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. 2017 Oct 22;51(1):e12397. doi: 10.1111/cpr.12397

AFAP1‐AS1: A novel oncogenic long non‐coding RNA in human cancers

Fuyou Zhang 1, Jianfa Li 1,2, Huizhong Xiao 1,3, Yifan Zou 1,4, Yuchen Liu 1,✉, Weiren Huang 1,3,4
PMCID: PMC6528908  PMID: 29057544

Abstract

Long non‐coding RNAs (lncRNAs), a group of non‐protein‐coding RNAs with more than 200 nucleotides in length, are involved in multiple biological processes, such as the proliferation, apoptosis, migration and invasion. Moreover, numerous studies have shown that lncRNAs play important roles as oncogenes or tumour suppressor genes in human cancers. In this paper, we concentrate on actin filament‐associated protein 1‐antisense RNA 1 (AFAP1‐AS1), a well‐known long non‐coding RNA that is overexpressed in various tumour tissues and cell lines, including oesophageal cancer, pancreatic ductal adenocarcinoma, nasopharyngeal carcinoma, lung cancer, hepatocellular carcinoma, ovarian cancer, colorectal cancer, biliary tract cancer and gastric cancer. Moreover, high expression of AFAP1‐AS1 was associated with the clinicopathological features and cancer progression. In this review, we sum up the current studies on the characteristics of AFAP1‐AS1 in the biological function and mechanism of human cancers.

1. INTRODUCTION

Nowadays, cancer is one of the major causes of death all over the world.1, 2 According to mortality data collected by the National Center for Health Statistics, it is estimated that 1 688 780 new cancer cases and 600 920 cancer deaths will take place in the United States in 2017.3 In order to fight against cancer effectively, we should make a great effort to find more precise diagnostic biomarkers and effective therapeutic targets.

Recently, increasing evidence has shown that the non‐coding portion of the genome has a crucial functional importance in both normal physiology and diseases.4, 5, 6 Long non‐coding RNAs (lncRNAs), a group of non‐protein‐coding RNAs with more than 200 nucleotides in length, play a vital role in regulating significant cellular functions, including cell proliferation, differentiation, apoptosis, invasion, metabolism, developmental timing and immune responses.7, 8, 9, 10, 11, 12 However, mutation of lncRNAs will cause cancer initiation and promote the metastasis of malignancy.13, 14, 15 For instance, lncRNA metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) was first found in lung cancer metastasis. Many studies had demonstrated that lncRNA MALAT1 was overexpressed in various cancer, and it might act as a potential biomarker and therapeutic target in cancer treatment.16, 17, 18 LncRNA MALAT1 might function as an oncogene through controlling alternative splicing process in breast cancer, influencing the expression of N‐cadherin and E‐cadherin in bladder cancer, combining with a multifunctional RNA‐binding protein in colorectal cancer (CRC) and osteosarcoma.19, 20, 21, 22 LncRNA HOX antisense intergenic RNA (HOTAIR) induced cancer invasion and metastasis by regulating PRC2 target genes in breast cancer and epithelial‐mesenchymal transition (EMT) programme in gastric cancer (GC).23, 24 LncRNA H19 was upregulated in GC and associated with miR‐675, p53 and Isthmin1 that improved cells proliferation, migration and invasion.25, 26, 27, 28, 29 Among so many cancer‐related lncRNAs, actin filament‐associated protein 1‐antisense RNA 1 (AFAP1‐AS1) was initially discovered in oesophageal adenocarcinoma in 2013.30 Then, numerous recent studies had focused on lncRNA AFAP1‐AS1 and demonstrated that it was upregulated in many cancers and played an important role in tumour progression. A meta‐analysis had shown that high expression of AFAP1‐AS1 in human cancers was closely related to poor clinical outcome such as lymph node metastasis and distant metastasis.31 Hence, we chose it as the main research object to summarize its characteristics in the biological function and mechanism of human cancers.

