Networks in Cancer. Front Cell Dev Biol (2020) 8:222. doi: 10.3389/fcell.2020.00222 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Barak V, Goike H, Panaretakis KW, Einarsson R. Clinical Utility of Cytokeratins as Tumor Markers. Clin Biochem (2004) 37(7):529–40. doi: 10.1016/j.clinbiochem.2004.05.009 [DOI] [PubMed] [Google Scholar]
- 15. Sun J, Min H, Yu L, Yu G, Shi Y, Sun J. The Knockdown of LncRNA AFAP1-AS1 Suppressed Cell Proliferation, Migration, and Invasion, and Promoted Apoptosis by Regulating miR-545-3p/Hepatoma-Derived Growth Factor Axis in Lung Cancer. Anti-Cancer Drugs (2020) 32(1):11–21. doi: 10.1097/CAD.0000000000001003 [DOI] [PubMed] [Google Scholar]
- 16. Zhong Y, Yang L, Xiong F, He Y, Tang Y, Shi L, et al. Long Non-Coding RNA AFAP1-AS1 Accelerates Lung Cancer Cells Migration and Invasion by Interacting With SNIP1 to Upregulate C-Myc. Signal Transduction Targeted Ther (2021) 6(1):1–13. doi: 10.1038/s41392-021-00562-y [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Cai B, Wang X, Qa B, Li P, Xue Q, Zhang J, et al. LncRNA AFAP1-AS1 Knockdown Represses Cell Proliferation, Migration, and Induced Apoptosis in Breast Cancer by Downregulating SEPT2 via Sponging miR-497-5p. Cancer Biother Radiopharmaceut (2020). doi: 10.1089/cbr.2020.3688 [DOI] [PubMed] [Google Scholar]
- 18. Zhang X, Zhou Y, Mao F, Lin Y, Shen S, Sun Q. lncRNA AFAP1-AS1 Promotes Triple Negative Breast Cancer Cell Proliferation and Invasion via Targeting miR-145 to Regulate MTH1 Expression. Sci Rep (2020) 10(1):1–11. doi: 10.1038/s41598-020-64713-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Zhang X, Li F, Zhou Y, Mao F, Lin Y, Shen S, et al. Long Noncoding RNA AFAP1-AS1 Promotes Tumor Progression and Invasion by Regulating the miR-2110/Sp1 Axis in Triple-Negative Breast Cancer. Cell Death Dis (2021) 12(7):1–11. doi: 10.1038/s41419-021-03917-z [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Zhang K, Liu P, Tang H, Xie X, Kong Y, Song C, et al. AFAP1-AS1 Promotes Epithelial-Mesenchymal Transition and Tumorigenesis Through Wnt/β-Catenin Signaling Pathway in Triple-Negative Breast Cancer. Front Pharmacol (2018) 9:1248. doi: 10.3389/fphar.2018.01248 [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
- 21. Han M, Gu Y, Lu P, Li J, Cao H, Li X, et al. Exosome-Mediated lncRNA AFAP1-AS1 Promotes Trastuzumab Resistance Through Binding With AUF1 and Activating ERBB2 Translation. Mol Cancer (2020) 19(1):1–18. doi: 10.1186/s12943-020-1145-5 [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
