Identification of a competing endogenous RNA axis "SVIL-AS1/miR-103a/ICE1" associated with chemoresistance in lung adenocarcinoma by comprehensive bioinformatics analysis

Abstract

Background: Chemotherapy is an important treatment for lung cancer. The molecular mechanism of lung adenocarcinoma (LUAD) chemoresistance is not completely understood.

Methods: Weighted gene co-expression network analysis (WGCNA) was applied to screen the modules related to chemosensitivity using the data of LUAD patients receiving chemotherapy in The Cancer Genome Atlas database. GDCRNATools package was used to establish competing endogenous RNA (ceRNA) network based on the key chemotherapy-related module. Kaplan-Meier and risk models were used to analyze the influence of genes in the ceRNA network on the prognosis of LUAD patients receiving chemotherapy. Cell counting kit-8, reverse transcription-quantitative PCR, and dual-luciferase reporter assay were used to detect the effects of abnormal expression of genes in the ceRNA network on the proliferation and IC50 of cisplatin (DDP)-resistant LUAD cells, and the targeting relationship of genes in the ceRNA network. The signaling pathways and functions of ICE1 in LUAD were analyzed by LinkOmics and CancerSEA databases, and validated by Western blot.

Results: Midnightblue module was the only WGCNA module positively correlated with chemosensitivity, in which the function of genes was related to cancer progression. SVIL-AS1/miR-103a/ICE1 was constructed based on midnightblue module. High expression of SVIl-AS1 and ICE1 corresponded to a favorable prognosis. High expression of miR-103a corresponded to a dismal prognosis. SVIl-AS1 was downregulated in DDP-resistant LUAD cells. SVIL-AS1 overexpression retarded the proliferation and DDP resistance of DDP-resistant LUAD cell. miR-103a was sponged by SVIL-AS1 and directly targeted ICE1. miR-103a overexpression and ICE1 knockdown overturned the suppressive effect of SVIL-AS1 overexpression on cell proliferation and DDP resistance. Further bioinformatics analysis and experimental verification showed that SVIL-AS1/miR-103a-3p/ICE1 axis can enhance DNA damage caused by chemotherapeutic agents.

Conclusions: SVIL-AS1 inhibited chemoresistance by acting as a sponge for miR-103a and upregulating ICE1 expression, which may be a potential therapeutic target for chemotherapy in LUAD.

Keywords: chemoresistance; competing endogenous RNA; lung adenocarcinoma; prognosis; weighted gene co-expression network analysis.