Oxaliplatin Activated LINC00205/miR-495-3p/CMTM6 Through Inducing H3K4me1 to Promote Oxaliplatin Resistance of Gastric Cancer

Abstract

Background Current evidence has shown the increasing importance of PD-L1 based immunotherapy in treating gastric cancer patients. In this manuscript, we aim to investigate the role of LINC00205/miR-495-3p/CMTM6 axis in mediating PD-L1 expression of gastric cancer.

Methods Human gastric cancer cell lines were obtained and cultured under standard conditions. Gastric cancer tissues were collected from patients with informed consent, and the study was ethically approved. Cell transfection was performed using siRNA and plasmids. qRT-PCR was used to quantify mRNA levels, and the influence of H3K4me1 on gene expression was predicted using bioinformatics tools.

Results LINC00205 was overexpressed in gastric cancer both in vivo and in vitro. Furthermore, LINC00205 was associated with advanced T and N stage and PD-L1 expression; besides, LINC00205 high expression led to poor prognosis of gastric cancer. In vitro experiments showed that LINC00205 aberrantly high expressed in gastric cancer cells; moreover, LINC00205 knock down decreased the cell viability, migration and invasion ability and promoted cell apoptosis. Then we found that LINC00205 knock down decrease the expression of CMTM6 both in protein and mRNA level. Furthermore, we have detected impaired transcription level of CMTM6 after LINC00205 knock down. Based on Starbase V3.0, we predicted that miR-495-3p interacted with CMTM6 and LINC00205; the prediction was then confirmed by ChIP assay. miR-495-3p could negatively regulate CMTM6 expression. In addition, CMTM6 overexpression could reverse the effect of LINC00205 knockdown on PD-L1 expression and CD8+ T cell cytotoxicity.

Conclusion Our study has shown that LINC00205/ U2AF2/ CMTM6 axis plays an important role in regulating CD8+ T cell cytotoxicity and might provide clues for improving PD-L1 based immunotherapy effects in gastric cancer.

Note:
Funding Information: This research was supported by the Scientific and Technological Development Research Project Foundation of Shaanxi Province, No.2018SF-055.

Conflict of Interests: The authors declare no conflicts of interest

Ethical Approval: The research was granted approval by the ethical review board of the Stomatology Faculty at Xi'an Jiaotong University, with all participants providing written, informed consent in accordance with the study's objectives.

Keywords: LINC00206, miR-495-3p, CMTM6, H3K4me1, PD-L1