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2604.Full-Text.Pdf Published OnlineFirst February 26, 2019; DOI: 10.1158/0008-5472.CAN-18-3842 Cancer Molecular Cell Biology Research Retinoic Acid–Related Orphan Receptor C Regulates Proliferation, Glycolysis, and Chemoresistance via the PD-L1/ITGB6/STAT3 Signaling Axis in Bladder Cancer Dalong Cao1,2,3, Zihao Qi4, Yangyang Pang5, Haoran Li2,3,6, Huyang Xie7, Junlong Wu1,3, Yongqiang Huang1,3, Yao Zhu1,3, Yijun Shen1,3, Yiping Zhu1,3, Bo Dai1,3, Xin Hu2, Dingwei Ye1,2,3, and Ziliang Wang2,8 Abstract Retinoic acid–related orphan receptor C (RORC) is a of the PD-L1/ITGB6 signaling pathway, which further inhib- member of the nuclear orphan receptor family and performs ited bladder cell proliferation and glucose metabolism and critical regulatory functions in cell proliferation, metastasis, increased cisplatin-induced apoptosis. These findings reveal and chemoresistance in various types of malignant tumors. that RORC regulates bladder cancer cell proliferation, glu- Here we showed that expression of RORC is lost in tumor cose metabolism, and chemoresistance by participating in tissues of bladder cancer patients. Enhanced expression of the PD-L1/ITGB6/STAT3 signaling axis. Moreover, this new RORC suppressed cell proliferation and glucose metabolism understanding of PD-L1 signaling may guide the selection of and increased cisplatin-induced apoptosis in vitro and in vivo. therapeutic targets to prevent tumor recurrence. RORC bound the promoter region of programmed death ligand-1 (PD-L1) and negatively regulated PD-L1 expression. Significance: These findings suggest that RORC-mediated PD-L1 directly interacted with integrin b6 (ITGB6) and regulation of a PD-L1/ITGB6/FAK/STAT3 signaling axis in activated the ITGB6/FAK signaling pathway. RORC pre- bladder cancer provides several potential therapeutic targets vented the nuclear translocation of STAT3 via suppression to prevent tumor progression. Introduction cancers and accounted for nearly 80.5 per 100,000 new cases and 32.9 per 100,000 deaths in 2015 (1, 2). Approximately Bladder cancer is one of the most common malignancies 70% of bladder cancer cases are non–muscle-invasive bladder worldwide and is also the most common cancer of the geni- cancer, treated by transurethral resection of bladder tumor and tourinary system in China, which ranked the eighth among all followedbyintravesicaltreatment.However,uptotwothirds of patients will relapse or progress to muscle-invasive bladder 1Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, cancer (MIBC; ref. 3). For MIBC, radical cystectomy is often China. 2Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, performed, followed by chemotherapy and radiotherapy, but China. 3Department of Oncology, Shanghai Medical College, Fudan University, only 50% of patients will survive for 5 years (3, 4). Thus, there 4 Shanghai, China. Huadong Hospital Affiliated to Fudan University, Shanghai, is still a need for finding new methods for the treatment of 5 fi China. Department of Urology, Jiading District Central Hospital Af liated bladder cancer. Shanghai University of Medicine and Health Sciences, Shanghai, China. 6Depart- ment of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Nuclear receptors (NR) are a class of ligand-based transcription Shanghai, China. 7Department of Urology, Affiliated Hospital of Nantong Uni- factors that are widely distributed in organisms. There are various versity, Nantong, China. 8Department of Obstetrics and Gynecology, Xinhua members of NRs, which constitute a large family and can be Hospital Affiliated to Shanghai Jiaotong University School Medicine, Shanghai, divided into three categories: steroid hormone receptors, nonste- China. roid hormone receptors, and nuclear orphan receptors. NRs, Note: Supplementary data for this article are available at Cancer Research served as molecular switches, play key roles in diverse cellular Online (http://cancerres.aacrjournals.org/). processes, including cell proliferation, differentiation, and D.L. Cao, Z.H. Qi, Y.Y. Pang, and H.R. Li contributed equally to this article. homeostasis (5). NRs are involved in a multitude of pathologic Corresponding Authors: Ziliang Wang, Xinhua Hospital Affiliated to Shanghai processes, including carcinogenesis, and hence are supposed as Jiaotong University School Medicine, 1665 Kongjiang Road, Shanghai 200092, novel therapeutic targets (6, 7). Nuclear orphan receptors referred China. Phone: 86-21-34777310; E-mail: [email protected] or to those molecules that sequence similar to known receptors [email protected]; and Dingwei Ye, Department of Urology, Fudan Univer- without an identified natural ligand. sity Shanghai Cancer Center, Department of Oncology, Shanghai Medical Receptor retinoic