Long noncoding RNAs: role and contribution in pancreatic cancer

ABSTRACT

Noncoding RNAs are proclaimed to be expressed in various cancer types and one such type is found to be pancreatic ductal adenocarcinoma (PDAC). The long noncoding RNAs (LncRNAs) affect the migration, invasion, and growth of tumor cells by playing important roles in the process of epigenesis, post-transcription, and transcriptional regulation along with the maintenance of apoptosis and cell cycle. It is quite subtle whether the alterations in lncRNAs would impact PDAC progression and development. This review throws a spotlight on the lncRNAs associated with tumor functions: MALAT-1, HOTAIR, HOXA13, H19, LINC01559, LINC00460, SNHG14, SNHG16, DLX6-AS1, MSC-AS1, ABHD11-AS1, DUXAP8, DANCR, XIST, DLEU2, etc. are upregulated lncRNAs whereas GAS5, HMlincRNA717, MIAT, LINC01111, lncRNA KCNK15-AS1, etc. are downregulated lncRNAs inhibiting the invasion and progression of PDAC. These data provided helps in the assessment of lncRNAs in the development, metastasis, and occurrence of PDAC and also play a vital role in the evolution of biomarkers and therapeutic agents for the treatment of PDAC.

1. Introduction

Pancreatic ductal adenocarcinoma (PDAC) attains 8% in the rate of 5-y survival and is the deadliest among all the cancer types with a higher risk of mortality [1]. The mortality and incidence of pancreatic cancer are increasing with age and the disease is common in men than in women. Obesity, physical inactivity, alcohol consumption, family history, diabetes mellitus, smoking of cigarettes are the causative agents of pancreatic cancer and some of it is unknown [2]. Patients are at higher risk of malignancies due to the syndromes of cancer that are inherited and the rate of pancreatic cancer development depends upon the cancer syndrome and genetic mutations ranging between less than 5% and 40% [3]. Most patients are at an advanced, non-curable stage whose survival is enhanced by chemotherapy techniques [4]. The surgically resectable patients receive adjuvant or non-adjuvant versus radiation-associated chemotherapy. Patients developing metastatic disease are treated with gemcitabine or other therapeutic agents in combination with gemcitabine, having no benefit with the overall survival rate. The investigations on genetics and biology have been in progress for the development of potential drug targets for pancreatic cancer treatment [5]. Genetic markers have occupied a vast interest in the prevalence of PDAC including the function and expression of long noncoding RNAs (lncRNAs) in interaction with miRNAs or protein-coding genes. The noncoding RNAs are classified into short noncoding RNAs and long noncoding RNAs, of which long noncoding RNAs are of great concern. The lncRNAs ranging between 200 nt and greater than 100 kb are antisense, intronic, intergenic, and are overlapping with other ncRNAs and protein-coding genes [6]. The role of lncRNAs in controlling regulatory functions such as chromatin modulation, RNA maturation, translation, splicing, and chromosome architecture has been highlighted through various studies [7]Table 1. There are no appropriate protocols available for pancreatic cancer treatment at present. This review is enlightened with the upregulation or downregulation of lncRNAs associated with the alteration of growth, prognosis, migration, and invasion of pancreatic cancer cells leading to the development of novel therapeutic drug targets.

Table 1.

List of Lnc RNAs up and down regulated in pancreatic cancer

lncRNAs	Alterations	Confirmed targets	References
HOTTIP	Down	WDR5-MLL complex	[14,15]
MALAT-1	Up	PRC2, ERK/MAPK pathway, Wnt pathway, SFPQ/PTBP2 complex	[22,24–27]
HOTAIR	Up	HK2, rs4759314, rs200349340	[11,35,39]
LINC01559	Up	YAP protein	[45]
LINC01133	Up	DKK1, LRP6	[46]
LINC01197	Down	TCF4, β-catenin	[47]
LINC00958	Up	PAX8	[49]
LINC01207	Up	AGR2	[52]
LINC01121	Up	GLP1R	[53]
SNHG14	Up	Annexin A2, KLF2, P15	[54,56]
SNHG1	Up	Notch-1	[61]
siAFAP1-AS1	Up	MMP-1	[63]
ADPGK-AS1	Up	ZEB-1	[64]
SBF2-AS1	Up	TWF-1	[68]
MSC-AS1	Up	CDK14	[70]
AGAP2-AS1	Up	ANGPTL4, ANKRD1	[71]
ABHD11-AS1	Up	CA199, pPI3K, pAKT	[51,74]
AF339813	Up	NUF2	[76]
HULC	Up	PI3K, AKT	[11,77]
DUXAP8	Up	HIF-1a	[77]
DANCR	Up	Wnt/β-catenin, E2F2	[81,88]
MEG3, MEG8	Up	p53	[82–85]
PVT1	Up	TGF-β1 and p-Smad2/3	[35,93]
MTA2TR	Up	NORAD	[95–97]
TUG1	Up	Smad3, Smad2, MMP2, E-cadherin, MMP9	[98–100]
UCA1	Up	miR-135a	[101,105]
XIST	Up	YAP, TGF-β1	[107,108]
CCHE1	Up	ROR	[110]
CRNDE	Up	IRS1	[111]
NEAT1	Up	miR-506-3p	[113]
SUMO1P3	Up	E-cadherin, N-cadherin, β-catenin	[114]
DIO3OS	Up	ALDOA	[116]
EPIC1	Up	YAP1	[117]
HCP5	Up	HDGF	[118]
MIR155HG	Up	miR-802	[120]
uc.345	Up	hnRNPL	[121]
Sox2ot	Up	miR-200	[122]
ANRIL	Up	ATM-E2F1	[123]
Gas5	Down	CDK6, SOCS3, PTEN	[125–127]
CF129	Down	FOXC2, p53	[130]
CASC2	Down	PTEN	[134,136]
MIAT	Down	miR-133	[136]
PCTST	Down	TACC3	[136]
LINC01111	Down	SAPK/JNK signaling	[137]
KCNK15-AS1	Down	ALKBH5	[156]
PXN-AS1	Down	miR-3064	[157]
GSTM3TV2	Up	OLR, LAT2	[143,144]

