LncRNA NNT‐AS1 promotes non‐small cell lung cancer progression through regulating miR‐22‐3p/YAP1 axis

Abstract

Background Lung cancer is the leading cause of cancer‐related mortality worldwide. Studies have demonstrated that long noncoding RNA nicotinamide nucleotide transhydrogenase‐antisense RNA1 (NNT‐AS1) functioned as an oncogene in most malignancies, including non‐small cell lung cancer (NSCLC). This study aimed to investigate the underlying mechanisms of NNT‐AS1 in NSCLC progression. Methods The levels of NNT‐AS1, miR‐22‐3p and Yes‐associated protein (YAP1) were detected by qRT‐PCR in NSCLC tissues and cells. Kaplan‐Meier analysis was conducted to analyze the correlation between NNT‐AS1 expression and overall survival of NSCLC patients. Cell proliferation was evaluated by MTT assay. Cell migration and invasion were assessed using transwell assay. The protein levels of YAP1 and EMT‐related proteins were detected by western blot. The molecular mechanism was predicted by starBase2.0 and validated by dual‐luciferase reporter assay or RNA pull‐down assay. Xenograft analysis was carried out to analyze tumor growth in vivo. Results We found that the levels of NNT‐AS1 and YAP1 were enhanced, while miR‐22‐3p expression was decreased in NSCLC tissues and cells. High NNT‐AS1 expression was correlated with poor prognosis. NNT‐AS1 knockdown impeded proliferation, migration, invasion and EMT of NSCLC cells. NNT‐AS1 targeted miR‐22‐3p, and YAP1 was a target of miR‐22‐3p in NSCLC cells. Furthermore, NNT‐AS1 facilitated the progression of NSCLC by regulating miR‐22‐3p/YAP1 axis. NNT‐AS1 knockdown repressed tumor growth in vivo. Conclusion NNT‐AS1 facilitated proliferation, migration, invasion and EMT of NSCLC cells by sponging miR‐22‐3p and regulating YAP1 expression, which might provide a potential biomarker and therapeutic target for NSCLC.

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

“…Previous studies have investigated the underlying mechanisms of NNT-AS1 in carcinogenesis. Overexpression of NNT-AS1showed positive association with poorer OS, advanced tumor stage, LNM, depth of invasion [30], vessel invasion and differentiation in numerous cancers. Functional assays revealed that NNT-AS1 could promote proliferation, weaken cell cycle arrest and alleviate apoptosis by competing with CDK6 for miR-363 binding in hepatocellular carcinoma [18].…”

“…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].…”

TRPM2-AS promotes bladder cancer-genesis by targeting miR-22-3p thus releasing GINS2 mRNA

“…Besides, miR-22-3p has also been reported to participate in a more complex network, the competitive endogenous RNA (ceRNA) network. For instance, miR-22-3p was reported to be involved in a ceRNA network pathway that included lncRNA NNT-AS1 and YAP1, thus regulating the malignancy phenotypes of NSCLC cells [43]. In gastric cancer, miR-22-3p was reported to be regulated by lncRNA CTC-497E21.4 thus regulating NET1 expression to suppress the malignant development of gastric cancer [44].…”

Identification of Key Genes and Pathways in Breast Cancer Based on Bioinformatic Analysis

“…Previous work shows that miR-22 already be considered as a tumor suppressor or promoter in different cancers (Orang et al, 2019). Furthermore, multiple findings suggesting miR-22 have been implicated in non-small-cell lung cancer (NSCLC) through gene regulation (Ding et al, 2020;He et al, 2020). However, the role of miR-22 in BC remains unclear and need further exploration.…”