LncRNA POU6F2-AS2 contributes to malignant phenotypes and paclitaxel resistance by promoting SKP2 expression in stomach adenocarcinoma

This study aimed to investigate the role and mechanism of POU6F2-AS2 in the development of gastric cancer. POU6F2-AS2 expression was considerably higher in clinical stomach adenocarcinoma (STAD) tissues and gastric cancer cell lines (MKN-28 and MGC-803) than in neighbouring normal tissues and gastric mucosa epithelial cells (GES-1). POU6F2-AS2 overexpression resulted in a low overall survival probability, progression-free survival probability and post progression survival probability, as well as increased cell viability, migration and invasion of gastric cancer cells, thereby inhibiting apoptosis. Based on RNA pull-down, cycloheximide and MG132 incubation experiments, POU6F2-AS2 promoted SKP2 by stabilizing NONO expression. In addition, in vivo silencing of POU6F2-AS2 in gastric cancer cells can inhibit tumour progression and produce a synergistic antitumour effect when combined with paclitaxel. POU6F2-AS2 is overexpressed in STAD, which is attributed to a bad prognosis. In vitro and in vivo experiments have confirmed that the POU6F2-AS2/NONO/SKP2 axis promotes STAD progression, and that the silencing of POU6F2-AS2 plays a synergistic antitumour effect when combined with paclitaxel. Therefore, POU6F2-AS2 may be potentially developed as a target to inhibit STAD and reduce chemoresistance.

本研究旨在探讨POU6F2-AS2在胃癌发生发展中的作用及机制。临床胃腺癌（STAD）组织及胃癌细胞系（MKN-28、MGC-803）中POU6F2-AS2的表达水平显著高于邻近正常组织及胃黏膜上皮细胞（GES-1）。过表达POU6F2-AS2会降低胃癌患者的总体生存概率、无进展生存概率及进展后生存概率，同时可增强胃癌细胞的增殖活力、迁移与侵袭能力，并抑制细胞凋亡。基于RNA pull-down、放线菌酮（cycloheximide）及MG132孵育实验，本研究发现POU6F2-AS2通过稳定NONO的表达来促进SKP2的功能。此外，在体内沉默胃癌细胞中的POU6F2-AS2可抑制肿瘤进展，且与紫杉醇（paclitaxel）联合使用时可产生协同抗肿瘤效应。POU6F2-AS2在胃腺癌中高表达，且与不良预后密切相关。体内外实验均证实，POU6F2-AS2/NONO/SKP2信号轴可促进胃腺癌的进展，而沉默POU6F2-AS2联合紫杉醇可发挥协同抗肿瘤作用。因此，POU6F2-AS2有望成为抑制胃腺癌进展、降低化疗耐药性的潜在治疗靶点。