2. Long noncoding RNAs in pancreatic cancer

2.1. H19

The H19 gene is a paternally imprinted gene that codes for an RNA which is believed to be a long noncoding RNA sequence. The H19 RNA shows strong evidence to be an oncogene. Several studies have linked the overexpression of H19 with tumor formation and propagation. Multiple cancer studies show high H19 expression within the tumor cells. Injecting H19 RNA into tumor cells has also shown a rise in tumor progression in certain cases [8]. In a study about H19 in pancreatic cancer, it was found that H19 lncRNA is highly expressed in the cancer cells (of the pancreas) when compared to the normal cells around it. The upregulation of H19 could also be linked to primary tumors that metalized, while downregulation of H19 was found to show the PDAC progression. H19 promotes pancreatic cancer’s progression by depressing the let-7 suppression of the target area causing an increase of HMGA-2-mediated EMT [9]. The proliferation and migration of cells are suppressed when lncRNA H19 and PFTK1 are inhibited by the miR‐194 expression [10]. Furthermore, the downregulation of H19 leads to the impairment of prognosis in PDAC [11].

H19 overexpression has been linked to the downregulation of p53 during stressed conditions. Downregulation of p53 during stress leads to the upregulation of H19, indicating p53 may be a suppressor to H19 [12]. A common stress condition that may lead to H19 upregulation in tumor cells is hypoxia [13]. Hypoxia-inducible factor-lα (HIF-lα) facilitates H19 production when p53 is downregulated.

Currently, H19 is being used as a target for possible cancer treatment techniques. Due to its high expression in cancer cells, it may be possible to target desired drug/toxins by paring them with H19 regulatory sequences, causing them to be directly targeted in cancer cells where H19 is highly expressed [11].

2.2. LncRNA HOXA transcript at the distal tip (HOTTIP)

HOTTIP is an lncRNA encoded by a gene at the 5ʹ tip of the HOXA locus that has been shown to play a role in cancer progression. It is known to coordinate the activity of several of the HOXA genes. Chromosomal looping brings the lncRNA closer to the HOXA genes, and then HOTTIP binds to the WDR5 protein and forms a complex with histone methyltransferase protein MLL. WDR5-MLL complex is targeted to the HOXA region and caused H3K4 methylation and activates the gene of the HOXA locus [14]. In a study relating to HOTTIP to cancer, it was shown that the downregulation of HOTTIP or silencing of HOTTIP leads to slowing down of tumor cell proliferation as well as impairment of EMT. HOTTIP was also found to be expressed more in tumor cells than normal cells [15]. Besides, the expression level of HOTTIP-005, a splice variant of HOTTIP was found to be much higher in cell lines with cancer cells than in normal cells. The level of HOTTIP expression was then related to patient survival, and it was demonstrated that high expression of HOTTIP-005 was a poor prognostic factor for patients with pancreatic cancer [16].

HOXA13 is a gene that is involved in PDAC progression, and this gene is part of the HOXA locus whose activity is controlled by HOTTIP and is one of the major targets of the lncRNA, further linking HOTTIP to cancer progression. The dysregulation of HOTTIP affects the cell prognosis in pancreatic cancer [11,17,18]. The HOTTIP does not regulate HOXA13 [19] but the modulation of HOXA13 coordinates HOTTIP to promote chemoresistance, cell proliferation, and can also be used as a biomarker for diagnosis in Pancreatic adenocarcinoma [15]. Furthermore, resistance against gemcitabine is promoted by the regulation of HOXA13, and its knockdown was shown to result in reduced tumor volume [20,21].