- 22. Shi D, Wu F, Mu S, Hu B, Zhong B, Gao F, et al. LncRNA AFAP1-AS1 Promotes Tumorigenesis and Epithelial-Mesenchymal Transition of Osteosarcoma Through RhoC/ROCK1/p38MAPK/Twist1 Signaling Pathway. J Exp Clin Cancer Res (2019) 38(1):1–12. doi: 10.1186/s13046-019-1363-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Fei D, Zhang X, Lu Y, Tan L, Xu M, Zhang Y. Long Noncoding RNA AFAP1-AS1 Promotes Osteosarcoma Progression by Regulating miR-497/IGF1R Axis. Am J Trans Res (2020) 12(5):2155. doi: 10.1038/s41419-021-03917-z [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Li R, Liu S, Li Y, Tang Q, Xie Y, Zhai R. Long Noncoding RNA AFAP1−AS1 Enhances Cell Proliferation and Invasion in Osteosarcoma Through Regulating Mir−4695−5p/TCF4−β−Catenin Signaling. Mol Med Rep (2018) 18(2):1616–22. doi: 10.3892/mmr.2018.9131 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Feng Y, Zhang Q, Wang J, Liu P. Increased lncRNA AFAP1-AS1 Expression Predicts Poor Prognosis and Promotes Malignant Phenotypes in Gastric Cancer. Eur Rev Med Pharmacol Sci (2017) 21(17):3842–9. [PubMed] [Google Scholar]
- 26. Yuan X, Li J, Cao Y, Jie Z, Zeng Y. Long Non-Coding RNA AFAP1-AS1 Promotes Proliferation and Migration of Gastric Cancer by Downregulating KLF2. Eur Rev Med Pharmacol Sci (2020) 24(2):673–80. [DOI] [PubMed] [Google Scholar]
- 27. Guo J-Q, Li S-J, Guo G-X. Long Noncoding RNA AFAP1-AS1 Promotes Cell Proliferation and Apoptosis of Gastric Cancer Cells via PTEN/p-AKT Pathway. Digestive Dis Sci (2017) 62(8):2004–10. doi: 10.1007/s10620-017-4584-0 [DOI] [PubMed] [Google Scholar]
- 28. Ma H-W, Xi D-Y, Ma J-Z, Guo M, Ma L, Ma D-H, et al. Long Noncoding RNA AFAP1-AS1 Promotes Cell Proliferation and Metastasis via the miR-155-5p/FGF7 Axis and Predicts Poor Prognosis in Gastric Cancer. Dis Markers (2020) 2020. doi: 10.1155/2020/8140989 [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
- 29. Mi X, Xu R, Hong S, Xu T, Zhang W, Liu M. M2 Macrophage-Derived Exosomal lncRNA AFAP1-AS1 and microRNA-26a Affect Cell Migration and Metastasis in Esophageal Cancer. Mol Ther-Nucleic Acids (2020) 22:779–90. doi: 10.1016/j.omtn.2020.09.035 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Shen W, Yu L, Cong A, Yang S, Wang P, Han G, et al. Silencing lncRNA AFAP1-AS1 Inhibits the Progression of Esophageal Squamous Cell Carcinoma Cells via Regulating the miR-498/VEGFA Axis. Cancer Manage Res (2020) 12:6397. doi: 10.2147/CMAR.S254302 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Leng W, Liu Q, Zhang S, Sun D, Guo Y. LncRNA AFAP1-AS1 Modulates the Sensitivity of Paclitaxel-Resistant Prostate Cancer Cells to Paclitaxel via miR-195-5p/FKBP1A Axis. Cancer Biol Ther (2020) 21(11):1072–80. doi: 10.1080/15384047.2020.1829266 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Wang K, Sun H, Sun T, Qu H, Xie Q, Lv H, et al. Long Non-Coding RNA AFAP1-AS1 Promotes Proliferation and Invasion in Prostate Cancer via Targeting miR-512-3p. Gene (2020) 726:144169. doi: 10.1016/j.gene.2019.144169 [DOI] [PubMed] [Google Scholar]
