Identification of a cisplatin resistant-based prognostic immune related gene signature in MIBC

Yunfei Wu; Zhijie Xu; Guanghou Fu; Xiaoyi Chen; Junjie Tian; Hairong Cai; Peng Jiang; Baiye Jin

Translational Oncology (Jun 2024)

Identification of a cisplatin resistant-based prognostic immune related gene signature in MIBC

Yunfei Wu,
Zhijie Xu,
Guanghou Fu,
Xiaoyi Chen,
Junjie Tian,
Hairong Cai,
Peng Jiang,
Baiye Jin

Affiliations

Yunfei Wu: Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China; Zhejiang Engineering Research Center for Urinary Bladder Carcinoma Innovation Diagnosis and Treatment, Hangzhou, 310024, China
Zhijie Xu: Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China; Zhejiang Engineering Research Center for Urinary Bladder Carcinoma Innovation Diagnosis and Treatment, Hangzhou, 310024, China
Guanghou Fu: Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China; Zhejiang Engineering Research Center for Urinary Bladder Carcinoma Innovation Diagnosis and Treatment, Hangzhou, 310024, China
Xiaoyi Chen: Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China; Zhejiang Engineering Research Center for Urinary Bladder Carcinoma Innovation Diagnosis and Treatment, Hangzhou, 310024, China
Junjie Tian: Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China; Zhejiang Engineering Research Center for Urinary Bladder Carcinoma Innovation Diagnosis and Treatment, Hangzhou, 310024, China
Hairong Cai: Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China; Zhejiang Engineering Research Center for Urinary Bladder Carcinoma Innovation Diagnosis and Treatment, Hangzhou, 310024, China
Peng Jiang: Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China; Zhejiang Engineering Research Center for Urinary Bladder Carcinoma Innovation Diagnosis and Treatment, Hangzhou, 310024, China; Corresponding authors.
Baiye Jin: Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China; Zhejiang Engineering Research Center for Urinary Bladder Carcinoma Innovation Diagnosis and Treatment, Hangzhou, 310024, China; Corresponding authors.

Journal volume & issue: Vol. 44
p. 101942

Abstract

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Cisplatin resistance plays a significant role in the dismal prognosis and progression of muscle-invasive bladder cancer (MIBC). However, the strategies to predict prognosis and cisplatin resistance are inefficient, and it remains unclear whether cisplatin resistance is associated with tumor immunity. In this study, we integrated the transcriptional data from cisplatin-resistant cell lines and a TCGA-MIBC cohort to establish cisplatin-resistance-related cluster classification and a cisplatin-resistance-related gene risk score (CRRGRS). Kaplan–Meier survival curves showed that compared with those in low CRRGRS group, MIBC patients belonging to high CRRGRS group had worse prognosis in TCGA-MIBC cohort and external GEO cohorts. Meanwhile, CRRGRS was able to help forecast chemotherapy and immunotherapy response of MIBC patients in the TGCA cohort and IMvigor210 cohort. Moreover, compared with the low CRRGRS group, the high CRRGS group possessed a relatively immunosuppressive “cold tumor” phenotype with a higher tumor immune dysfunction and exclusion (TIDE) score, ESTIMATE score, stromal score and immune score and a lower immunophenoscore (IPS) score. The upregulated expression levels of immune checkpoint genes, including PD-1, PD-L1 and CTLA4, in the high CRRGRS group also further indicated that a relative immunosuppressive tumor microenvironment may exist in MIBC patients belonging to high CRRGRS group. In addition, we integrated CRRGRS and clinical characteristics with prognostic value to develop a nomogram, which could help forecast overall survival of MIBC patients. Furthermore, DIAPH3 was identified as a regulator of proliferation and cisplatin resistance in MIBC. The expression of DIAPH3 was increased in cisplatin-resistant cell lines and chemotherapy-unsensitive people. Further mechanism exploration revealed that DIAPH3 facilitated tumor proliferation and cisplatin resistance by regulating the NF-kB and epithelial-mesenchymal transition (EMT) pathways. In conclusion, the comprehensive investigations of CRRGRS increased the understanding of cisplatin resistance and provided promising insights to restrain tumor growth and overcome chemoresistance by targeting DIAPH3.

Published in Translational Oncology

ISSN: 1944-7124 (Print); 1936-5233 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.journals.elsevier.com/translational-oncology/

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