2.3. Metastasis-associated long adenocarcinoma transcript 1 (MALAT-1)

MALAT-1 is an lncRNA that is over expressed in several types of cancers. MALAT-1 involves the Hippo-YAP signaling pathway when highly expressed [22] and regulates cell proliferation, apoptosis. MALAT-1 has been linked to tumor progression and invasion. Consequently, high levels of MALAT-1 may indicate tumor prognosis [23]. MALAT-1 acts via the polycomb repressive complex 2 (PRC2) [24], the ERK/MAPK pathway [25], the Wnt pathway [26], and the SFPQ/PTBP2 complex [27] to promote tumor proliferation. MALAT-1 can also lead to growth factor Sβ-induced epithelial-mesenchymal transition by downregulation of E-cadherin and upregulation of N-cadherin and fibronectin [28].

The expression of MALAT-1 is upregulated in PDAC tissues [11] and has a major clinical significance because of its involvement in the mTOR signaling pathway and the MAPK signaling pathway [29]. Overexpression of this gene induces cell cycle arrest, tumorigenicity, metastasis, and invasion in pancreatic cancer [21,30] in a meta-analysis conducted, a high association was found between MALAT-1 overexpression and the TNM stage of the PDAC tumor. Further, a high concentration of MALAT-1 has been proven to be associated with lower chances of patient survival. These facts indicate that MALAT-1 may find use as a prognostic factor in PDAC patients [31,32]. The silencing of MALAT-1 promotes apoptosis in all cells, regardless of whether or not they are resistant to gemcitabine due to the involvement of miR-216a in pancreatic cancer [33].

2.4. Hox antisense intergenic RNA (HOTAIR)

HOTAIR is an lncRNA localized near the HOXC gene cluster. HOTAIR is more highly expressed in advanced cancer tissue as compared to newly developed tumors or normal tissue [34]. As HOTAIR is highly expressed [35] in the late stage of cancer, it can be used as a prognostic factor to determine patient survivability [36]. Low expression of HOTAIR has been correlated with high survival rates in patients while high expression of HOTAIR has been found to indicate a very low chance of survival as well as advanced tumor progression [37]. Studies have also determined that HK2 expression increases when HOTAIR is upregulated [11], thereby promoting the energy metabolism of cancer cells in PDAC. The overexpression of HK2 was not found to have a specific effect on the expression of HOTAIR [38]

The two minor alleles rs4759314 and rs200349340 of HOTAIR are highly expressed in pancreatic cancer patients and hence, may be considered a part of the genetic basis of pancreatic cancer [39]. Besides, the expression of notch3 is regulated by HOTAIR via competition for the binding of miR-613 making the notch3-HOTAIR-miR-613 complex a drug target in pancreatic cancer [40].

Kim et al. have concluded that the targeted silencing of HOTAIR leads to slowing down tumor progression and induces apoptosis [41]. Furthermore, HOTAIR promotes proliferation, migration, chemoresistance. The expression of HOTAIR expression affects pancreatic cancer cells resistant to TRAIL-induced apoptosis and also regulates the expression of DR5 [42]. One study has reported that it is induced by gemcitabine [43] and the efficiency of radiotherapy is also increased in pancreatic cancer [44].

3. Selective long noncoding RNAs – upregulated in pancreatic cancer

Of the long intergenic noncoding RNAs (lincRNAs), a few have been identified as upregulated in patients with pancreatic cancer. LINC01559 is upregulated in pancreatic adenocarcinoma (PDAC) tissues. This leads to an enhancement in YAP transcriptional activity due to the interaction between LINC01559 and the YAP protein [45]. LINC01133 is also upregulated and research has found that knocking out of LINC01133 decreased proliferation in PDAC patients both in vivo and in vitro [46]. Ling et al. have determined that Wnt/β-catenin signaling pathway is restrained when LINC01197 is downregulated by disrupting the interaction between TCF4 and β-catenin in PDAC [47]. Besides, LINC00460 is upregulated in PDAC and the study suggests that it may find use as a molecular diagnostic biomarker in pancreatic cancer [48]. Further, the upregulation of LINC00958 has been associated with a higher expression of PAX8 in pancreatic cancer. According to Chen et al., the progression of pancreatic cancer can be prevented by inhibiting PAX8 when LINC00958 is silenced with the binding of miR-330-5p [49]. Lastly, there is an upregulation of LINC00994 and RUNX2 in PDAC, along with the downregulation of miR-765-3p. This phenomenon promotes cell cycle arrest at the G1 phase and apoptosis. Research shows that cell invasion, migration, and growth are inhibited when LINC00994 is silenced in pancreatic cancer [50]. The lincRNA LINC00176 has also been found to be overexpressed in PDAC patients [51]. Also, a study has found that lncRNA LINC01207 is overexpressed in PDAC patients. The impairment of miR-143-5p was proven to help prevent cell progression by targeting the expression of AGR2. It does so by silencing LINC01207 [52]. LINC01121 has also been determined to be upregulated and acts as a tumor promoter in pancreatic cancer. Its function in the translational repression of GLP1R promotes the migration, invasion, and proliferation of cancer cells while inhibiting apoptosis in pancreatic cancer [53].