2. IDENTIFICATION OF AFAP1‐AS1

Actin filament‐associated protein 1 (formerly AFAP‐110), an actin cross‐linking protein and a cSrc‐binding partner, is a member of the AFAP family which includes AFAP1, AFAP1 like‐1 and AFAP1 like‐2/XB‐130.32, 33 There are 2 pleckstrin homology domains in AFAP1, and one of them involves a protein kinase C‐binding site and carboxy‐terminal domains.33, 34 On the basis of multimerization associated with its leucine zipper and binding to actin filaments through its carboxy‐terminal actin filament‐binding domain, AFAP1 can crosslink actin filaments.34

Long non‐coding RNA AFAP1‐AS1 with 6810 bp in length is mapped to the 4p16.1 region of human chromosome 4. Moreover, AFAP1‐AS1 is transcribed from the AFAP1 gene in the antisense direction, containing several overlapping and complementary regions among the exons of AFAP1‐AS1 and AFAP135 (Figure 1). Antisense lncRNAs like AFAP1‐AS1 are oriented in an antisense direction regard to a protein‐coding gene in the opposite strand, and AFAP1‐AS1 can affect the expression of AFAP1.36, 37, 38, 39 Further experiments have demonstrated that AFAP1‐AS1 was overexpressed in cancer tissues and cell lines, such as oesophageal cancer, pancreatic ductal adenocarcinoma (PDAC), nasopharyngeal carcinoma (NPC) and lung cancer. In addition, overexpression of AFAP1‐AS1 was closely associated with tumour size, lymphatic metastasis, distant metastasis, tumour‐node‐metastasis (TNM) stage and poor prognosis of cancer patients. Using siRNA to impair the expression of AFAP1‐AS1 inhibited cell proliferation, migration and invasion and induced cell apoptosis through regulating related genes or signalling pathways.30, 35, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58 In this review, the related clinicopathological characteristics and molecular functions of this lncRNA in cancers are presented in Tables 1 and 2.

Figure 1.

Figure 1

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Long non‐coding RNAs (lncRNA) actin filament‐associated protein 1‐antisense RNA 1 (AFAP1‐AS1) is mapped to the 4p16.1 region of human chromosome 4. AFAP1‐AS1 is transcribed from AFAP1 gene in the antisense direction, containing several overlapping and complementary regions among the exons of AFAP1‐AS1 and AFAP1

Table 1.

Overexpression of actin filament‐associated protein 1‐antisense RNA 1 (AFAP1‐AS1) is associated with clinicopathological features

Cancer types Clinicopathological features References
Oesophageal cancer Tumour size, tumour depth, lymphatic metastasis, distant metastasis, TNM stage, poor prognosis, shorter progression‐free survival and overall survival chemoradioresistance 40, 41
Pancreatic ductal adenocarcinoma Lymph node metastasis, perineural invasion, poor survival overall survival, progression‐free survival 42
Nasopharyngeal carcinoma Lymph node metastasis, distant tumour metastasis, TNM stage, poor prognosis, EBV infection poor overall survival, poor relapse‐free survival 35, 43, 44
Lung cancer Clinical stage, smoking history, infiltration degree, lymph node metastasis, distant metastasis, poor prognosis tumour progression, poor survival 46, 47, 48
Hepatocellular carcinoma Tumour size, TNM stage, lymph‐vascular space invasion poor prognosis 49, 50
Ovarian cancer Resistance response, FIGO stage 51
Colorectal cancer Tumour size, TNM stage, distant metastasis, poor prognosis poor overall survival and disease‐free survival 52, 53, 54
Biliary tract cancers Tumour size, vascular invasion, TNM stage, poor prognosis, poor overall survival 55, 56, 57
Gastric cancer Poor survival 58
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TNM: tumour‐node‐metastasis; EBV: Epstein‐Barr virus; FIGO: International Federation of Gynecology and Obstetrics.

Table 2.

Functional characterization of the actin filament‐associated protein 1‐antisense RNA 1 (AFAP1‐AS1) in tumours

