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

Abstract

Long non-coding RNAs (lncRNAs) have been shown to play a significant role in the progression of many cancers, including pancreatic cancer (PC). However, the biological function and regulatory mechanisms of lncRNAs in PC remains largely unclear. The aim of this study was to identify and evaluate the potential functions of lncRNAs in PC and reveal the underlying mechanisms of their effects. Screening of published microarray data (GEO accession Nos. GSE16515 and GSE32688), revealed lncRNA AFAP1-AS1 to be one of the most upregulated lncRNAs in PC tissues. High expression of AFAP1-AS1 was correlated with advanced stages, tumor size and lymph node metastasis, as well as with poorer overall survival in patients with PC. Functionally, knockdown of AFAP1-AS1 by transfection with siRNA inhibited the proliferative and invasive capacities of PaCa-2 and SW1990 PC cells, promoted apoptosis of PC cells in vitro, and impaired in-vivo tumorigenicity. In particular, it was hypothesized that AFAP1-AS1 may act as a competitive endogenous RNA (ceRNA), effectively becoming a sink for miR-133a whose expression was found to be downregulated in PC tissues and cell lines, and which was negatively correlated with the expression of AFAP1-AS1. We also found that the IGF1R oncogene which is an important regulator of MEK/ERK signaling pathway, was positively regulated by AFAP1-AS1 through ameliorating miR-133a-mediated IGF1R repression in PC tissues. Moreover, we demonstrated that knockdown of IGF1R by transfection with si-IGF1R suppressed cell proliferation, invasion and migration of PaCa-2 and SW1990 PC cells, suggesting that IGF1R may function as an oncogene in PC cells. Further investigations revealed that miR-133a reversed the biological effects of AFAP1-AS1 on PC cells. Collectively, the findings provide new evidence that AFAP1-AS1 could regulate the progression of pancreatic cancer by acting as a ceRNA, and suggest it has potential for use as both a biomarker for the early detection PC and for the development of individualized therapies for PC.

RETRACTED ARTICLE: LncRNA SNHG7 promotes pancreatic cancer proliferation through ID4 by sponging miR-342-3p

“…LncRNAs, a kind of non-coding RNAs with more than 200 nt in length, are reported to play roles in a variety of human cancers, including PC [3][4][5][6]. For example, HOT-TIP, MALAT1 and MEG3 are regarded as important regulators of tumor progression [7].…”

Long Noncoding RNA AFAP1-AS1 Promotes Cell Proliferation and Metastasis via the miR-155-5p/FGF7 Axis and Predicts Poor Prognosis in Gastric Cancer

“…The knockdown of AFAP1-AS1 was validated to inhibit GC cell proliferation migration and AFAP1-AS1, also known as AFAP1-AS and AFAP1AS, is an antisense lncRNA 6810 bp in length located at the chromosome Chr4p16.1 [29]. AFAP1-AS1 has been reported to be aberrantly expressed and is able to function as a regulator of tumorigenesis in many tumors, including breast cancer, pancreatic cancer, non-small cell lung cancer, and colorectal cancer [19,20,22,30]. Guo et al [31] identified that AFAP1-AS1 was upregulated in GC cells and regulated GC cell proliferation and apoptosis via the PTEN/p-AKT pathway.…”

“…Increasing studies have demonstrated that lncRNAs regulated gene expression through functioning as microRNA (miRNA) sponge or competing endogenous RNA (ceRNA) and play significant regulatory roles in tumor biology via various mechanisms associating with the aggressive development of cancer, including cell proliferation, differentiation, apoptosis, invasion, metabolism, developmental timing, and immune responses [16][17][18]. Recent studies have shown that lncRNA AFAP1-AS1 functions as a ceRNA in pancreatic cancer, breast cancer, lung cancer, and colorectal cancer [19][20][21][22]. However, the detailed function and mechanism of AFAP1-AS1 in the pathogenesis of GC remains unclear.…”

Emerging roles of MiR-133a in human cancers

“…MiR-133a could not only suppress cell proliferation, induce cell cycle arrest at G0/G1 stage and accelerate cell apoptosis, but also inhibit cell migration and invasion in vivo and in vitro via targeting IGF-1R and negatively regulating downstream AKT and ERK signal pathway [36][37][38]. In PC, AFAP1-AS1 was reported to induce IGF1R transcription and activate the AKT/ERK pathways to promote EMT and cell metasis by sponging miR-133a [39]. Downregulation of miR-133a-3p functioned as a supportive factor in bone metastasis of prostate cancer (PCa) possibly by targeting EGFR, FGFR1, IGF1R and MET, and inactivating PI3K/AKT signaling pathway [40].…”