Small Nucleolar RNA Host Genes (SNHGs) that play a critical role in PDAC have also been identified. In particular, SNHG14 is highly expressed which promotes cell growth and suppresses apoptosis by modulating the expression of annexin A2 in pancreatic cancer [54]. Further, poor prognosis in pancreatic cancer can be predicted by dysregulating SNHG15; it also acts as a biomarker and a therapeutic agent [55]. Its effect on growth is enhanced by the restraining the expression of KLF2 and P15. The induction of apoptosis and inhibition of the proliferation of cells can be achieved by knocking down SNHG15 [56]. SNHG7 and SNHG16 are also upregulated and their knockdown has been proven to inhibit the proliferation and migration of pancreatic cancer cells [57–59]. Additionally, Song et al. have discovered that SNHG8 inhibits apoptosis, promotes cell proliferation, and reduces chemosensitivity when due to its overexpression in PDAC patients [60]. SNHG11 has also been found to be overexpressed in PDAC patients [51]. Further, Cui et al. have found that SNHG1 is upregulated in pancreatic cancer patients. Cell migration and invasion were found to be suppressed by the knockdown of SNHG1, which inhibits the activity of the Notch-1 signaling pathway in pancreatic cancer cells [61].

Among antisense lncRNAs, research has found that cell progression, apoptosis, and cell cycle arrest were inhibited by siAFAP1-AS1 in combination with oridonin [62] and that this lncRNA is upregulated in pancreatic cancer [63]. ADPGK-AS1 has been found to suppress apoptotic activity and promote cell migration in PDAC patients due to its upregulation in conjugation with the downregulation of miR-205 [64]. DLX6-AS1 is upregulated in PDAC, which results in the attenuation of the endogenous function of miR-181b. This in turn promotes the invasiveness and proliferation of cancer cells [65]. Another study has found that ZEB2-AS1 is upregulated and that there is a decrease in the migration and invasion of cells when ZEB2-AS1 is inhibited, alluding to its possible use as a biomarker and a therapeutic agent in pancreatic cancer [66]. Further, initiation of tumor angiogenesis and the insufficiency of nutrients in pancreatic cancer have been attributed to the overexpression of JHDM1D-AS1 [67]. SBF2-AS1 has been found a higher expression level, and its competitive binding with miR-142-3p inhibits TWF1 expression in pancreatic cancer [68]. Cell proliferation and invasion are promoted and apoptosis inhibited by DLX6-AS1 which is highly expressed in PDAC. This informs its possible use as a target for diagnosis upon the combined action of miR-497-5p, FZD4, FZD6, Wnt/β-catenin signaling pathway in pancreatic cancer [69]. MSC-AS1 is also upregulated in pancreatic cancer patients, with a higher expression level of miR-29b-3p which negatively regulates MSC-AS1 and CDK14 and is associated with poor prognosis [70]. Work by Hui et al. has found that the regulation of ANGPTL4 and ANKRD1 transcription promotes the migration and growth of pancreatic cancer cells by AGAP2-AS1, which has a higher expression level [71]. Other research has found that the silencing of HOXA-AS2 inhibits cell cycle arrest, proliferation [72,73]. ABHD11-AS1 is overexpressed in PDAC patients and the combination of ABHD11-AS1 and CA199 can be used as a biomarker for diagnostic purposes [74]. The overexpression of this lncRNA is associated with metastasis. Furthermore, the expression of pPI3K and pAKT is decreased when there is a knockdown of ABHD11-AS1 whereas the expression of PI3K and AKT remains unaffected in pancreatic cancer [51]. Additionally, the lncRNA LOXL-AS1 has been proven to promote pancreatic progression. The suppression of this lncRNA and miR-28-5p inhibits cell proliferation and invasion in pancreatic cancer [75].

Another lncRNA involved in PDAC is AF339813, which is regulated by NUF2. In a study to examine NUF2 expression in cancer cells from patients with pancreatic cancer, it was found that AF33 9813 was expressed as a much higher concentration in cancer cells than in normal cells. Downregulation of AF33 8813 also reduced tumor cell progression and induced apoptosis in cancer cells [76]. Highly upregulated in liver cancer (HULC) also has a higher expression level in pancreatic cancer tissues [11] and the downregulation of miR-15a promotes cell migration, proliferation, and invasion by activating the pathway of PI3K/AKT when HULC is overexpressed [77]. Hu et al. have found that the expression of NUF2 is elevated in pancreatic cancer patients and that it plays a major role in the phenotypes of pancreatic cancer by regulating LncRNA AF339813 [76]. DUXAP8 is also highly expressed in pancreatic cancer cells. A study has found that proliferation and apoptosis are inhibited by silencing the lncRNA DUXAP8 using siRNA or shRNA [77]. Further, the proliferation and the inhibition of cancer cells and apoptosis respectively are promoted by GHET1 which is highly expressed in pancreatic cancer cells [78]. The upregulation of HNRNPU in PDAC tissues regulates cell migration, proliferation, and invasion [79]. Pancreatic cancer cell migration has also been found to be suppressed by the silencing of ZFP91-P and so, this could be used as a target for gene therapy because of its regulating activity in cancer cell proliferation and migration [80]. The lncRNA DANCR has also been found to be overexpressed in PDAC and promotes pancreatic cancer progression. It does under its regulation of the proliferation and migration of pancreatic cancer cells through the downstream of Wnt/β-catenin signaling pathway [81].

