The driver role of JAK‐STAT signalling in cancer stemness capabilities leading to new therapeutic strategies for therapy‐ and castration‐resistant prostate cancer

U‐Ging Lo; Yaojing Chen; Junjie Cen; Su Deng; Junghang Luo; Haiyen Zhau; Lin Ho; Chih-Ho Lai; Ping Mu; Leland W.K. Chung; Jer‐Tsong Hsieh

doi:10.1002/ctm2.978

journal article Open Access Jul 31, 2022

The driver role of JAK‐STAT signalling in cancer stemness capabilities leading to new therapeutic strategies for therapy‐ and castration‐resistant prostate cancer

U‐Ging Lo Yaojing Chen Junjie Cen Su Deng

Junghang Luo Haiyen Zhau Lin Ho Chih-Ho Lai

Ping Mu

Leland W.K. Chung Jer‐Tsong Hsieh

Clinical and Translational Medicine Vol. 12 No. 8 · Wiley

View at Publisher Save 10.1002/ctm2.978

Abstract

AbstractBackgroundLineage plasticity in prostate cancer (PCa) has emerged as an important mechanism leading to the onset of therapy‐ and castration‐resistant PCa (t‐CRPC), which is closely associated with cancer stem cell (CSC) activity. This study is to identify critical driver(s) with mechanism of action and explore new targeting strategy.MethodsVarious PCa cell lines with different genetic manipulations were subjected to in vitro prostasphere assay, cell viability assay and in vivo stemness potential. In addition, bioinformatic analyses such as Ingenuity pathway and Gene Set Enrichment Analysis were carried out to determine clinical relevance. The in vivo anti‐tumour activity of JAK or STAT1 inhibitors was examined in clinically relevant t‐CRPC model.ResultsWe demonstrated the role of interferon‐related signalling pathway in promoting PCa stemness, which correlated with significant elevation of interferon related DNA damage resistance signature genes in metastatic PCa. Inhibition of JAK‐STAT1 signalling suppresses the in vitro and in vivo CSC capabilities. Mechanistically, IFIT5, a unique downstream effector of JAK‐STAT1 pathway, can facilitate the acquisition of stemness properties in PCa by accelerating the turnover of specific microRNAs (such as miR‐128 and ‐101) that can target several CSC genes (such as BMI1, NANOG, and SOX2). Consistently, knocking down IFIT5 in t‐CRPC cell can significantly reduce in vitro prostasphere formation as well as decrease in vivo tumour initiating capability.ConclusionsThis study provides a critical role of STAT1‐IFIT5 in the acquisition of PCSC and highlights clinical translation of JAK or STAT1 inhibitors to prevent the outgrowth of t‐CRPC.

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Details

Published: Jul 31, 2022
Vol/Issue: 12(8)
License: View

Authors

U

U‐Ging Lo

Department of Urology University of Texas Southwestern Medical Center Dallas Texas USA

Y

Yaojing Chen

Department of Urology University of Texas Southwestern Medical Center Dallas Texas USA; Department of Microbiology and Immunology Graduate Institute of Biomedical Sciences College of Medicine Chang Gung University Taoyuan Taiwan

J

Junjie Cen

Department of Urology First Affiliated Hospital Sun Yat‐sen University Guangdong China

S

Su Deng

Department of Molecular Biology University of Texas Southwestern Medical Center Dallas Texas USA

J

Junghang Luo

Department of Urology First Affiliated Hospital Sun Yat‐sen University Guangdong China

H

Haiyen Zhau

Uro‐Oncology Research Department of Medicine Cedars‐Sinai Medical Center Los Angeles California USA

L

Lin Ho

Department of Life Sciences National Chung Hsing University Taichung Taiwan

C

Chih-Ho Lai

Department of Microbiology and Immunology Graduate Institute of Biomedical Sciences College of Medicine Chang Gung University Taoyuan Taiwan

P

Ping Mu

Department of Molecular Biology University of Texas Southwestern Medical Center Dallas Texas USA

L

Leland W.K. Chung

Uro‐Oncology Research Department of Medicine Cedars‐Sinai Medical Center Los Angeles California USA

J

Jer‐Tsong Hsieh

Department of Urology University of Texas Southwestern Medical Center Dallas Texas USA

Cite This Article

U‐Ging Lo, Yaojing Chen, Junjie Cen, et al. (2022). The driver role of JAK‐STAT signalling in cancer stemness capabilities leading to new therapeutic strategies for therapy‐ and castration‐resistant prostate cancer. Clinical and Translational Medicine, 12(8). https://doi.org/10.1002/ctm2.978

The driver role of JAK‐STAT signalling in cancer stemness capabilities leading to new therapeutic strategies for therapy‐ and castration‐resistant prostate cancer

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