Cancer types Expression Effects Related gene Role References
Oesophageal cancer Upregulated Hypomethylation proliferation colony formation, migration, invasion, apoptosis, cycle arrest — Oncogene 30, 40, 41
Pancreatic ductal adenocarcinoma Upregulated Proliferation, cycle arrest migration, invasion, EMT process E‐cadherin, N‐cadherin, vimentin, Slug, Snail1 Oncogene 42
Nasopharyngeal carcinoma Upregulated Migration, invasion AFAP1 protein, GTPase family, Pfn1, Lasp1, PD‐1, lncRNA MALAT1, lncRNA AL359062 Oncogene 35, 43, 44
Lung cancer Upregulated Proliferation, apoptosis migration, invasion AFAP1 protein, GTPase family, Pfn1 Lasp1 Oncogene 45, 46, 47, 48
Hepatocellular carcinoma Upregulated Proliferation, migration, invasion, apoptosis, cycle arrest PCNA, MMP‐9, cyclin D1, Bax, RhoA/Rac2, Ki67, Bcl‐2 Oncogene 49, 50
Ovarian cancer Upregulated Proliferation, apoptosis Oncogene 51
Colorectal cancer Upregulated EMT process, proliferation, cycle arrest
colony formation
migration, invasion 		E‐cadherin, N‐cadherin, vimentin, fibronectin, MMP‐9, AFAP1 Oncogene 52, 53, 54
Biliary tract cancers Upregulated EMT process, proliferation colony formation, cell cycle
migration, invasion 		Twist1, vimentin, E‐cadherin, C‐myc, cyclin D1, MMP‐2, MMP‐9, AFAP1 Oncogene 55, 56, 57
Gastric cancer Upregulated Proliferation
apoptosis 		PTEN/p‐AKT, Bcl‐2, PARP, Caspase 3, Caspase 9, Bax Oncogene 58
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EMT: epithelial‐mesenchymal transition; GTP: guanosine triphosphate; Pfn1: profilin 1; Lasp1: LIM and SH3 protein 1; PD‐1: programmed death 1; MALAT1: metastasis‐associated lung adenocarcinoma transcript 1; PCNA: proliferating cell nuclear antigen; MMP: matrix metalloproteinase; Bcl‐2: B‐cell CLL/lymphoma 2 protein; Bax: BCL2‐associated X protein; RhoA: ras homologue family member A; Rac2: rac family small GTPase 2; Ki67: Antigen Ki‐67; C‐myc: MYC proto‐oncogene, bHLH transcription factor; PTEN: phosphatase and tensin homologue; AKT: AKT serine/threonine kinase 1; PARP: poly‐ADP‐ribose polymerase.

3. AFAP1‐AS1 IN VARIOUS CANCERS

3.1. Oesophageal cancer

Oesophageal cancer is the eighth most frequent types of cancer and is the sixth leading cause of tumour‐related death all over the world.59, 60 There are 2 primary histological subtypes of oesophageal cancer, including oesophageal adenocarcinoma (OAC) and oesophageal squamous cell carcinoma (OSCC).61, 62 OSCC accounts for more than 95% of oesophageal cancer.63 OAC is one of the fastest growing cancers in the Western world, while OSCC is the main subtype of oesophageal cancer in Asia.3, 64 Although different kinds of treatment have been developed, including chemotherapy, radiotherapy and surgery, the long‐term survival rate of oesophageal cancer is still extremely low.64, 65 Because of the rising morbidity and poor prognosis of oesophageal cancer patients, it is urgent to look for new tumour markers and therapeutic targets for early diagnosis and advanced treatment of oesophageal cancer patients.

Wu et al30 reported that AFAP1‐AS1 was exceedingly hypomethylated and overexpressed in Barrett's oesophagus and OAC tissues and OAC cell lines. Further functional analyses demonstrated that AFAP1‐AS1 was an oncogene in the oesophagus cancer. Inhibition of AFAPA‐AS1 by siRNA in OAC cells reduced cell proliferation, colony formation, migration and invasion, increased apoptosis and induced G2/M phase arrest. However, the expression of AFAP1‐AS1 was irrelevant with AFAP1 expression. They drew a conclusion that the overexpression of AFAP1‐AS1, which exerted functional pro‐cancerous effects in oesophageal cells, was associated with hypomethylation.

Subsequent studies demonstrated that AFAP1‐AS1 was increased in OSCC, and high expression of AFAP1‐AS1 was closely associated with tumour size, tumour depth, lymphatic metastasis, distant metastasis and TNM stage. Moreover, those OSCC patients with increased AFAP1‐AS1 level have shorter progression‐free survival and overall survival. Overexpression of AFAP1‐AS1 will lead to tumour resistance to radiotherapy and chemotherapy in OSCC patients who received definitive chemoradiotherapy. Furthermore, knockdown of AFAP1‐AS1 in OSCC cells suppressed cell proliferation and colony formation and induced cell apoptosis.40, 41 Therefore, AFAP1‐AS1 may work as a novel prognostic marker and potential therapeutic target for oesophageal cancer.

3.2. Pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma, one of the most aggressive solid malignancies, is the fourth leading cause of cancer‐related deaths all over the world.66, 67 PDAC is characterized by a fatal disease with early metastasis and resistance to chemotherapy and radiation therapy.7, 68 Although the study of PDAC has made rapid progress in the last decades, the 5‐year survival rate of PDAC patients is still only around 5%‐7%.69, 70 Therefore, it is crucial to identify reliable biomarkers for early diagnosis of PDAC patients.