Research has shown that the overexpression of MEG3 induced the proliferation of pancreatic cancer cells by activating p53 expression [82,83]. MEG3 may also find uses as a prognostic factor and a curative agent in pancreatic cancer [84]. Both MEG3 and MEG8 are upregulated in pancreatic cancer cell lines. However, the expression of MEG3 was found to be fourfold to fivefold that of MEG8 in pancreatic cancer cell lines [85]. Studies have also found that tumor growth is suppressed by the DANCR gene knockout and that DANCR in combination with IGF2BP2 promotes the pathogenicity of pancreatic cancer [86]. miR-33b regulation inhibits cell proliferation when DANCR is downregulated [87] and miR-214-5p helps DANCR positively modulate the expression of E2F2 in pancreatic cancer cells [88]. It is upregulated when miR-135a is downregulated and the proliferation of pancreatic cancer cells is promoted when DANCR is overexpressed [89]. These facts have led to the conclusion that the DANCR gene may act as a therapeutic agent and also a biomarker for diagnosis [90].

The expression of PVT1 is also increased in PDAC tissues [35]. This lncRNA is related to the growth of tumors [91] and promotes cell proliferation in PDAC tissues [92]. The epithelial to mesenchymal transition is promoted through the activation of TGF-β signaling by knocking down PVT1. The overexpression and knockdown of PVT1 lead to the upregulation and downregulation of both TGF-β1 and p-Smad2/3 respectively in pancreatic cancer [93]. The downregulation of p21 helps PVT1 in the promotion of EMT and the proliferation of cells in pancreatic cancer [94].

Studies have found that MTA2TR is overexpressed and inhibits the proliferation of cells both in vivo, in vitro by upregulating MTA2 in pancreatic cancer [95], while cell migration, proliferation, and invasion are inhibited by knocking down NORAD which is highly expressed and is associated with poor survival rate in pancreatic cancer [96,97]. AFAP1 and PANDAR are both also upregulated in pancreatic cancer, and the overexpression of AFAP1 helps in the prediction of metastasis [54]. TUG1 is also overexpressed which leads to the phosphorylation of Smad3 and Smad2 in pancreatic cancer cells [98]. When silenced, it inhibits proliferation and promotes apoptosis; its resistance against gemcitabine is also enhanced [99,100]. The level of expression of MMP2, E-cadherin, and MMP9 increases simultaneously with TUG1 expression [100]. Yet another highly expressed gene in PDAC tissue is UCA1 [101], which influences metastasis, cell growth, and used as a biomarker for diagnosis [102,103]. While it is downregulated, UCA1 can be used as a novel strategy for treatment under a molecular basis in pancreatic cancer [104]. The targeting of miR-135a makes UCA1 an oncogene promoting cell growth in pancreatic cancer [105,106]

XIST is upregulated when miR-141-3p, miR-429 and miR-133a are downregulated. Cell proliferation, invasion, and migration are inhibited by knocking down XIST in pancreatic cancer ¹¹⁵XIST directly targets and suppress miR-34a-5p which helps in the promotion of proliferation and invasion of pancreatic cancer cells [107]. The silencing of XIST has been proven to result in the reduction and suppression of the expression of YAP and TGF-β1-induced EMT respectively and vice versa in pancreatic cancer [108]. The effects of CCHE1 on cell invasion and migration are reversed by knocking down ROCK1 siRNA [109], while the knockdown of ROR inhibits invasion, proliferation, and migration, and reduces tumorigenicity. Additionally, CCAT1 is upregulated in pancreatic cancer. Researchers have found that cell migration and proliferation were inhibited and that the G0/G1 phase cell cycle arrest is regulated by the silencing of CCAT1 [110].

Wang et al. have proven that CRNDE is upregulated and associated with poor prognosis in PDAC patients. miR-384 sponging helps the expression of IRS1 to be positively regulated along with CRNDE. The invasion, migration, and proliferation of cells are inhibited both in vivo and in vitro by knocking down CRNDE in pancreatic cancer [111]. Also, the upregulation of IRAIN is associated with the size of the tumor and its knockdown helps to inhibit the proliferation of cells and induce apoptosis in pancreatic cancer [112]. NEAT1 is also highly expressed and its effect in promoting the tumor was enhanced by negatively modulating miR-506-3p in pancreatic cancer [113].

The upregulation of SUMO1P3 leads to poor prognosis and its downregulation leads to an increase in the expression of E-cadherin [an epithelial marker] and N-cadherin, and a decrease in the expression of vimentin and β-catenin [mesenchymal markers] in pancreatic cancer [114]. CCDC26 is also upregulated and is associated with the size and number of tumors in pancreatic cancer. Tumor growth is arrested and apoptosis promoted by knocking down CCDC26 [115]. Also, DIO3OS is highly expressed and inhibits the expression of miRNA-122 by directly binding to it the knockdown of DIO3OS and the overexpression of miRNA-122 can be overcome by re-expressing ALDOA in pancreatic cancer cells [116]. EPIC1 is also highly expressed in pancreatic cancer and is associated with tumor size and metastasis. The interaction between lnc-EPIC1 and YAP1 helps in the progression of cancer cells [117].

