Identification and validation of a novel necroptosis-related prognostic signature in cervical squamous cell carcinoma and endocervical adenocarcinoma

Weiyu Zhang; Wujun Cao; Zhuting Tong; Qinqin Jin; Xiya Jiang; Yinting Yang; Hui Yao; Guo Chen; Wei Gao; Yuting Zhu; Shuguang Zhou

doi:10.3389/fonc.2022.1011000

Identification and validation of a novel necroptosis-related prognostic signature in cervical squamous cell carcinoma and endocervical adenocarcinoma

Front Oncol. 2022 Sep 16:12:1011000. doi: 10.3389/fonc.2022.1011000. eCollection 2022.

Authors

Weiyu Zhang^{1

2}, Wujun Cao³, Zhuting Tong⁴, Qinqin Jin^{1

2}, Xiya Jiang^{1

2}, Yinting Yang^{1

2}, Hui Yao^{1

2}, Guo Chen^{1

2}, Wei Gao^{1

2}, Yuting Zhu^{1

2}, Shuguang Zhou^{1

2}

Affiliations

¹ Department of Gynecology, Anhui Medical University Affiliated Maternity and Child Healthcare Hospital, Hefei, China.
² Department of Gynecology, Anhui Province Maternity and Child Healthcare Hospital, Hefei, China.
³ Department of Clinical Laboratory, Anhui Province Maternity and Child Healthcare Hospital, Hefei, China.
⁴ Department of Radiation Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.

Abstract

Background: The purpose of this study was to investigate the prognostic signature of necroptosis-related lncRNAs (NRLs) and explore their association with immune-related functions and sensitivity of the therapeutic drug in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC).

Methods: UCSC Xena provided lncRNA sequencing and clinical data about CESC, and a necroptosis gene list was obtained from the KEGG database. NRLs were selected by structuring a co-expression network of lncRNAs and necroptosis-related genes. To further screen lncRNAs, we used the univariate Cox regression method, Lasso regression, and multivariate Cox regression. Afterward, an NRL signature was established. We used the xCell algorithm and single-sample gene set enrichment analysis (ssGSEA) to clarify the pertinence between immune infiltration and NRL expressions in CESC patients and explored the relationship between the target lncRNAs and immune-related genes. By leveraging the GDSC database, the therapy-sensitive response of the prognostic signature was forecasted and an experimental validation was performed. We performed GSEA with the aim of recognizing the potential pathway related to the individual prognostic signature.

Results: The two prognostic NRLs (AC009095.1 and AC005332.4) showed significant diversity and constituted the NRL signature. On the grounds of our signature, risk score was an independent element which was bound up with patient outcome (HR = 4.97 CI: 1.87-13.2, P = 0.001). The CESC patients were classified by the median risk score. Immune infiltration analysis revealed significant increases in CD4 + Tcm, eosinophils, epithelial cells, fibroblasts, NKT, plasma cells, platelets, and smooth muscle in the high-risk group (P< 0.05). Target lncRNAs also showed some correlation with NRGs. The estimated IC50 values of bicalutamide, CHIR.99021, and imatinib were lower in the high-risk group. Through the subsequent experimental validation, both AC009095.1 and AC005332.4 were significantly more highly expressed in SiHa than in Hela. AC009095.1 was expressed more highly in SiHa than in HUCEC, but the expression of AC005332.4 was reversed.

Conclusions: This study elucidated that NRLs, as a novel signature, were indispensable factors which can significantly influence the prognosis of patients with CESC and could provide novel clinical evidence to serve as a potential molecular biomarker for future therapeutic targets.

Keywords: cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC); immune; long noncoding RNA (lncRNA); necroptosis-related lncRNAs (NRLs); prognostic signature; therapeutic agents.