Ye et al42 demonstrated that AFAP1‐AS1 was upregulated in PDAC tissues and cell lines compared with corresponding normal counterparts. Overexpression of AFAP1‐AS1 was associated with lymph node metastasis, perineural invasion, poor survival, overall survival and progression‐free survival of PDAC patients. In addition, knockdown of AFAP1‐AS1 reduced proliferation and induced G2/M phase arrest in PDAC cells. Knockdown of AFAP1‐AS1 in PDAC cells inhibited migration and invasion by influencing the expression of EMT‐related genes, including E‐cadherin, N‐cadherin, vimentin, Slug and Snail1. As we know, EMT is deemed to be the essential process of cancer progression, enhancing tumour migration, invasion and metastasis.71, 72, 73, 74 During the EMT process, epithelial cells lose epithelial status, apico‐basal polarity and cell‐cell adhesion so as to transform into mesenchymal cells.74, 75, 76 In order to distinguish diverse functions, EMT is classified into 3 types: primary/type 1, secondary/type 2 and tertiary/type 3. Type 1 is associated with implantation, embryogenesis and organogenesis. Type 2 takes part in wound healing, tissue regeneration and organ development. Type 3 promotes tumour metastasis.77, 78, 79 During cancer progression and metastasis, the expression of some EMT‐related genes is changed, such as mesenchymal genes (fibronectin, N‐cadherin and vimentin) are increased while epithelial genes (E‐cadherin and ZO‐1) are decreased.80, 81 Ye et al42 also found that inhibition of AFAP1‐AS1 reduced PDAC cell tumorigenicity in nude mice. However, amplification of AFAP1‐AS1 produced opposite effects (Figure 2). In conclusion, AFAP1‐AS1 has potential value as a prognostic biomarker and therapeutic target in PDAC.

Figure 2.

Figure 2

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Knockdown of actin filament‐associated protein 1‐antisense RNA 1 (AFAP1‐AS1) reduced proliferation and induced G2/M phase arrest in pancreatic ductal adenocarcinoma (PDAC) cells. Knockdown of AFAP1‐AS1 in PDAC cells inhibited migration and invasion by influencing the expression of epithelial‐mesenchymal transition (EMT)‐related genes (E‐cadherin, N‐cadherin, vimentin, Slug, Snail1)

3.3. Nasopharyngeal carcinoma

Nasopharyngeal carcinoma, a unique disease to Southeast Asia, is associated with the Epstein‐Barr virus (EBV).82, 83 About 75%‐90% of NPC cases are diagnosed at advanced stages due to the non‐specific symptoms at an early stage and poor accessibility for physical examination.84, 85 The main clinical treatment of NPC is radiotherapy over the past few decades, but many patients finally die because of recurrence and distant metastasis.86, 87 Therefore, it is essential to find therapeutic targets and prognostic biomarkers for accurate early diagnosis of high‐risk populations and evaluation of NPC treatment.

Bo et al35 reported that AFAP1‐AS1 was upregulated in NPC samples compared with non‐tumour nasopharyngeal epithelial samples, and amplification of AFAP1‐AS1 was associated with NPC metastasis and poor prognosis. Knockdown of AFAP1‐AS1 by siRNAs suppressed tumour cell migration and invasion. However, AFAP1‐AS1 has no effects on cell viability, cell cycle progression and apoptosis. Knockdown of AFAP1‐AS1 could increase AFAP1 protein level, induce the loss of stress filament integrity and influence the expression of many proteins related to small GTPase signalling Rho/Rac pathway in NPC cells. Hence, they suspected that AFAP1‐AS1 might promote cancer cell migration and invasion by interfering with AFAP1 expression, small GTPase signalling Rho/Rac pathway and the loss of stress filament integrity (Figure 3). They also carried out nude mouse experiments and discovered that knockdown of AFAP1‐AS1 inhibited NPC cell metastasis to mouse lungs. Based on the previous studies, Tang et al43 found that the expression of AFAP1‐AS1 was positively correlated with programmed death 1 (PD‐1), an immune escape marker. They concluded that AFAP1‐AS1 and PD‐1 were co‐expressed in infiltrating lymphocytes in NPC tissue and the co‐expression predicted poor prognosis of NPC. Moreover, overexpression of AFAP1‐AS1 or PD‐1 was correlated with distant metastasis at relapse. He et al44 identified that 3 circulating lncRNAs (MALAT1, AFAP1‐AS1 and AL359062) may act as potential biomarkers for NPC, and the three‐lncRNA signature could contribute to the identification of early NPC patients. Besides, high expression of these 3 lncRNAs was closely related to advanced NPC tumour node metastasis stages and EBV infection. These findings suggest that AFAP1‐AS1 may serve as a cancer‐promoting gene and a potential therapeutic target in NPC.

