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.
Highlights
Ovarian cancer (OC) is one of the most common gynecological malignant tumors with high mortality, seriously affecting women’s health worldwide (Chen et al, 2016)
The co-expression network containing 91 nodes (25 lncRNA nodes and 66 mRNA nodes) and 99 edges showed that lncRNA ABO19440.50 and LINC00221 appeared to be correlated with the same mRNAs, including IRF4, MS4A4E, SNX29, SLC4A4, CD48, RAB36, CD38, FRAS1, IGLL5, BCR, GNAZ, PRAME, RSPH14, CTNNA1, and CECR2, indicating that they had similar regulatory functions (Figure 2D)
Considering that the phosphorylation of epidermal growth factor receptor (EGFR) is an important intracellular signal that occurs during tumor progression, relating to the previous biological functions such as angiogenesis and the lipid metabolism in tumor, we focused on this signal pathway
Summary
Ovarian cancer (OC) is one of the most common gynecological malignant tumors with high mortality, seriously affecting women’s health worldwide (Chen et al, 2016). The research accumulation of immune regulation of solid tumor tissues made the immunotherapy as a promising alternative (Gralewska et al, 2020) recently, the clinical strategy for OC is still cytoreductive surgery combined with platinum-based chemotherapy (Coleman et al, 2013; Syrios et al, 2014) due to the curative uncertainty and high cost. There is an alarming increase in the incidence of resistance to chemotherapy drugs, with only 75% of the patients being responsive to the first-line chemotherapy regimen, and most patients gradually develop secondary platinum resistance (Chi et al, 2009; Santiago-O’farrill et al, 2020), leading to a five-year survival rate of less than 45% (Openshaw et al, 2015; Webb and Jordan, 2017). The tumor immune microenvironment (TIME) has been proven to mediate tolerance to chemotherapeutic drugs and reflect the response rate to immunotherapy (Aggarwal et al, 2009; Van Zyl et al, 2018). It is urgent to clarify the mechanism of immune components responsible for OC progression, and search novel and effective biomarkers to predict response to chemotherapeutics and develop new therapeutic strategies
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