- 33. Lian Y, Xiong F, Yang L, Bo H, Gong Z, Wang Y, et al. Long Noncoding RNA AFAP1-AS1 Acts as a Competing Endogenous RNA of miR-423-5p to Facilitate Nasopharyngeal Carcinoma Metastasis Through Regulating the Rho/Rac Pathway. J Exp Clin Cancer Res (2018) 37(1):1–17. doi: 10.1186/s13046-018-0918-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Yuan Z, Xiu C, Song K, Pei R, Miao S, Mao X, et al. Long Non-Coding RNA AFAP1-AS1/miR-320a/RBPJ Axis Regulates Laryngeal Carcinoma Cell Stemness and Chemoresistance. J Cell Mol Med (2018) 22(9):4253–62. doi: 10.1111/jcmm.13707 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Liu B, Yan L, Chi Y, Sun Y, Yang X. Long Non-Coding RNA AFAP1-AS1 Facilitates Ovarian Cancer Progression by Regulating the miR-107/PDK4 Axis. J Ovarian Res (2021) 14(1):1–11. doi: 10.1186/s13048-021-00808-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Wu X-B, Feng X, Chang Q-M, Zhang C-W, Wang Z-F, Liu J, et al. Cross-Talk Among AFAP1-AS1, ACVR1 and microRNA-384 Regulates the Stemness of Pancreatic Cancer Cells and Tumorigenicity in Nude Mice. J Exp Clin Cancer Res (2019) 38(1):1–15. doi: 10.1186/s13046-019-1051-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Yu S, Yang D, Ye Y, Liu P, Chen Z, Lei T, et al. Long Noncoding RNA Actin Filament-Associated Protein 1 Antisense RNA 1 Promotes Malignant Phenotype Through Binding With Lysine-Specific Demethylase 1 and Repressing HMG Box-Containing Protein 1 in Non-Small-Cell Lung Cancer. Cancer Sci (2019) 110(7):2211–25. doi: 10.1111/cas.14039 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Peng B, Liu A, Yu X, Xu E, Dai J, Li M, et al. Silencing of lncRNA AFAP1-AS1 Suppressed Lung Cancer Development by Regulatory Mechanism in Cis and Trans. Oncotarget (2017) 8(55):93608. doi: 10.18632/oncotarget.20549 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39. Zhuang Y, Jiang H, Li H, Dai J, Liu Y, Li Y, et al. Down-Regulation of Long Non-Coding RNA AFAP1-AS1 Inhibits Tumor Cell Growth and Invasion in Lung Adenocarcinoma. Am J Trans Res (2017) 9(6):2997. [PMC free article] [PubMed] [Google Scholar]
- 40. Liu Y, Li Q, Hosen MR, Zietzer A, Flender A, Levermann P, et al. Atherosclerotic Conditions Promote the Packaging of Functional microRNA-92a-3p Into Endothelial Microvesicles. Circ Res (2019) 124(4):575–87. doi: 10.1161/CIRCRESAHA.118.314010 [DOI] [PubMed] [Google Scholar]
- 41. Luo HL, Huang MD, Guo JN, Fan RH, Xia XT, He JD, et al. AFAP1-AS1 Is Upregulated and Promotes Esophageal Squamous Cell Carcinoma Cell Proliferation and Inhibits Cell Apoptosis. Cancer Med (2016) 5(10):2879–85. doi: 10.1002/cam4.848 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42. Wu W, Bhagat TD, Yang X, Song JH, Cheng Y, Agarwal R, et al. Hypomethylation of Noncoding DNA Regions and Overexpression of the Long Noncoding RNA, AFAP1-AS1, in Barrett’s Esophagus and Esophageal Adenocarcinoma. Gastroenterology (2013) 144(5):956–66. e4. doi: 10.1053/j.gastro.2013.01.019 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43. Li Z, Ding Z, Rong D, Tang W, Cao H. Overexpression of lncRNA AFAP1−AS1 Promotes Cell Proliferation and Invasion in Gastric Cancer. Oncol Lett (2019) 18(3):3211–7. doi: 10.3892/ol.2019.10640 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44. Lai Z, Lin P, Weng X, Su J, Chen Y, He Y, et al. MicroRNA-574-5p Promotes Cell Growth of Vascular Smooth Muscle Cells in the Progression of Coronary Artery Disease. Biomed Pharmacother (2018) 97:162–7. doi: 10.1016/j.biopha.2017.10.062 [DOI] [PubMed] [Google Scholar]