Figure 3.

Figure 3

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Knockdown of actin filament‐associated protein 1‐antisense RNA 1 (AFAP1‐AS1) in nasopharyngeal carcinoma (NPC) cells suppressed migration and invasion by increasing AFAP1 protein levels, inducing the loss of stress filament integrity and influencing the expression of many proteins in the small GTPase signalling Rho/Rac pathway (RhoA, Rac2, Rab10, Rab11a, Rhogdi and Pfn1 were significantly upregulated, but RhoC, Rab11b and Lasp1 were significantly downregulated)

3.4. Lung cancer

Lung cancer is the leading cause of cancer‐related mortality all over the world.88, 89 According to histopathological presentation, lung cancer is divided into 4 primary histological subtypes: small cell lung cancer, squamous cell carcinoma (SCC), adenocarcinoma (ADC) and large cell carcinoma (LCC).90 SCC, ADC and LCC are collectively called non‐small cell lung cancer (NSCLC) that accounts for almost 80% of lung cancer.91 Despite recent progresses of surgical resection, chemoradiotherapy or target drugs, lung cancer patients have a poor prognosis due to metastasis and recurrence.92, 93, 94 The 5‐year overall survival rate of advanced lung cancer patients is less than 15%.95 Hence, it is very important to find adequate tumour biomarkers for early diagnosis and metastasis identification in lung cancers.

Yu et al45 used microarray gene expression analysis and quantitative real‐time polymerase chain reaction analysis to identify that 551 lncRNAs were upregulated in NSCLC tissues, and AFAP1‐AS1 expression changed the most among the upregulated lncRNAs. Deng et al46 confirmed the above results. They also found that augmented expression of AFAP1‐AS1 was closely associated with clinical stage, smoking history, infiltration degree, lymph node metastasis, distant metastasis and poor prognosis in NSCLC patients. Next, Zeng et al47 found that AFAP1‐AS1 was significantly upregulated in lung cancer, and AFAP1‐AS1 upregulation was associated with tumour progression and poor survival. In vitro experiments demonstrated that knockdown of AFAP1‐AS1 suppressed tumour cell migration and invasion. Silence of AFAP1‐AS1 also increased the levels of its antisense protein‐coding gene, AFAP1, but had no significantly effect on AFAP1 mRNA. In addition, repression of AFAP1‐AS1 influenced some Rho/Rac GTPase family members and actin cytokeratin signalling pathway. Therefore, they speculated that AFAP1‐AS1 might promote migration and invasion in lung cancer by interfering with the expression of AFAP1 and some small GTPases (Figure 4). Recently, Zhuang et al48 reported that AFAP1‐AS1 was overexpressed in ADC and associated with survival time. Knockdown of AFAP1‐AS1 suppressed cell growth, induced apoptosis and inhibited invasion. Taken together, these results suggest that AFAP1‐AS1 may function as an oncogenic lncRNA and a potential prognostic biomarker and therapeutic target in lung cancer.

Figure 4.

Figure 4

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Knockdown of actin filament‐associated protein 1‐antisense RNA 1 (AFAP1‐AS1) suppressed migration and invasion in lung cancer by increasing the levels of AFAP1 and influencing some Rho/Rac GTPase Rhogdi proteins and actin‐binding proteins (RhoA, Rac2, Rab10, Rab11a, Rhogdi and Pfn1 were upregulated, but RhoC, Rab11b and Lasp1 were downregulated)

3.5. Hepatocellular carcinoma

Hepatocellular carcinoma (HCC), developing on the basis of pre‐existing chronic liver disease and cirrhosis, is the fifth most commonly diagnosed cancer and the third leading cause of cancer death all around the world.96, 97 Unlimited cell growth and invasion are the main characteristic of HCC. Because of delayed diagnosis and rapid metastasis, the treatment of advanced HCC is still in a dilemma, and the 5‐year survival rate of HCC patients is only about 7%.98, 99, 100 Lots of experiments have proved that HCC occurs in company with genetic or epigenetic mutation.101, 102, 103 Therefore, it is vital to find novel tumour biomarkers and understand the pathogenesis of HCC.