The expression of HCP5 is upregulated in PDAC. The targeting of HDGF through miR-214-3p helps HCP5 to regulate the proliferation, autophagy, migration, invasion, and apoptosis in pancreatic cancer cells which are resistant to gemcitabine [118]. Further, a study has found that cell proliferation is inhibited and apoptosis promoted by the downregulation of HOST2 [119]. MIR155HG is also highly expressed in pancreatic cancer and is associated with poor prognosis. Its silencing has been found to promote cell growth. Its effect on the growth of the tumor is achieved by negatively regulating miR-802 in pancreatic cancer [120]. Liu et al. report that uc.345 has a higher expression level in pancreatic cancer, leading to an increase in the level of protein and transcripts of hnRNPL, a downstream target of uc.345 which promotes tumorigenesis [121]. Other studies have found that Sox2ot has a higher expression level and its competitive binding with miR-200 promotes the invasion and metastasis of cells in PDAC [122]. ANRIL also has a higher level of expression and its silencing along with the inhibition of ATM-E2F1 signaling pathway decreases the ability of migration and invasion of cells in pancreatic cancer [123]. Further, DLEU2 is upregulated with a higher expression of SMAD2 and a lower expression level of miR‐455, both of which are associated with poor survival in pancreatic cancer [124].

4. Selective long noncoding RNAs – downregulated in pancreatic cancer

Various studies have found that the expression of the Growth arrest-specific 5 (Gas5) lncRNA is significantly lower in pancreatic cancer cells when compared to normal cells. Gas5 inhibition reduces the G0/G1 phase and prolongs the S phase of the cell cycle. Overexpression of Gas5 inhibits cell proliferation. Gas5 negatively regulates CDK6 and therefore, knockdown of CDK6 will reduce Gas5 induced proliferation in cells [125]. miR-221 and SOCS3 are both regulated by GAS5 in pancreatic cancer [126]. The suppression of metastasis in pancreatic cancer has been achieved by the upregulation of GAS5, which positively regulates PTEN-induced tumor-suppressor pathway with the help of miR-32-5p [127]. Other work has discovered a correlation between tumor size and the concentration of the lncRNA ENST00000480739, which has lower expression in PDAC patients. The results of this study show that larger tumor sizes will have a lower amount of these lncRNAs [128]. Its mechanism of action is enhanced when alpha prolyl hydroxylases, osteosarcoma amplified-9, and a protein interacting with hypoxia-inducible factor 1 are upregulated in pancreatic cancer [129]. Also, CF129 has been found to cause a decrease in the expression of FOXC2 and p53, which inhibits migration and proliferation of pancreatic cancer cells. This lncRNA is underexpressed in pancreatic cancer patients [130].

HMlincRNA717 is reportedly downregulated in pancreatic cancer and acts as a biomarker for cancer progression [131]. There is also a lower expression of lncRNA-ATB in pancreatic cancer tissues. This lncRNA has a critical role in cancer growth and prognosis [132]. Additionally, research has shown that there is a lower level of expression of the lncRNAs C9orf139, MIR600HG, and RP11‐436K8.1 in PDAC patients [133]. CASC2 is also downregulated in pancreatic cancer [134] and the anti-metastatic activity of CASC2 is affected by PTEN Downregulation and furthermore, the effect of MIAT downregulation on the migration, growth, and invasion of pancreatic cancer cells can be reversed by inhibiting the expression of miR-133 [135]. The progression and invasion of cells are inhibited by repressing the expression of TACC3 by PCTST, a lncRNA that has a lower expression level in pancreatic cancer [136].

Among the long intergenic noncoding RNAs (lincRNAs), LINC01111 is downregulated in PDAC tissues and there is a reported reduction in the malignancy of pancreatic cancer cells when LINC01111 is overexpressed. The metastasis and the progression of the tumor are enhanced due to the decrease in LINC01111, which activates the pathway of SAPK/JNK signaling [137]. Besides, susceptibility is increased by LINC00673 rs11655237 through the downregulation of LINC00673 in pancreatic cancer [138].

Of the antisense (AS) lncRNAs, the motility of pancreatic cancer cells is inhibited by ALKBH5 through the demethylation of lncRNA KCNK15-AS1, which is downregulated [156]. The level of expression of PXN-AS1 is also low, and its overexpression leads to a decrease in the proliferation, invasion of cells, and the formation of spheres. The effects of PXN-AS1 in pancreatic cancer can be revoked by restating miR-3064 [157].