- 45. Liu W, Li Y, Zhang Y, Shen X, Su Z, Chen L, et al. Circulatinglong Non-Coding RNA FEZF1-AS1 and AFAP1-AS1 Serve as Potential Diagnostic Biomarkers for Gastric Cancer. Pathol-Res Pract (2020) 216(1):152757. doi: 10.1016/j.prp.2019.152757 [DOI] [PubMed] [Google Scholar]
- 46. Fang M, Zhang M, Wang Y, Wei F, Wu J, Mou X, et al. Long Noncoding RNA AFAP1-AS1 Is a Critical Regulator of Nasopharyngeal Carcinoma Tumorigenicity. Front Oncol (2020) 10:2510. doi: 10.3389/fonc.2020.601055 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47. Bo H, Gong Z, Zhang W, Li X, Zeng Y, Liao Q, et al. Upregulated Long Non-Coding RNA AFAP1-AS1 Expression Is Associated With Progression and Poor Prognosis of Nasopharyngeal Carcinoma. Oncotarget (2015) 6(24):20404. doi: 10.18632/oncotarget.4057 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48. Zhong Y, Wang Y, Dang H, Wu X. LncRNA AFAP1-AS1 Contributes to the Progression of Endometrial Carcinoma by Regulating miR-545-3p/VEGFA Pathway. Mol Cell Probes (2020) 53:101606. doi: 10.1016/j.mcp.2020.101606 [DOI] [PubMed] [Google Scholar]
- 49. Shi X, Zhang H, Wang M, Xu X, Zhao Y, He R, et al. LncRNA AFAP1-AS1 Promotes Growth and Metastasis of Cholangiocarcinoma Cells. Oncotarget (2017) 8(35):58394. doi: 10.18632/oncotarget.16880 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50. Lu X, Zhou C, Li R, Deng Y, Zhao L, Zhai W. Long Noncoding RNA AFAP1-AS1 Promoted Tumor Growth and Invasion in Cholangiocarcinoma. Cell Physiol Biochem (2017) 42(1):222–30. doi: 10.1159/000477319 [DOI] [PubMed] [Google Scholar]
- 51. Zhao Y, Chu Y, Sun J, Song R, Li Y, Xu F. LncRNA GAS8-AS Inhibits Colorectal Cancer (CRC) Cell Proliferation by Downregulating lncRNA AFAP1-As1. Gene (2019) 710:140–4. doi: 10.1016/j.gene.2019.05.040 [DOI] [PubMed] [Google Scholar]
- 52. Wang F, Ni H, Sun F, Li M, Chen L. Overexpression of lncRNA AFAP1-AS1 Correlates With Poor Prognosis and Promotes Tumorigenesis in Colorectal Cancer. Biomed Pharmacother (2016) 81:152–9. doi: 10.1016/j.biopha.2016.04.009 [DOI] [PubMed] [Google Scholar]
- 53. Han X, Wang L, Ning Y, Li S, Wang Z. Long Non-Coding RNA AFAP1-AS1 Facilitates Tumor Growth and Promotes Metastasis in Colorectal Cancer. Biol Res (2016) 49(1):1–7. doi: 10.1186/s40659-016-0094-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54. Tang J, Zhong G, Wu J, Chen H, Jia Y. Long Noncoding RNA AFAP1-AS1 Facilitates Tumor Growth Through Enhancer of Zeste Homolog 2 in Colorectal Cancer. Am J Cancer Res (2018) 8(5):892. [PMC free article] [PubMed] [Google Scholar]