Zhang et al49 and Lu et al50 investigated the effects of AFAP1‐AS1 in HCC. Their findings demonstrated that AFAP1‐AS1, an independent predictor of overall survival, was apparently upregulated in HCC tissues compared with the adjacent non‐tumour tissues. Overexpression of AFAP1‐AS1 was associated with tumour size, TNM stage, lymph‐vascular space invasion and poor prognosis in HCC. Their results suggested that silencing of AFAP1‐AS1 impaired cell proliferation, migration and invasion through mediating some gene expressions related to proliferation and invasion in vitro. Moreover, Zhang et al49 reported that silencing of AFAP1‐AS1 promoted cell apoptosis and cycle arrest in S phase by upregulating the expression of Bax (BCL2‐associated X protein) and downregulating the expression of cyclin D1. Silencing of AFAP1‐AS1 also suppressed the activation of RhoA/Rac2 (ras homologue family member A/rac family small GTPase 2) signalling to decrease RhoA and Rac2 expression in HCC cells (Figure 5). Hence, they suspected that AFAP1‐AS1 may accelerate the progression and invasion in HCC by upregulating the RhoA/Rac2 signalling. Tumour xenograft studies showed that knockdown of AFAP1‐AS1 suppressed xenograft tumour growth in vivo. The above results suggest that AFAP1‐AS1 may play an important role in HCC development and serve as a therapeutic target of HCC.

Figure 5.

Figure 5

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Silencing of actin filament‐associated protein 1‐antisense RNA 1 (AFAP1‐AS1) in hepatocellular carcinoma (HCC) cells inhibited proliferation, migration and invasion through mediating proliferation‐ and invasion‐related gene expression in vitro (PCNA, MMP‐9, Ki67 and Bcl‐2 was downregulated, but Bax was upregulated). Silencing of AFAP1‐AS1 induced cell apoptosis and cycle arrest in S phase by upregulating the expression of Bax and downregulating the expression of cyclin D1. Silencing of AFAP1‐AS1 also suppressed the expression of RhoA and Rac2 to repress the progression and invasion in HCC

3.6. Ovarian cancer

Ovarian cancer (OC) is the third most widespread carcinoma of the female reproductive system.104 Despite the advances in surgery, diagnostic method and new chemotherapy, OC mortality rate is still high because most patients are diagnosed at an advanced stage.105, 106, 107 Therefore, it is exceedingly important to study its molecular mechanisms.

Yang et al51 reported that AFAP1‐AS1 was overexpressed in OC tissue samples and cell lines compared with corresponding normal counterparts. They found that high expression of AFAP1‐AS1 was obviously associated with aggressive clinicopathological parameters of OC, including resistance response and International Federation of Gynecology and Obstetrics (FIGO) stage. Then, knockdown of AFAP1‐AS1 suppressed cell proliferation and increased cell apoptosis. Therefore, their results indicate that AFAP1‐AS1 can serve as a novel oncogene and therapeutic target for OC.

3.7. Colorectal cancer

Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide.104, 108 Although advanced treatments, involving the combination of surgery, radiation therapy, chemotherapy and targeted therapy, are utilized to improve the prognosis of CRC patients, the recurrence and metastasis of CRC are still unavoidable.109, 110 The incidence and mortality of CRC will reduce by screening CRC from curable early stage, so we need to find a novel diagnostic and prognostic indicator for CRC.

Some experimental results proved that AFAP1‐AS1 was aberrantly overexpressed in CRC tissues and cells lines, and overexpression of AFAP1‐AS1 predicted poor prognosis of CRC patients.52, 53, 54 Wang et al52 found that upregulation of AFAP1‐AS1 was closely correlated with tumour size, TNM stage, distant metastasis, poorer overall survival and disease‐free survival. AFAP1‐AS1 inhibition suppressed cell proliferation, colony formation, migration and invasion. Moreover, suppression of AFAP1‐AS1 enhanced G0/G1 cell cycle arrest and the protein level of AFAP1 while having no effect on the mRNA level of AFAP1.52, 53 We suspected that AFAP1‐AS1 may affect some transcription factors expression related to AFAP1 protein, and AFAP1‐AS1 is irrelevant with AFAP1 transcription. Han et al53 found that knockdown of AFAP1‐AS1 inhibited tumour metastasis‐associated genes expression associated with EMT progression. Western blot results showed that the expression of E‐cadherin was elevated, but the expression of N‐cadherin, vimentin, fibronectin and matrix metalloproteinase 9 (MMP‐9) was reduced (Figure 6). They confirmed that knockdown of AFAP1‐AS1 inhibited tumour formation and hepatic metastasis of CRC cells in nude mice. In conclusion, these results suggest that AFAP1‐AS1 may act as an oncogene and a promising diagnostic and therapeutic target for CRC.