4.1. Selective long noncoding RNAs – highly established as indications so far in pancreatic cancer treatment and prognosis

The lncRNAs GAS5, AP000221.1, and CTC-338M12.5 are expressed differentially and show resistance against pancreatic cancer with an increase in the dosage of gemcitabine. They can hence be used as a biomarker and a therapeutic agent [139]. In particular, miR-181 c-5p helps GAS5 regulate the Hippo signaling pathway to neutralize the multidrug-resistant development in pancreatic cancer [140]. Also, the therapeutic potential of targeting the pathway and the de-suppressing activity of KRAS expression is mediated by the lncRNA NUTF2P3-001 in pancreatic cancer [141], making it a possible therapeutic target. Furthermore, TUG1 is overexpressed, leading to the phosphorylation of Smad3 and Smad2 in pancreatic cancer cells. When this lncRNA is silenced, it inhibits proliferation and promotes apoptosis, and its resistance against gemcitabine is also enhanced. The level of expression of MMP2, E-cadherin, and MMP9 increases simultaneously with TUG1 expression [99].

RP11-567G11.1 is upregulated in pancreatic cancer cells and its depletion increases the sensitivity of the cancer cells to gemcitabine and CYP1A1 is also upregulated in pancreatic cancer and can be used as a prognostic marker for gemcitabine sensitivity [142]. Studies have found that chemo-resistant activity is promoted by GSTM3TV2, which has a higher expression level in pancreatic cancer [143] along with the upregulation of OLR and LAT2, which leads to gemcitabine resistance [144]. The expression of HCP5 is also upregulated. The targeting of HDGF through miR-214-3p helps HCP5 to regulate proliferation, autophagy, migration, invasion, and apoptosis in pancreatic cancer cells which are resistant to gemcitabine [118]. SBF2-AS1 has been found to have a higher expression level in pancreatic cancer, which is associated with gemcitabine resistance. It is competitive binding with miR-142-3p inhibits TWF1 expression in pancreatic cancer. Pancreatic cancer cells that are resistant to gemcitabine can be promoted to apoptosis with the inhibition of cell proliferation by knocking down SBF2-AS1 [68].

Drug resistance in pancreatic cancer has also been found to be mediated by the lncRNAs MIR210HG, SNHG1, and LOC729970 when co-expressed with mRNAs such as SPNS2, RAB3D, and DDX17. These lncRNAs can thus be used as prognostic markers in pancreatic cancer [145]. Furthermore, the upregulation of SNHG8 promotes cell proliferation and inhibits apoptosis in PDAC patients. The overexpression of this lncRNA also reportedly reduces chemosensitivity in PDAC [60].

5. Conclusion

LncRNA research remains in its infancy owing to its large transcriptome, which is yet to be identified and characterized. The biology of lncRNAs elucidated is from the very few lncRNAs that have been identified and characterized. As more lncRNAs are added to the list, they open up a variety of possibilities in terms of their functions and roles. This can be seen by the tissue-specific expression of lncRNAs in pancreatic cancer which show their diversity by interactions with miRNAs, protein-encoding genes among the many other functions which have not been understood yet. Understanding the roles and functions of lncRNAs and their subsequent characterization, functional changes such as the interaction between lncRNA and protein, antisense RNA-mediated regulation of gene can lead to them serving as potential markers and therapeutic targets in the suppression of pancreatic cancer.

