Retinoic Acid-Related Orphan Receptor C Regulates Proliferation, Glycolysis, and Chemoresistance via the PD-L1/ITGB6/STAT3 Signaling Axis in Bladder Cancer.

Dalong Cao,Huyang Xie,Yao Zhu,Ziliang Wang,Dingwei Ye,Yiping Zhu,Zihao Qi,Xin Hu,Haoran Li,Junlong Wu,Yijun Shen,Bo Dai,Yangyang Pang,Yongqiang Huang

doi:10.1158/0008-5472.can-18-3842

Abstract

Retinoic acid-related orphan receptor C (RORC) is a member of the nuclear orphan receptor family and performs critical regulatory functions in cell proliferation, metastasis, and chemoresistance in various types of malignant tumors. Here we showed that expression of RORC is lost in tumor tissues of bladder cancer patients. Enhanced expression of RORC suppressed cell proliferation and glucose metabolism and increased cisplatin-induced apoptosis in vitro and in vivo. RORC bound the promoter region of programmed death ligand-1 (PD-L1) and negatively regulated PD-L1 expression. PD-L1 directly interacted with integrin β6 (ITGB6) and activated the ITGB6/FAK signaling pathway. RORC prevented the nuclear translocation of STAT3 via suppression of the PD-L1/ITGB6 signaling pathway, which further inhibited bladder cell proliferation and glucose metabolism and increased cisplatin-induced apoptosis. These findings reveal that RORC regulates bladder cancer cell proliferation, glucose metabolism, and chemoresistance by participating in the PD-L1/ITGB6/STAT3 signaling axis. Moreover, this new understanding of PD-L1 signaling may guide the selection of therapeutic targets to prevent tumor recurrence. SIGNIFICANCE: These findings suggest that RORC-mediated regulation of a PD-L1/ITGB6/FAK/STAT3 signaling axis in bladder cancer provides several potential therapeutic targets to prevent tumor progression.

Highlights

Bladder cancer is one of the most common malignancies worldwide and is the most common cancer of the genitourinary system in China, which ranked the eighth among allNote: Supplementary data for this article are available at Cancer Research Online.D.L
receptor C (RORC) is downregulated in bladder urothelial cancer patients To evaluate whether RORC expression was associated with clinicopathologic features of bladder cancer patients, we first www.aacrjournals.org performed immunostaining with antibodies against RORC in tissue microarrays from 155 bladder cancer patients (FUSCC cohort) and found that RORC immunostaining was highly expressed in 51% (n 1⁄4 79) of patients and underexpressed in the other 49% (n 1⁄4 76) of patients (Fig. 1A and B)
standard uptake value (SUV) were obtained from the positron emission tomography/computed tomography (PET/CT) scan data from 29 bladder urothelial carcinoma patients to evaluate the association of SUV values with RORC expression in bladder cancer tissues

Summary

Introduction

Bladder cancer is one of the most common malignancies worldwide and is the most common cancer of the genitourinary system in China, which ranked the eighth among all. The RORC/PD-L1/ITGB6/STAT3 Signaling Axis in Bladder Cancer aggressive basal-like breast cancer and negatively associated with histologic grade in several human cohorts [9]. The expression and function of RORC in human bladder cancer cells remain largely unexplored. We identified that the expression of RORC was downregulated in tumors from bladder cancer patients, with significantly lower levels found in bladder cancer patients with advanced tumor stage and resistant to chemotherapy. RORC functions as a key determinant of programmed death ligand-1 (PD-L1) overexpression and aberrant signaling in bladder cancer cells. RORC was determined to regulate cell proliferation, glucose metabolism, and chemoresistance via suppressing the PD-L1/ITGB6/STAT3 signaling axis in bladder cancer. Our findings establish RORC as a previously unsuspected key player and a novel therapeutic target for bladder cancer

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Discussion