- 55. Bo H, Fan L, Li J, Liu Z, Zhang S, Shi L, et al. High Expression of lncRNA AFAP1-AS1 Promotes the Progression of Colon Cancer and Predicts Poor Prognosis. J Cancer (2018) 9(24):4677. doi: 10.7150/jca.26461 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56. Abdul S, Majid A, Wang J, Liu Q, Sun M-Z, Liu S. Bidirectional Interaction of lncRNA AFAP1-AS1 and CRKL Accelerates the Proliferative and Metastatic Abilities of Hepatocarcinoma Cells. J Advanced Res (2020) 24:121–30. doi: 10.1016/j.jare.2020.03.010 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57. Zhang J-Y, Weng M-Z, Song F-B, Xu Y-G, Liu Q, Wu J-Y, et al. Long Noncoding RNA AFAP1-AS1 Indicates a Poor Prognosis of Hepatocellular Carcinoma and Promotes Cell Proliferation and Invasion via Upregulation of the RhoA/Rac2 Signaling. Int J Oncol (2016) 48(4):1590–8. doi: 10.3892/ijo.2016.3385 [DOI] [PubMed] [Google Scholar]
- 58. Lu X, Zhou C, Li R, Liang Z, Zhai W, Zhao L, et al. Critical Role for the Long Non-Coding RNA AFAP1-AS1 in the Proliferation and Metastasis of Hepatocellular Carcinoma. Tumor Biol (2016) 37(7):9699–707. doi: 10.1007/s13277-016-4858-8 [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
- 59. Bo H, Fan L, Gong Z, Liu Z, Shi L, Guo C, et al. Upregulation and Hypomethylation of lncRNA AFAP1−AS1 Predicts a Poor Prognosis and Promotes the Migration and Invasion of Cervical Cancer. Oncol Rep (2019) 41(4):2431–9. doi: 10.3892/or.2019.7027 [DOI] [PubMed] [Google Scholar]
- 60. Dai W, Tian Y, Jiang B, Chen W. Down-Regulation of Long Non-Coding RNA AFAP1-AS1 Inhibits Tumor Growth, Promotes Apoptosis and Decreases Metastasis in Thyroid Cancer. Biomed Pharmacother (2018) 99:191–7. doi: 10.1016/j.biopha.2017.12.105 [DOI] [PubMed] [Google Scholar]
- 61. Wang Y, Lan Q. Long Non-Coding RNA AFAP1-AS1 Accelerates Invasion and Predicts Poor Prognosis of Glioma. Eur Rev Med Pharmacol Sci (2018) 22(16):5223–9. [DOI] [PubMed] [Google Scholar]
- 62. Yang S, Lin R, Si L, Cui M, Zhang X, Fan L. Expression and Functional Role of Long Non-Coding RNA AFAP1-AS1 in Ovarian Cancer. Eur Rev Med Pharmacol Sci (2016) 20(24):5107–12. [PubMed] [Google Scholar]
- 63. Lou S, Xu J, Wang B, Li S, Ren J, Hu Z, et al. Downregulation of lncRNA AFAP1-AS1 by Oridonin Inhibits the Epithelial-to-Mesenchymal Transition and Proliferation of Pancreatic Cancer Cells. Acta Biochim Biophys Sin (2019) 51(8):814–25. doi: 10.1093/abbs/gmz071 [DOI] [PubMed] [Google Scholar]
- 64. Chen B, Li Q, Zhou Y, Wang X, Zhang Q, Wang Y, et al. The Long Coding RNA AFAP1-AS1 Promotes Tumor Cell Growth and Invasion in Pancreatic Cancer Through Upregulating the IGF1R Oncogene via Sequestration of miR-133a. Cell Cycle (2018) 17(16):1949–66. doi: 10.1080/15384101.2018.1496741 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65. Zhou J, Liu M, Chen Y, Xu S, Guo Y, Zhao L. Cucurbitacin B Suppresses Proliferation of Pancreatic Cancer Cells by ceRNA: Effect of miR-146b-5p and lncRNA-AFAP1-As1. J Cell Physiol (2019) 234(4):4655–67. doi: 10.1002/jcp.27264 [DOI] [PubMed] [Google Scholar]