Figure 6.

Figure 6

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Actin filament‐associated protein 1‐antisense RNA 1 (AFAP1‐AS1) knockdown in colorectal cancer (CRC) cells suppressed cell proliferation, colony formation, migration and invasion, induced G0/G1 cell cycle arrest and improved the protein level of AFAP1. Knockdown of AFAP1‐AS1 inhibited tumour metastasis‐associated genes expression in terms of epithelial‐mesenchymal transition (EMT; the expression of E‐cadherin was elevated, but the expression of N‐cadherin, vimentin, fibronectin and MMP‐9 was reduced)

3.8. Biliary tract cancers

Biliary tract cancers (BTC) consist of gallbladder cancer (GBC) and cholangiocarcinoma (CCA). GBC accounts for 80%‐95% of BTC, while CCA makes up the rest. CCA is divided into intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.111 CCA is one of the most aggressive and lethal tumours, originating from biliary epithelial cells lining the bile duct.112 GBC is a highly invasive malignancy neoplasm, and the overall 5‐year survival of GBC is less than 5%.113, 114 It is hard to diagnose BTC at an early stage because of non‐symptomatic manifestation and lack of sensitive biomarkers. Hence, finding early diagnostic markers and novel therapeutic targets is urgently needed.

Ma et al55 found that AFAP1‐AS1 was significantly elevated in GBC tissues and GBC cell lines and associated with tumour sizes and poor prognosis. Besides, knockdown of AFAP1‐AS1 suppressed cell growth and invasion. Further experiments demonstrated that knockdown of AFAP1‐AS1 impaired the EMT process in GBC cells via downregulating the transcription factor Twist1 and vimentin and upregulating the E‐cadherin. These findings showed that AFAP1‐AS1 may promote GBC cells invasion through accelerating EMT process (Figure 7).

Figure 7.

Figure 7

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Knockdown of actin filament‐associated protein 1‐antisense RNA 1 (AFAP1‐AS1) in gallbladder cancer (GBC) cells suppressed cell proliferation and inhibited cell invasion through regulating the epithelial‐mesenchymal transition (EMT) process. Then, AFAP1‐AS1 was knockdown and simultaneously induced by TGF‐β1 treatment in GBC cells influencing EMT process by downregulating the transcription factor Twist1 and vimentin and upregulating the E‐cadherin

Shi et al56 and Lu et al57 investigated the effects of AFAP1‐AS1 in CCA at the same time. Their findings demonstrated that AFAP1‐AS1 was overexpressed in CCA tissues and cell lines, and AFAP1‐AS1 overexpression was associated with tumour size, vascular invasion, advance TNM stage, poor overall survival and prognosis. In addition, AFAP1‐AS1 knockdown in vitro suppressed cell proliferation and colony formation, induced G0/G1 cell cycle arrest and inhibited S‐G2/M transition. Moreover, AFAP1‐AS1 knockdown downregulated the expression of c‐Myc (MYC proto‐oncogene, bHLH transcription factor) and cyclin D1 that plays an important role in cell proliferation. Silence of AFAP1‐AS1 weakened cell migration and invasion by increasing AFAP1 mRNA and protein expression and reducing matrix metalloproteinase 2 (MMP‐2) and MMP‐9 expression in vitro. In addition, AFAP1‐AS1 inhibition reduced cell stress filament integrity and repressed CCA cell tumour growth and CCA metastasis in vivo (Figure 8). Taken together, these results suggest that AFAP1‐AS1 produces oncogenic effects in BTC and may become an effective diagnostic and therapeutic target for BTC.

Figure 8.

