Identification of a Novel Immune-Related lncRNA CTD-2288O8.1 Regulating Cisplatin Resistance in Ovarian Cancer Based on Integrated Analysis

Tingwei Liu; Jiacheng Shen; Qizhi He; Shaohua Xu

doi:10.3389/fgene.2022.814291

Identification of a Novel Immune-Related lncRNA CTD-2288O8.1 Regulating Cisplatin Resistance in Ovarian Cancer Based on Integrated Analysis

Front Genet. 2022 Feb 14:13:814291. doi: 10.3389/fgene.2022.814291. eCollection 2022.

Authors

Tingwei Liu¹, Jiacheng Shen¹, Qizhi He², Shaohua Xu¹

Affiliations

¹ Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.
² Department of Pathology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.

Abstract

Ovarian cancer (OC) is the most lethal gynecological malignancy, in which chemoresistance is a crucial factor leading to the poor prognosis. Recently, immunotherapy has brought new light for the treatment of solid tumors. Hence, as a kind of immunologically active cancer, it is reasonably necessary to explore the potential mechanism between immune characteristics and cisplatin resistance in OC. Our study focused on the important role of cisplatin resistance-related lncRNAs on mediating the OC tumor immune microenvironment (TIME) using an integrative analysis based on the Cancer Genome Atlas (TCGA) database. First, the cisplatin resistance-related differentially expressed lncRNAs (DELs) and mRNAs (DEMs) were preliminarily screened to construct a DEL-DEM co-expression network. Next, the protein-protein interaction (PPI) network and pivot analysis were performed to reveal the relevance of these lncRNAs with tumor immune response. Second, the novel lncRNA CTD-2288O8.1 was identified as a key gene for the OC cisplatin resistance formation by qRT-PCR and survival analysis. Gain- and loss-of-function assays (Cell Counting Kit-8 (CCK-8) assay, wound-healing scratch assay, transwell assay, and colony formation assay) further verified the activity of CTD-2288O8.1 in OC progression as well. Third, gene set enrichment analysis (GSEA) was applied along with the correlation analyses of CTD-2288O8.1 with ImmuneScore, tumor-infiltrating immune cells (TICs), and immune inhibitory checkpoint molecules, illustrating that CTD-2288O8.1 was strongly associated with the TIME and has the potential to predict the effect of OC immunotherapy. In addition, basic experiments demonstrated that the expression of CTD-2288O8.1 impacted the EGFR/AKT signal pathway activity of OC tumor cells. Of greater significance, it promoted the M2 polarization of macrophage, which is a type of the most important components of the TIME in solid tumor. Taking together, our study revealed cisplatin resistance-related lncRNAs closely linked with tumor immunity in OC, underscoring the potential mechanism of the TIME in conferring cisplatin resistance, which provided the research basis for further clinical treatment. CTD-2288O8.1 was identified to mediate cisplatin resistance and affect the response of immunotherapy, which could serve as a promising biomarker for guiding clinical treatment and improving prognosis in OC.

Keywords: EGFR; cisplatin resistance; immunotherapy; long non-coding RNA; ovarian cancer; tumor microenvironment.