Comprehensive analyses identify RIPOR2 as a genomic instability-associated immune prognostic biomarker in cervical cancer

Abstract

Cervical cancer (CC) is a malignancy that tends to have a poor prognosis when detected at an advanced stage; however, there are few studies on the early detection of CC at the genetic level. The tumor microenvironment (TME) and genomic instability (GI) greatly affect the survival of tumor patients via effects on carcinogenesis, tumor growth, and resistance. It is necessary to identify biomarkers simultaneously correlated with components of the TME and with GI, as these could predict the survival of patients and the efficacy of immunotherapy. In this study, we extracted somatic mutational data and transcriptome information of CC cases from The Cancer Genome Atlas, and the GSE44001 dataset from the Gene Expression Omnibus database was downloaded for external verification. Stromal components differed most between genomic unstable and genomic stable groups. Differentially expressed genes were screened out on the basis of GI and StromalScore, using somatic mutation information and ESTIMATE methods. We obtained the intersection of GI- and StromalScore-related genes and used them to establish a four-gene signature comprising RIPOR2, CCL22, PAMR1, and FBN1 for prognostic prediction. We described immunogenomic characteristics using this risk model, with methods including CIBERSORT, gene set enrichment analysis (GSEA), and single-sample GSEA. We further explored the protective factor RIPOR2, which has a close relationship with ImmuneScore. A series of in vitro experiments, including immunohistochemistry, immunofluorescence, quantitative reverse transcription PCR, transwell assay, CCK8 assay, EdU assay, cell cycle detection, colony formation assay, and Western blotting were performed to validate RIPOR2 as an anti-tumor signature. Combined with integrative bioinformatic analyses, these experiments showed a strong relationship between RIPOR2 with tumor mutation burden, expression of genes related to DNA damage response (especially PARP1), TME-related scores, activation of immune checkpoint activation, and efficacy of immunotherapy. To summarize, RIPOR2 was successfully identified through comprehensive analyses of the TME and GI as a potential biomarker for forecasting the prognosis and immunotherapy response, which could guide clinical strategies for the treatment of CC patients.

RIPOR2 Expression Decreased by HPV-16 E6 and E7 Oncoproteins: An Opportunity in the Search for Prognostic Biomarkers in Cervical Cancer

“…In agreement, a recent study identified a four gene antitumor signature related to the tumor microenvironment, which included RIPOR2, CCL22, PAMR1, and FBN1 genes [ 54 ]. Authors found that tumors with high expression of RIPOR2, had a lower mutation burden, and higher levels of CD8 + T cells.…”

Transcriptome Analysis Reveals the Age-Related Developmental Dynamics Pattern of the Longissimus Dorsi Muscle in Ningxiang Pigs

“…It was shown that RIPOR2 (Rho family-interacting cell polarization regulator 2) exerts inhibitory effects on RHO activity and cellular functions affected by RHO, mainly related to RHO signaling and skeletal muscle cell migration, associated with growth and differentiation [28]. Another impressive finding [29] was the intrinsic relationship between RIPOR2 and T cells, with significantly higher levels of CD 8+ T cells with high RIPOR2 expression. Meanwhile, RIPOR2 has RHOA-dependent effects on various T cell activities, including T cell polarization, adhesion, and migration.…”

A panel of seven immune-related genes can serve as a good predictive biomarker for cervical squamous cell carcinoma

“…As for TME and genomic instability can greatly affect patients’ prognosis by causing cancer, promoting tumor growth and increasing drug resistance, some hold the view that it is necessary to identify biomarkers which correlate with both TME and genomic instability to predict and evaluate patients’ survival and response to immunotherapy. Combined with comprehensive bioinformatics analysis, RIPOR2 was found to be closely related to tumor mutation burden (TMB), gene expression associated with DNA damage response (such as PARP1), TME-related scores, immune checkpoint activation, and immunotherapy efficacy ( Xu F. et al, 2022 ). Lymph node metastasis of cervical cancer has always been a major obstacle in treatment.…”