Cytoskeleton regulator RNA expression on cancer-associated fibroblasts is associated with prognosis and immunotherapy response in bladder cancer

Yucai Wu; Yangyang Xu; Shiming He; Yifan Li; Ninghan Feng; Jian Fan; Yanqing Gong; Xuesong Li; Liqun Zhou

doi:10.1016/j.heliyon.2023.e13707

Cytoskeleton regulator RNA expression on cancer-associated fibroblasts is associated with prognosis and immunotherapy response in bladder cancer

Heliyon. 2023 Feb 13;9(3):e13707. doi: 10.1016/j.heliyon.2023.e13707. eCollection 2023 Mar.

Authors

Yucai Wu^{1

2

3

4}, Yangyang Xu^{1

2

3

4}, Shiming He^{1

2

3

4}, Yifan Li⁵, Ninghan Feng⁶, Jian Fan^{1

2

3

4}, Yanqing Gong^{1

2

3

4}, Xuesong Li^{1

2

3

4}, Liqun Zhou^{1

2

3

4}

Affiliations

¹ Department of Urology, Peking University First Hospital, Beijing, China.
² Institute of Urology, Peking University, Beijing, China.
³ National Urological Cancer Center, Beijing, China.
⁴ Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Peking University, Beijing, China.
⁵ Department of Urology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Jiangsu, China.
⁶ Wuxi No 2 People's Hospital, Jiangsu, China.

Abstract

Background: Dysregulation of long noncoding RNAs (lncRNAs) has been reported to be associated with multiple tumors where they act as tumor suppressors or accelerators. The lncRNA CYTOR was identified as an oncogene involved in many cancers, such as gastric cancer, colorectal cancer, hepatocellular carcinoma, and renal cell carcinoma. However, the role of CYTOR in bladder cancer (BCa) has rarely been reported.

Methods: Using cancer datasets from The Cancer Genome Atlas (TCGA) program, we analyzed the association between CYTOR expression and prognostic value, oncogenic pathways, antitumor immunity and immunotherapy response in BCa. The influence of CYTOR on the immune infiltration pattern in the urothelial carcinoma microenvironment was further verified in our dataset. Single-cell analysis revealed the role of CYTOR in the tumor microenvironment (TME) of BCa. Finally, we evaluated the expression of CYTOR in BCa in the Peking University First Hospital (PKU-BCa) dataset and its correlation with the malignant phenotype of BCa in vitro and in vivo.

Results: The results indicated that CYTOR was highly expressed in multiple cancer samples, including BCa, and increased CYTOR expression contributed to poor overall survival (OS). Additionally, elevated CYTOR expression was significantly correlated with clinicopathological features of BCa, such as female sex, advanced TNM stage, high histological grade and non-papillary subtype. Functional characterization revealed that CYTOR may be involved in immune-related pathways and the epithelial mesenchymal transformation (EMT) process. Moreover, CYTOR had a significant association with infiltrating immune cells, including M2 macrophages and regulatory T cells (Tregs). CYTOR facilitates the crosstalk between cancer-associated fibroblasts (CAFs) and macrophages, and mediates M2 polarization of macrophages. Correlation analysis revealed a positive correlation between CYTOR expression and programmed cell death-1 (PD-1)/programmed death ligand 1 (PD-L1)/expression and other targets for specific immunotherapy in BCa, which are recognized to predict the efficacy of immunotherapy.

Conclusions: These results suggest that CYTOR serves as a potential biomarker for predicting survival outcome, TME cell infiltration characteristics and immunotherapy response in BCa.

Keywords: BCa, Bladder cancer; Bladder cancer; CAFs, Cancer-associated fibroblasts; CIBERSOFT, Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts; CYTOR; CYTOR, Cytoskeleton regulator RNA; EMT, Epithelial mesenchymal transformation; Immune infiltration; Immunotherapy; LncRNAs, Long non-coding RNAs; MIBC, Muscle-invasive bladder cancer; OS, Overall survival; PCA, Principal component analysis; PD-1, Programmed cell death-1; PD-L1, Programmed death ligand 1; RT-qPCR, Reverse transcription-quantitative polymerase chain reaction; Survival; TCGA, The Cancer Genome Atlas; TME, Tumor microenvironment; UMI, Unique molecular identifier; UTUC, Upper-tract urothelial carcinoma.