Long Noncoding RNA ANRIL Promotes Non–Small Cell Lung Cancer Cell Proliferation and Inhibits Apoptosis by Silencing KLF2 and P21 Expression

Abstract

Recent evidence highlights long noncoding RNAs (lncRNA) as crucial regulators of cancer biology that contribute to essential cancer cell functions such as cell proliferation, apoptosis, and metastasis. In non-small cell lung cancer (NSCLC), several lncRNAs' expressions are misregulated and have been nominated as critical actors in NSCLC tumorigenesis. LncRNA ANRIL was first found to be required for the PRC2 recruitment to and silencing of p15 INK4B , the expression of which is induced by the ATM-E2F1 signaling pathway. Our previous study showed that ANRIL was significantly upregulated in gastric cancer, and it could promote cell proliferation and inhibit cell apoptosis by silencing of miR99a and miR449a transcription. However, its clinical significance and potential role in NSCLC is still not documented. In this study, we reported that ANRIL expression was increased in NSCLC tissues, and its expression level was significantly correlated with tumor-node-metastasis stages and tumor size. Moreover, patients with high levels of ANRIL expression had a relatively poor prognosis. In addition, taking advantage of loss-of-function experiments in NSCLC cells, we found that knockdown of ANRIL expression could impair cell proliferation and induce cell apoptosis both in vitro and vivo. Furthermore, we uncover that ANRIL could not repress p15 expression in PC9 cells, but through silencing of KLF2 and P21 transcription. Thus, we conclusively demonstrate that lncRNA ANRIL plays a key role in NSCLC development by associating its expression with survival in patients with NSCLC, providing novel insights on the function of lncRNA-driven tumorigenesis.

The lncRNA XIST exhibits oncogenic properties via regulation of miR-449a and Bcl-2 in human non-small cell lung cancer

“…For example, knockdown of the lncRNA TATDN1 has been shown to inhibit tumor growth and metastasis in NSCLC cells by inhibiting β-catenin and Ezrin; thus, TATDN1 may be a potential prognostic factor and therapeutic target for NSCLC [21] . In addition, the lncRNA ANRIL has been found to be significantly upregulated in NSCLC tissues, and its expression promotes cell proliferation and inhibits cell apoptosis in vitro and in vivo [22] . Moreover, HOTAIR, MALAT1 and SBF2-AS1 have been shown to exert oncogenic functions in NSCLC [23][24][25] .…”

Downregulation of long non-coding RNA TRIM52-AS1 functions as a tumor suppressor in renal cell carcinoma

“…LncRNAs have been reported to be important in cell apoptosis, particularly in the escape of cancer cells from apoptosis (20)(21)(22). To determine the impact of TRIM52-AS1 on RCC cell apoptosis, flow cytometry was performed to detect the rate of apoptosis in the cells.…”

Expression and prognostic significance of cyclin‑dependent kinase inhibitor 1A in patients with resected gastric adenocarcinoma

“…As CDKN1A is a tumor suppressor, we hypothesize that epigenetic changes, such as promoter methylation, may be one of the mechanisms underlying the low CDKN1A expression in RGA tissues; promoter methylation is capable of inhibiting gene transcript and protein expression, as identified by Watanabe et al (32), who suggested that abnormal genomic methylation may be involved in the reduced expression of CDKN1A in adult T-cell leukemia/lymphoma (32). A study conducted by Nie et al (33) indicated that long noncoding RNAs (lncRNA) may also serve a role in regulation of CDKN1A transcription; the authors demonstrated that the lncRNA antisense noncoding RNA in the INK4 locus was upregulated in non-small cell lung cancer (NSCLC) tissues, and that this lncRNA promoted NSCLC cell proliferation and inhibited NSCLC cell apoptosis through the inhibition of Krüppel-like factor 2 and CDKN1A transcription (33). These studies additionally demonstrate that CDKN1A is a key regulator of the cell cycle, and may be a target for cancer treatment.…”