Identification of a novel 5-methylcytosine-related signature for prognostic prediction of kidney renal papillary cell carcinoma and a Putative target for drug repurposing

Zhen Zhang; Chunhua Cao; Chun-Li Zhou; Xilong Li; Changhong Miao; Li Shen; Rajeev K Singla; Xihua Lu

doi:10.1016/j.tranon.2023.101741

Identification of a novel 5-methylcytosine-related signature for prognostic prediction of kidney renal papillary cell carcinoma and a Putative target for drug repurposing

Transl Oncol. 2023 Oct:36:101741. doi: 10.1016/j.tranon.2023.101741. Epub 2023 Jul 29.

Authors

Zhen Zhang¹, Chunhua Cao², Chun-Li Zhou³, Xilong Li⁴, Changhong Miao⁵, Li Shen⁶, Rajeev K Singla⁷, Xihua Lu⁸

Affiliations

¹ Department of Anesthesiology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China. Electronic address: zlyyzhangzhen2130@zzu.edu.cn.
² Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang 441021, China; Institute of Oncology, Hubei University of Arts and Science, Xiangyang 441021, China.
³ Department of Anesthesiology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang 441021, China.
⁴ Department of Anesthesiology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.
⁵ Department of Anesthesiology, Cancer Hospital of Fudan University, Shanghai 200032, China.
⁶ Department of Biomedical Engineering, Hong Kong Polytechnic University, Hong Kong SAR, China.
⁷ Joint Laboratory of Artificial Intelligence for Critical Care Medicine, Department of Critical Care Medicine and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China; School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab-144411, India. Electronic address: rajeevsingla26@gmail.com.
⁸ Department of Anesthesiology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China. Electronic address: zlyyluxihua0258@zzu.edu.cn.

Abstract

Background: Many studies have demonstrated the crucial roles of 5-methylcytosine (m5C) RNA methylation in cancer pathogenesis.

Methods: Two datasets, including TCGA-KIRP and ICGC, and related clinical information were downloaded, where the expression of 13 m5C regulators was examined. We applied LASSO regression to construct a multi-m5C-regulator-based signature in the TCGA cohort, which was further validated using the ICGC cohort. Univariate and multivariate Cox regressions were applied to evaluate the independent prognostic value of our model. The differences in biological functions and immune characterizations between high and low-risk groups divided based on the risk scores were also investigated via multiple approaches, such as enrichment analyses, mutation mining, and immune scoring. Finally, the sensitivities of commonly used targeted drugs were tested, and the connectivity MAP (cMAP) was utilized to screen potentially effective molecules for patients in the high-risk group. Experimental validation was done following qPCR tests in Caki-2 and HK-2 cell lines.

Results: 3 m5C regulators, including ALYREF, DNMT3B and YBX1, were involved in our model. Survival analysis revealed a worse prognosis for patients in the high-risk group. Cox regression results indicated our model's superior predictive performance compared to single-factor prognostic evaluation. Functional enrichment analyses indicated a higher mutation frequency and poorer tumor microenvironment of patients in the high-risk group. qPCR-based results revealed that ALYREF, DNMT3B, and YBX1 were significantly up-regulated in Caki-2 cell lines compared with HK-2 cell lines. Molecules like BRD-K72451865, Levosimendan, and BRD-K03515135 were advised by cMAP for patients in the high-risk group.

Conclusion: Our study presented a novel predictive model for KIRP prognosis. Furthermore, the results of our analysis provide new insights for investigating m5C events in KIRP pathogenesis.

Keywords: 5-methylcytosine; Kidney cancer; Kidney renal papillary cell carcinoma; Prognostic signature; Renal cell carcinoma; Tumor microenvironment; Tumor therapy.