TEAD4 modulated LncRNA MNX1-AS1 contributes to gastric cancer progression partly through suppressing BTG2 and activating BCL2

Abstract

Background: Gastric cancer (GC) is the third leading cause of cancer-related mortality globally. Long noncoding RNAs (lncRNAs) are dysregulated in obvious malignancies including GC and exploring the regulatory mechanisms underlying their expression is an attractive research area. However, these molecular mechanisms require further clarification, especially upstream mechanisms. Methods: LncRNA MNX1-AS1 expression in GC tissue samples was investigated via microarray analysis and further determined in a cohort of GC tissues via quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. Cell proliferation and flow cytometry assays were performed to confirm the roles of MNX1-AS1 in GC proliferation, cell cycle regulation, and apoptosis. The influence of MNX1-AS1 on GC cell migration and invasion was explored with Transwell assays. A xenograft tumour model was established to verify the effects of MNX1-AS1 on in vivo tumourigenesis. The TEAD4-involved upstream regulatory mechanism of MNX1-AS1 was explored through ChIP and luciferase reporter assays. The mechanistic model of MNX1-AS1 in regulating gene expression was further detected by subcellular fractionation, FISH, RIP, ChIP and luciferase reporter assays. Results: It was found that MNX1-AS1 displayed obvious upregulation in GC tissue samples and cell lines, and ectopic expression of MNX1-AS1 predicted poor clinical outcomes for patients with GC. Overexpressed MNX1-AS1 expression promoted proliferation, migration and invasion of GC cells markedly, whereas decreased MNX1-AS1 expression elicited the opposite effects. Consistent with the in vitro results, MNX1-AS1 depletion effectively inhibited the growth of xenograft tumour in vivo. Mechanistically, TEAD4 directly bound the promoter region of MNX1-AS1 and stimulated the transcription of MNX1-AS1. Furthermore, MNX1-AS1 can sponge miR-6785-5p to upregulate the expression of BCL2 in GC cells. Meanwhile, MNX1-AS1 suppressed the transcription of BTG2 by recruiting polycomb repressive complex 2 to BTG2 promoter regions. Conclusions: Our findings demonstrate that MNX1-AS1 may be able to serve as a prognostic indicator in GC patients and that TEAD4-activatd MNX1-AS1 can promote GC progression through EZH2/BTG2 and miR-6785-5p/ BCL2 axes, implicating it as a novel and potent target for the treatment of GC.

The prognostic utility and clinical outcomes of MNX1-AS1 expression in cancers: a systematic review and meta-analysis

“…The combined results presented that patients with MNX1-AS1 over-expression were susceptible to suffer from unfavorable prognosis in gastric cancer and lung cancer. The pooling results of the study are consistent with most of the original literatures, which recommend that MNX1-AS1 high expression might be associated with worse prognosis of malignant cancer patients[6,8,9].Moreover, the sensitivity analysis proved the stability and reliability of the pooled results. The heterogeneity of gastric cancer (I-squared = 0.0%, P = 0.943), lung cancer (I-squared = 0.0%, P = 0.508), and sample sizes ≥ 100 (I-squared = 0.0%, 0.559) subgroups was lower than the overall heterogeneity in the study.…”

“…A total of 882 patients from the all eligible articles were included to evaluate prognostic value of MNX1-AS1 (presented in Table 1). All articles covered gastric cancer(GC) (n = 3) [8][9][10], lung cancer (LC) (n = 3) [6,20,21], other cancer(n = 3) including: esophageal squamous cell carcinoma (ESCC), cervical cancer (CC), epithelial ovarian cancer (EOC) [14,18,22].…”

“…Discussion MNX1-AS1, also known as MAYA and CCAT5, is located at chromosome 7q36.3 [6]. Upregulation of MNX1-AS1 expression has been found in a variety of cancers, including gastric cancer [8][9][10], lung cancer [6,20,21], esophageal squamous cell carcinoma [14,15], and estrogen-dependent cancer [7,18,22], etc. MNX1-AS1 play a role of functional oncogene in addition to activating AKT/mTOR pathway and its natural sense transcript MNX1 in breast cancer cells, it also promotes the process of EMT [7].…”

“…Motor neuron and pancreas homeobox 1-antisense RNA1 (MNX1-AS1), is the antisense strand of MNX1 (7q36.6), also known as MAYA and CCAT5, which maps to chromosome 7q36.3 [6,7]. Several studies for the first time provided that MNX1-AS1 has a sponge adsorption effect on miR-6785-5p, thereby up-regulating the expression of BCL2, and overexpression of MNX1-AS1 might facilitate the proliferation, migration and invasion of gastric cancer cells [8][9][10]. Knockdown of MNX1-AS1 might affect the expression of CDK4, cyclin D, Bax, and Bcl-2, which may inhibit proliferation and migration capabilities, and promote apoptosis of ovarian cancer cells [11].…”

PGM5-AS1 Inhibits the Malignant Phenotype of Colon Cancer Cells by Regulating PAEP and NME1

“…MNX1-AS1 (NR_038835), the lncRNA with the most signi cant upregulation of expression, is reported to inhibit carcinogenesis in glioblastoma by suppressing miR-4443 [14]. MNX1-AS1 partly regulates BTG2 and BCL2, thereby facilitating gastric cancer progression [15]. The up-regulated lncRNA UCA1 (NR_015379) promotes immune escape in gastric cancer by binding to anti-tumor miRNA [16].…”