2. Academic Validation
  3. Targeting the androgen receptor to enhance NK cell killing efficacy in bladder cancer by modulating ADAR2/circ_0001005/PD-L1 signaling

Targeting the androgen receptor to enhance NK cell killing efficacy in bladder cancer by modulating ADAR2/circ_0001005/PD-L1 signaling

  • Cancer Gene Ther. 2022 Aug 1. doi: 10.1038/s41417-022-00506-w.
Qing Liu  # 1 2,  Bosen You  # 1 2,  Jialin Meng  # 2,  Chi-Ping Huang  # 3,  Guanglu Dong 1,  Ronghao Wang 2,  Fuju Chou 2,  Shan Gao 1,  Chawnshang Chang 2 3,  Shuyuan Yeh 4,  Wanhai Xu 5
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Urology, and Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
  • 2 Departments of Urology, Pathology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA.
  • 3 Department of Urology, China Medical University/Hospital, Taichung, 404, Taiwan.
  • 4 Departments of Urology, Pathology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA. shuyuan_yeh@urmc.rochester.edu.
  • 5 Department of Urology, The 4th Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. xuwanhai@163.com.
  • # Contributed equally.
PMID: 35915245 DOI: 10.1038/s41417-022-00506-w
Abstract

Although Androgen Receptor (AR) can influence bladder Cancer (BCa) initiation and progression, its impact on tumor immune escape remains unclear. Here, we found that targeting AR could enhance natural killer (NK) cell tumor-killing efficacy by decreasing PD-L1 expression. Both antiandrogen treatment and AR knockdown effectively reduced membrane PD-LI expression to facilitate NK cell-mediated BCa cell killing by downregulating circ_0001005. Mechanistically, AR upregulated circRNA circ_0001005 expression via the RNA-editing gene ADAR2. circ_0001005 competitively sponged the miRNA miR-200a-3p to promote PD-L1 expression. A preclinical BCa xenograft mouse model further confirmed this newly identified signaling using the small molecule circ_0001005-shRNA to improve NK cell killing of BCa tumor cells. Collectively, these results suggest that targeting the newly identified ADAR2/circ_0001005/miR-200a-3p/PD-L1 pathway to impact antitumor immunity may suppress progression and boost immunotherapeutic efficacy in BCa.

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