- 66. Ye Y, Chen J, Zhou Y, Fu Z, Zhou Q, Wang Y, et al. High Expression of AFAP1-AS1 Is Associated With Poor Survival and Short-Term Recurrence in Pancreatic Ductal Adenocarcinoma. J Trans Med (2015) 13(1):1–11. doi: 10.1186/s12967-015-0490-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67. Mu Z, Dong D, Wei N, Sun M, Wang W, Shao Y, et al. Silencing of lncRNA AFAP1-AS1 Inhibits Cell Growth and Metastasis in Clear Cell Renal Cell Carcinoma. Oncol Res (2019) 27(6):653. doi: 10.3727/096504018X15420748671075 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68. Ma F, Wang S-H, Cai Q, Zhang M-D, Yang Y, Ding J. Overexpression of LncRNA AFAP1-AS1 Predicts Poor Prognosis and Promotes Cells Proliferation and Invasion in Gallbladder Cancer. Biomed Pharmacother (2016) 84:1249–55. doi: 10.1016/j.biopha.2016.10.064 [DOI] [PubMed] [Google Scholar]
- 69. Tang H, Zhu D, Zhang G, Luo X, Xie W. AFAP1-AS1 Promotes Proliferation of Pituitary Adenoma Cells Through miR-103a-3p to Activate PI3K/AKT Signaling Pathway. World Neurosurg (2019) 130:e888–e98. doi: 10.1016/j.wneu.2019.07.032 [DOI] [PubMed] [Google Scholar]
- 70. Tang H, Hou B, Ye Z, Ling C, Guo Y. Knockdown of Long Non-Coding RNA AFAP1-AS1 Inhibits Growth and Promotes Apoptosis in Pituitary Adenomas. Int J Clin Exp Pathol (2018) 11(3):1238. [PMC free article] [PubMed] [Google Scholar]
- 71. Liu F, Hu L, Pei Y, Zheng K, Wang W, Li S, et al. Long Non-Coding RNA AFAP1-AS1 Accelerates the Progression of Melanoma by Targeting miR-653-5p/RAI14 Axis. BMC Cancer (2020) 20(1):1–11. doi: 10.1186/s12885-020-6665-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72. Hao F, Mou Y, Zhang L, Wang S, Yang Y. LncRNA AFAP1-AS1 Is a Prognostic Biomarker and Serves as Oncogenic Role in Retinoblastoma. Biosci Rep (2018) 38(3):BSR20180384. doi: 10.1042/BSR20180384 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73. Wang Z-Y, Hu M, Dai M-H, Xiong J, Zhang S, Wu H-J, et al. Upregulation of the Long Non-Coding RNA AFAP1-AS1 Affects the Proliferation, Invasion and Survival of Tongue Squamous Cell Carcinoma via the Wnt/beta-Catenin Signaling Pathway (Retraction of Vol 17, Art No 3, 2018). 4 CRINAN ST, LONDON N1 9XW, ENGLAND: BMC CAMPUS; (2019). [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
- 74. Li M, Yu D, Li Z, Zhao C, Su C, Ning J. Long Non−Coding RNA AFAP1−AS1 Facilitates the Growth and Invasiveness of Oral Squamous Cell Carcinoma by Regulating the Mir−145/HOXA1 Axis. Oncol Rep (2021) 45(3):1094–104. doi: 10.3892/or.2020.7908 [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
- 75. Li W, Li N, Kang X, Shi K. Circulating Long Non-Coding RNA AFAP1-AS1 Is a Potential Diagnostic Biomarker for Non-Small Cell Lung Cancer. Clin Chim Acta (2017) 475:152–6. doi: 10.1016/j.cca.2017.10.027 [DOI] [PubMed] [Google Scholar]