Figure 8

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Actin filament‐associated protein 1‐antisense RNA 1 (AFAP1‐AS1) knockdown in cholangiocarcinoma (CCA) cells suppressed cell proliferation and colony formation and induced cell cycle arrest. AFAP1‐AS1 knockdown downregulated the expression of c‐Myc and cyclin D1, which played an important role in cell proliferation. AFAP1‐AS1 knockdown also inhibited cell migration and invasion by increasing AFAP1 protein and mRNA expression and reducing MMP‐2 and MMP‐9 expression. Moreover, AFAP1‐AS1 knockdown reduced cell stress filament integrity and repressed CCA cell tumour growth and CCA metastasis in a mice model

3.9. Gastric cancer

Gastric cancer, the fourth most commonly diagnosed cancer, is one of the major causes of cancer‐related death all over the world.115, 116 Although surgery and chemotherapy for GC have made great progress, GC patients at an advanced stage remain a poor prognosis, having an extremely low 5‐year survival rate.117, 118 Thus, it is urgent to find a new biomarkers for diagnosis and prognosis of GC.

Guo et al58 reported that AFAP1‐AS1 was overexpressed in GC tissues and cells compared with corresponding normal counterparts. AFAP1‐AS1 suppression inhibited cell proliferation through modulating phosphatase and tensin homologue (PTEN)/p‐AKT. In addition, decreased expression of AFAP1‐AS1 could impair the protein level of p‐AKT (AKT serine/threonine kinase 1) and strengthen the expression of PTEN. Moreover, AFAP1‐AS1 knockdown promoted cell apoptosis through decreasing the protein level of Bcl‐2 (B‐cell CLL/lymphoma 2 protein) and increasing the protein level of cleaved PARP (poly‐ADP‐ribose polymerase), Caspase 3, Caspase 9 and Bax. In conclusion, their results support that AFAP1‐AS1 may play a significant role as an indicator of poor survival and a therapeutic target for GC.

4. CONCLUSION

Long non‐coding RNA AFAP1‐AS1 plays an important role in cancer development and serves as an oncogenic lncRNA, which is overexpressed in all kinds of cancers, including oesophageal cancer, PDAC, NPC, lung cancer, HCC, OC, CRC, BTC and GC. High expression level of AFAP1‐AS1 in tumour tissues is correlated with clinicopathological characteristics, such as tumour size, lymphatic metastasis, distant metastasis, TNM stage, poor prognosis, overall survival and disease‐free survival. However, the precise concentration and detection method of AFAP1‐AS1 in the blood of cancer patients and healthy person are still unclear, impeding the clinical applications of AFAP1‐AS1. In order to carry out more deeper research and draw a more accurate conclusion, more cancer patients should be involved in the AFAP1‐AS1 study. Functional experiments demonstrated that AFAP1‐AS1 could promote tumour cell proliferation, migration and invasion and inhibit apoptosis. In addition, the involvement of some related genes or signalling pathways in the oncogenic function of AFAP1‐AS1 has been proved, such as EMT‐related genes and small GTPase signalling Rho/Rac pathway, but its particular upstream and downstream molecular mechanisms need to be systematically analysed in the future. Compared with other well‐studied lncRNAs such as MALAT1 and H19, the studies of AFAP1‐AS1 are not enough. So far, none of AFAP1‐AS1‐related miRNAs or mRNAs was found, and AFAP1‐AS1 research is still at an early stage. The relationship between AFAP1‐AS1 and proteins, miRNAs, mRNAs, ceRNAs and other lncRNAs should be better understood and investigated. Moreover, what is the role of AFAP1‐AS1 in the common pathogenesis of cancer such as chromosome abnormalities, DNA modification and histone modification? Previous studies also showed that knockdown of AFAP1‐AS1 increased the expression of AFAP1 in some cancers, but the combined actions, specific functions and regulatory molecules in tumour progression should be explored in great depth.

In conclusion, the recent studies suggest that lncRNA AFAP1‐AS1 produces oncogenic effects in human cancer and may become an effective diagnostic and therapeutic target for human cancer. With the development of AFAP1‐AS1 study, lncRNA AFAP1‐AS1 may be applied in clinical detection and treatment in the future.

CONFLICT OF INTEREST

All authors declare no conflict of interest.

ACKNOWLEDGMENTS

This work was supported by the National Key Basic Research Program of China (2014CB745201), National Natural Science Foundation of China [81402103], International S&T Cooperation program of China (ISTCP) (2014DFA31050), the National Science Foundation Projects of Guangdong Province (2014A030313717).

Zhang F, Li J, Xiao H, Zou Y, Liu Y, Huang W. AFAP1‐AS1: A novel oncogenic long non‐coding RNA in human cancers. Cell Prolif. 2018;51:e12397 10.1111/cpr.12397

These authors FZ, JL, HX and YZ have contributed equally to this work.

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