Long non‐coding RNA NNT‐AS1 sponges miR‐424/E2F1 to promote the tumorigenesis and cell cycle progression of gastric cancer

Abstract

Long non‐coding RNAs (lncRNAs) have been illustrated to function as important regulators in carcinogenesis and cancer progression. However, the roles of lncRNA NNT‐AS1 in gastric cancer remain unclear. In the present study, we investigate the biological role of NNT‐AS1 in gastric cancer tumorigenesis. Results revealed that NNT‐AS1 expression level was significantly up‐regulated in GC tissue and cell lines compared with adjacent normal tissue and normal cell lines. The ectopic overexpression of NNT‐AS1 indicated the poor prognosis of GC patients. In vitro experiments validated that NNT‐AS1 knockdown suppressed the proliferation and invasion ability and induced the GC cell cycle progression arrest at G0/G1 phase. In vivo xenograft assay, NNT‐AS1 silencing decreased the tumour growth of GC cells. Bioinformatics online program predicted that miR‐424 targeted the 3′‐UTR of NNT‐AS1. Luciferase reporter assay, RNA‐immunoprecipitation (RIP) and RNA pull‐down assay validated the molecular binding within NNT‐AS1 and miR‐424, therefore jointly forming the RNA‐induced silencing complex (RISC). Moreover, E2F1 was verified to act as the target gene of NNT‐AS1/miR‐424, indicating the NNT‐AS1/miR‐424/E2F1 axis. In conclusion, our study indicates that NNT‐AS1 sponges miR‐424/E2F1 to facilitate GC tumorigenesis and cycle progress, revealing the oncogenic role of NNT‐AS1 for GC.

The Role of Long Non-Coding RNA NNT-AS1 in Neoplastic Disease

“…In Erα-receptor-positive breast cancer cells, when E2 is monitored or E2 is given, the levels of miR-424 and E2F1 also increase [41,42]. In a gastric cancer study, the regulatory axis of NNT-AS1/miR-424/E2F1 was confirmed [32]. Therefore, the low expression of NNT-AS1 up-regulates miR-424 and E2F1, and the abnormal E2 level is likely to be correlated.…”

“…However, studies on the expression of NNT-AS1 in gastric, breast, and ovarian cancers seem to be contradictory. In gastric cancer, there have been three studies that have reported high levels of NNT-AS1 in tumor tissues and cell samples, and the performance of NNT-AS1 in subsequent in vivo and in vitro tests also verified its cancer-promoting function [32,33,35]. However, Farbod Esfandi et al found that compared with the adjacent samples, the NNT-AS1 levels detected in gastric cancer samples were overall down-regulated [34].…”

Upregulated Expression of LncRNA Nicotinamide Nucleotide Transhydrogenase Antisense RNA 1 is Correlated with Unfavorable Clinical Outcomes in Cancers

“…Recently, emerging studies have explored the possible link between expression of lncRNA NNT-AS1 and human tumors. Compared with adjacent noncancerous tissue and normal cell, upregulated NNT-AS1 expression was identi ed in most cancer tissues or cell lines and therefore indicated poor survival outcome, such as osteosarcoma [27], breast cancer [19], cervical cancer [26], gastric cancer [28], hepatocellular carcinoma [18], colorectal cancer [21], and non-small cell lung cancer (NSCLC) [2]. On the contrary, another study performed by Huang et al, claimed that NNT-AS1 was markedly downregulated in patients with ovarian cancer and ovarian cell lines [29].…”

“…Moreover, other pathways including PI3K/Akt/mTOR and Wnt/β-catenin signaling pathway were also found involved in the tumorigenesis and progression [26,15]. Besides, NNT-AS1 was capable of serving as a competing endogenous RNA (ceRNA) by sponging miR-485/BCL9 or miR-203 in cholangiocarcinoma [31,32], miR-1301-3p/PODXL or miR-496/HMGB1 in bladder cancer [3,33], miR-142-3p/ZEB1 in breast cancer [19], miR-424/E2F1 or miR-363 in gastric cancer [28,8], miR-22-3p/YAP1 or miR-129-5p in non-small cell lung cancer [34,30], and miR-320a in osteosarcoma [27], therefore alteration in cancer cell function resulting from NNT-AS1 downregulation may be rescued by miRNA inhibition. Notably, NNT-AS1 also showed a high expression level in drug-resistant NSCLC, which promoted the cisplatin resistance of cancer cells via the MAPK/Slug pathway [35].…”

<p>Role of miRNA-424 in Cancers</p>

“…84 With regards to the digestive system, Lnc-RNA NNT-AS1 can affect the tumorigenesis and cell cycle of gastric cancer cells by binding to miR-424/E2F1. 88 Moreover, in hepatocellular carcinoma, LncRNA-LINC00511 plays an important role in the malignant progression of HCC by regulating miR-424. 89 Another study has found that Lnc-RNA DLX6-AS1 increases the expression of WEE1 by targeting miR-424-5p, which in turn promotes hepatocellular carcinoma.…”