- 76. Leng X, Ding X, Wang S, Fang T, Shen W, Xia W, et al. Long Noncoding RNA AFAP1−AS1 Is Upregulated in NSCLC and Associated With Lymph Node Metastasis and Poor Prognosis. Oncol Lett (2018) 16(1):727–32. doi: 10.3892/ol.2018.8784 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 77. Deng J, Liang Y, Liu C, He S, Wang S. The Up-Regulation of Long Non-Coding RNA AFAP1-AS1 Is Associated With the Poor Prognosis of NSCLC Patients. Biomed Pharmacother (2015) 75:8–11. doi: 10.1016/j.biopha.2015.07.003 [DOI] [PubMed] [Google Scholar]
- 78. Wang M, Ma X, Zhu C, Guo L, Li Q, Liu M, et al. The Prognostic Value of Long non Coding RNAs in non Small Cell Lung Cancer: A Meta-Analysis. Oncotarget (2016) 7(49):81292. doi: 10.18632/oncotarget.13223 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 79. Sui J, Li Y-H, Zhang Y-Q, Li C-Y, Shen X, Yao W-Z, et al. Integrated Analysis of Long Non-Coding RNA−associated ceRNA Network Reveals Potential lncRNA Biomarkers in Human Lung Adenocarcinoma. Int J Oncol (2016) 49(5):2023–36. doi: 10.3892/ijo.2016.3716 [DOI] [PubMed] [Google Scholar]
- 80. Wei Y, Zhang X. Transcriptome Analysis of Distinct Long Non-Coding RNA Transcriptional Fingerprints in Lung Adenocarcinoma and Squamous Cell Carcinoma. Tumor Biol (2016) 37(12):16275–85. doi: 10.1007/s13277-016-5422-2 [DOI] [PubMed] [Google Scholar]
- 81. Rodrigues de Bastos D, Nagai MA. In Silico Analyses Identify lncRNAs: WDFY3-AS2, BDNF-AS and AFAP1-AS1 as Potential Prognostic Factors for Patients With Triple-Negative Breast Tumors. PloS One (2020) 15(5):e0232284. doi: 10.1371/journal.pone.0232284 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 82. Dianatpour A, Faramarzi S, Geranpayeh L, Mirfakhraie R, Motevaseli E, Ghafouri-Fard S. Expression Analysis of AFAP1-AS1 and AFAP1 in Breast Cancer. Cancer biomark (2018) 22(1):49–54. doi: 10.3233/CBM-170831 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 83. Zhou XL, Wang WW, Zhu WG, Yu CH, Tao GZ, Wu QQ, et al. High Expression of Long Non-Coding RNA AFAP1-AS1 Predicts Chemoradioresistance and Poor Prognosis in Patients With Esophageal Squamous Cell Carcinoma Treated With Definitive Chemoradiotherapy. Mol Carcinogenesis (2016) 55(12):2095–105. doi: 10.1002/mc.22454 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 84. Zhao H, Zhang K, Wang T, Cui J, Xi H, Wang Y, et al. Long Non−Coding RNA AFAP1−Antisense RNA 1 Promotes the Proliferation, Migration and Invasion of Gastric Cancer Cells and Is Associated With Poor Patient Survival. Oncol Lett (2018) 15(6):8620–6. doi: 10.3892/ol.2018.8389 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 85. Tang Y, He Y, Shi L, Yang L, Wang J, Lian Y, et al. Co-Expression of AFAP1-AS1 and PD-1 Predicts Poor Prognosis in Nasopharyngeal Carcinoma. Oncotarget (2017) 8(24):39001. doi: 10.18632/oncotarget.16545 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 86. He B, Zeng J, Chao W, Chen X, Huang Y, Deng K, et al. Serum Long Non-Coding RNAs MALAT1, AFAP1-AS1 and AL359062 as Diagnostic and Prognostic Biomarkers for Nasopharyngeal Carcinoma. Oncotarget (2017) 8(25):41166. doi: 10.18632/oncotarget.17083 [DOI] [PMC free article] [PubMed] [Google Scholar]