Abbreviation

H19 - H19 imprinted maternally expressed transcript; HMGA-2 - high mobility group AT-hook 2; PFTK1 - cyclin-dependent kinase 14; HIF-lα - hypoxia-inducible factor-lα; HOTTIP - HOXA distal transcript antisense RNA; HOXA - homeo box A cluster; WDR5 - WD repeat domain 5; MLL - lysine methyltransferase 2A; HOXA13 - homeobox A 13; MALAT-1 - metastasis associated long adenocarcinoma transcript 1; MAPK - mitogen-activated kinase-like protein; ERK - mitogen-activated protein kinase 1; SFPQ - splicing factor proline and glutamine rich; PTBP2 - polypyrimidine tract binding protein 2; mTOR - mechanistic target of rapamycin kinase; HOTAIR - Hox antisense intergenic RNA; HOXC - homeobox C cluster; HK2 - hexokinase 2; notch3 - notch receptor 3; DR5 - tumor necrosis factor receptor superfamily, member 10b; PAX8 - paired box 8; RUNX2 - RUNX family transcription factor 2; AGR2 - anterior gradient 2, protein disulphideisomerase family member; GLP1R - glucagon like peptide 1 receptor; SNHGs - Small Nucleolar RNA Host Genes; SNHG14 - Small Nucleolar RNA Host Gene 14; SNHG15 - Small Nucleolar RNA Host Gene 15; KLF2 - Kruppel like factor 2; P15 - phage-related protein/hypothetical protein; SNHG7 - Small Nucleolar RNA Host Gene 7; SNHG16 - Small Nucleolar RNA Host Gene 16; SNHG8 - Small Nucleolar RNA Host Gene 8; SNHG11 - Small Nucleolar RNA Host Gene 11; SNHG1 - Small Nucleolar RNA Host Gene 1; AFAP1 - actin filament associated protein 1; AS1 - myb-like HTH transcriptional regulator family protein; ADPGK - ADP dependent glucokinase; DLX6 - distal-less homeobox 6; BDH2 - 3-hydroxybutyrate dehydrogenase 2; TP73 - tumor protein p73; ZEB2 - zinc finger E-box binding homeobox 2; JHDM1D - lysine demethylase 7A; SBF2 - SET binding factor 2; TWF1 - twinfilin actin binding protein 1; FZD4 - frizzled class receptor 4; FZD6 - frizzled class receptor 6; MSC - musculin; CDK14 - cyclin-dependent kinase 14; ANGPTL4 - angiopoietin-like 4; ANKRD1 - ankyrin repeat domain 1; AGAP2 - ArfGAP with GTPase domain, ankyrin repeat and PH domain 2; ABHD11 - abhydrolase domain containing 11PI3K - phosphatidylinositol 3-kinase; AKT - AKT serine/threonine kinase 1; LOXL - lysyl oxidase like 1; HULC - highly upregulated in liver cancer; NUF2 - NUF2 component of NDC80 kinetochore complex; DUXAP8 - double homeobox Apseudogene 8; GHET1 - gastric carcinoma proliferation enhancing transcript 1; HNRNPU - heterogenous nuclear ribonucleoprotein U; DUXAP10 - double homeobox Apseudogene 10; BX111 - ZEB 1 transcriptional regulator RNA; ZFP91 - ZFP91 zinc finger protein, atypical E3 ubiquitin ligase; MEG3 - maternally expressed 3MEG8 - maternally expressed 8, small nucleolar RNA host gene; DANCR - differentiation antagonizing non-protein coding RNA; IGF2BP2 - insulin like growth factor 2 mRNA binding protein 2; E2F2 - E2F transcription factor 2; PVT1 - Pvt1 oncogene; TGF-β, TGF-β1 - transforming growth factor beta 1; p21 - cyclin-dependent kinase inhibitor 1A; MTA2 - metastasis associated 1 family member 2; NORAD - noncoding RNA activated by DNA damage; PANDAR - promoter of CDKN1A antisense DNA damage activated RNA; TUG1 - taurine upregulated 1; MMP9 - matrix metallopeptidase 9; UCA1 - urothelial cancer associated 1; XIST - X inactive specific transcript; CCHE1 - cervical carcinoma expressed PCNA regulatory lncRNA; ROR - long intergenic non-protein coding RNA, regulator of reprogramming; ROCK1 - Rho-associated coiled-coil containing protein kinase 1; CCAT1 - colon cancer associated transcript 1; CRNDE - colorectal neoplasia differentially expressed; IRS1 - insulin receptor substrate 1; IRAIN - IGF1R antisense imprinted non-protein coding RNA; NEAT1 - nuclear paraspeckle assembly transcript 1; SUMO1P3 - small ubiquitin-like modifier 1 pseudogene 3; CCDC26 - CCDC26 long noncoding RNADIO3OS - iodothyroninedeiodinase 3 opposite strand upstream RNA; ALDOA - aldolase, fructose-bisphosphate A; YAP1 - Yes1-associated transcriptional regulator; HCP5 - HLA complex P5HDGF - heparin binding growth factor; HOST2 - competing endogenous lncRNA 2 for microRNA let-7b; hnRNPL - heterogeneous nuclear ribonucleoprotein L; Sox2ot - SRY-box transcription factor 2 overlapping transcript (non-protein coding); MIR155HG - microRNA 155 host gene; ANRIL - cyclin dependent kinase inhibitor 2B antisense RNA 1; ATM - ATM serine/threonine kinase; E2F1 - E2F transcription factor 1; DLEU2 - deleted in lymphocytic leukemia 2; Gas5 - growth arrest-specific 5; CDK6 - cyclin-dependent kinase 6; SOCS3 - suppressor of cytokine signaling 3; FOXC2 - forkhead box C2; lncRNA-ATB - long noncoding RNA activated by TGF-beta; C9orf139 - chromosome 9 open reading frame 139; MIR600HG - microRNA 600 host gene; RP11 - pre-mRNA processing factor 31; CASC2 - cancer susceptibility 2; MIAT - myocardial infarction-associated transcript; TACC3 - transforming acidic coiled-coil containing protein 3; NLRP3 - NLR family pyrin domain containing 3; LINC01111 - long intergenic non-protein coding RNA 111; SAPK - mitogen-activated protein kinase 9; JNK - mitogen-activated protein kinase 8; LINC00673 - long intergenic non-protein coding RNA 673; lncRNA KCNK15-AS1 - KCNK15 and WISP2 antisense RNA 1; PXN-AS1 - PXN antisense RNA 1; CYP1A1 - cytochrome P450 family 1 subfamily A member 1; OLR - oxidized low-density lipoprotein receptor; LAT2 - linker for activation of T cells family member 2; SBF2-AS1 - SET binding factor 2 antisense RNA 1; MIR210HG - microRNA 210 host gene; SPNS2 - sphingolipid transporter 2; RAB3D - RAB3D, member RAS oncogene family; DDX17 - DEAD-box helicase 17

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