acid–related orphan receptor C (RORC, also College, Fudan University, 270 Dong'an Road, Shanghai 200032, China. E-mail: named RORg) is one of the family members of the nuclear orphan [email protected] receptors and functions as a DNA-binding transcription factor (8). doi: 10.1158/0008-5472.CAN-18-3842 Recently, the regulatory role of RORC in tumorigenesis has been Ó2019 American Association for Cancer Research. established. In breast cancer, RORC expression is decreased in 2604 Cancer Res; 79(10) May 15, 2019 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst February 26, 2019; DOI: 10.1158/0008-5472.CAN-18-3842 The RORC/PD-L1/ITGB6/STAT3 Signaling Axis in Bladder Cancer aggressive basal-like breast cancer and negatively associated with streptomycin (Biowest) and incubated at 37C in a humidified histologic grade in several human cohorts (9). In melanoma, the incubator with 5% CO2. expression of RORC was lower in melanomas than in nevi and decreased during tumor progression, with lowest levels found in Whole-body 18F-FDG positron emission tomography/ primary melanomas at stages III and IV and in melanoma metas- computed tomography tases (10). RORC-deficient mice are relatively healthy and fertile. Briefly, 18F-FDG was automatically made by a cyclotron However, the expression and function of RORC in human bladder (Siemens CTI RDS Eclipse ST) using an Explora FDG4 module. cancer cells remain largely unexplored. Patients had been fasting for more than 6 hours. Scanning started In this study, we identified that the expression of RORC was 1 hour after intravenous injection of the tracer (7.4 MBq/kg). The downregulated in tumors from bladder cancer patients, with images were acquired on a Siemens biograph 16HR positron significantly lower levels found in bladder cancer patients with emission tomography/computed tomography (PET/CT) scanner advanced tumor stage and resistant to chemotherapy. RORC with a transaxial intrinsic spatial resolution of 4.1 mm. CT scanning functions as a key determinant of programmed death ligand-1 was first initiated from the proximal thighs to the head, with (PD-L1) overexpression and aberrant signaling in bladder cancer 120 kV, 80–250 mA, pitch 3.6, and rotation time of 0.5 seconds. cells. Furthermore, RORC was determined to regulate cell prolif- Image interpretation was carried out on a multimodality computer eration, glucose metabolism, and chemoresistance via suppres- platform (Syngo; Siemens). Quantification of metabolic activity sing the PD-L1/ITGB6/STAT3 signaling axis in bladder cancer. was acquired using the standard uptake value (SUV) normalized Thus, our findings establish RORC as a previously unsuspected to body weight, and the SUVmax for each lesion was calculated. key player and a novel therapeutic target for bladder cancer. Plasmid construction and viral infection Materials and Methods The recombinant plasmid pENTER-RORC containing human full cDNA sequence of RORC was purchased from Vigene Bios- Patients and tissue samples ciences. Then the cDNA sequence of RORC was subcloned into Tissue microarrays were fabricated using formalin-fixed lentivirus vector. Lentivirus was produced by cotransfecting 293T paraffin-embedded tissues of carcinoma (n ¼ 155) and para- cells with pRSV-Rev, pMD2.G, pMDLg/pRRE, and pCDH-puro carcinoma (n ¼ 115) from patients with bladder urothelial cancer, expression vectors. The virus was harvested after 48 hours by who underwent radical cystectomy at the Fudan University filtering the virus-containing medium through 0.45-mm Steriflip Shanghai Cancer Center (FUSCC) from 2008 to 2012. Clinical filter (Millipore). Human bladder cancer cell lines 5637 and UC3 and pathologic characteristics for all participants included in this were infected by incubating cells with medium containing indi- study were collected from the patients' electronic database at cated virus and 1 ng/mL polybrene (Sigma) for 24 hours. Estab- FUSCC and then evaluated (Supplementary Table S1). Briefly, lished stable cell lines expressing RORC were constructed as the median age of the patients was 62 years (range, 33–83 years). A above. By following the same protocol, control cell lines were total of 86 (55.5%) patients were diagnosed with stage I–II while generated using infection with viruses containing the empty 69 (44.5%) patients with stage III–IV, and 11 (7.1%) patients vector. In addition, the human full cDNA sequence of PD-L1 was possessed with low-grade urothelial cancer while 144 (92.9%) purchased from Vigene Biosciences. patients with high-grade urothelial cancer. For chemotherapeutic Promoter sequences of PD-L1 (À3000–0 bp) were cloned from response, 35 (67.3%) patients were resistant to platinum-based genomic DNA prepared from
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