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Clin Cancer Res. 2019 Apr 8. doi: 10.1158/1078-0432.CCR-18-3239. [Epub ahead of print]

Leukemia Inhibitory Factor Promotes Castration-resistant Prostate Cancer and Neuroendocrine Differentiation by Activated ZBTB46.

Liu YN#1,2,3, Niu S#4, Chen WY5,6, Zhang Q7, Tao Y8, Chen WH9, Jiang KC9, Chen X8, Shi H10, Liu A10, Li J10, Li Y8, Lee YC11,12, Zhang X13, Huang J14.

Author information

1
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. liuy@tmu.edu.tw xzhang@tjh.tjmu.edu.cn jiaoti.huang@duke.edu.
2
TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
3
Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
4
Department of Urology, State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Chinese PLA Medical Academy, Beijing, China.
5
Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
6
Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
7
Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.
8
Department of Pathology, Duke University Medical Center, Durham, North Carolina.
9
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
10
Department of Pathology, The PLA General Hospital, Beijing, China.
11
PhD Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
12
Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan.
13
Department of Urology, State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Chinese PLA Medical Academy, Beijing, China. liuy@tmu.edu.tw xzhang@tjh.tjmu.edu.cn jiaoti.huang@duke.edu.
14
Department of Pathology, Duke University Medical Center, Durham, North Carolina. liuy@tmu.edu.tw xzhang@tjh.tjmu.edu.cn jiaoti.huang@duke.edu.
#
Contributed equally

Abstract

Purpose: The molecular targets for castration-resistant prostate cancer (CRPC) are unknown because the disease inevitably recurs, and therapeutic approaches for patients with CRPC remain less well understood. We sought to investigate regulatory mechanisms that result in increased therapeutic resistance, which is associated with neuroendocrine differentiation of prostate cancer and linked to dysregulation of the androgen-responsive pathway.Experimental Design: The underlying intracellular mechanism that sustains the oncogenic network involved in neuroendocrine differentiation and therapeutic resistance of prostate cancer was evaluated to investigate and identify effectors. Multiple sets of samples with prostate adenocarcinomas and CRPC were assessed via IHC and other assays.Results: We demonstrated that leukemia inhibitory factor (LIF) was induced by androgen deprivation therapy (ADT) and was upregulated by ZBTB46 in prostate cancer to promote CRPC and neuroendocrine differentiation. LIF was found to be induced in patients with prostate cancer after ADT and was associated with enriched nuclear ZBTB46 staining in high-grade prostate tumors. In prostate cancer cells, high ZBTB46 output was responsible for the activation of LIF-STAT3 signaling and neuroendocrine-like features. The abundance of LIF was mediated by ADT-induced ZBTB46 through a physical interaction with the regulatory sequence of LIF Analysis of serum from patients showed that cases of higher tumor grade and metastatic prostate cancer exhibited higher LIF titers.Conclusions: Our findings suggest that LIF is a potent serum biomarker for diagnosing advanced prostate cancer and that targeting the ZBTB46-LIF axis may therefore inhibit CRPC development and neuroendocrine differentiation after ADT.

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