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

Yen-Nien Liu, Shaoxi Niu, Wei-Yu Chen, Qingfu Zhang, Yulei Tao, Wei-Hao Chen, Kuo-Ching Jiang, Xufeng Chen, Huaiyin Shi, Aijun Liu, Jinhang Li, Yanjing Li, Yi-Chao Lee, Xu Zhang, Jiaoti Huang

研究成果: 雜誌貢獻文章

1 引文 (Scopus)

摘要

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.

指紋

Leukemia Inhibitory Factor
Castration
Prostatic Neoplasms
Androgens
Therapeutics
Prostate
Serum
Statistical Factor Analysis
Neoplasms
Adenocarcinoma
Research Design

引用此文

Leukemia Inhibitory Factor Promotes Castration-resistant Prostate Cancer and Neuroendocrine Differentiation by Activated ZBTB46. / Liu, Yen-Nien; Niu, Shaoxi; Chen, Wei-Yu; Zhang, Qingfu; Tao, Yulei; Chen, Wei-Hao; Jiang, Kuo-Ching; Chen, Xufeng; Shi, Huaiyin; Liu, Aijun; Li, Jinhang; Li, Yanjing; Lee, Yi-Chao; Zhang, Xu; Huang, Jiaoti.

於: Clinical cancer research : an official journal of the American Association for Cancer Research, 08.04.2019.

研究成果: 雜誌貢獻文章

Liu, Yen-Nien ; Niu, Shaoxi ; Chen, Wei-Yu ; Zhang, Qingfu ; Tao, Yulei ; Chen, Wei-Hao ; Jiang, Kuo-Ching ; Chen, Xufeng ; Shi, Huaiyin ; Liu, Aijun ; Li, Jinhang ; Li, Yanjing ; Lee, Yi-Chao ; Zhang, Xu ; Huang, Jiaoti. / Leukemia Inhibitory Factor Promotes Castration-resistant Prostate Cancer and Neuroendocrine Differentiation by Activated ZBTB46. 於: Clinical cancer research : an official journal of the American Association for Cancer Research. 2019.
@article{9e3c0110c2414fbf8aa51041b1d4e8e3,
title = "Leukemia Inhibitory Factor Promotes Castration-resistant Prostate Cancer and Neuroendocrine Differentiation by Activated ZBTB46",
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.",
author = "Yen-Nien Liu and Shaoxi Niu and Wei-Yu Chen and Qingfu Zhang and Yulei Tao and Wei-Hao Chen and Kuo-Ching Jiang and Xufeng Chen and Huaiyin Shi and Aijun Liu and Jinhang Li and Yanjing Li and Yi-Chao Lee and Xu Zhang and Jiaoti Huang",
note = "{\circledC}2019 American Association for Cancer Research.",
year = "2019",
month = "4",
day = "8",
doi = "10.1158/1078-0432.CCR-18-3239",
language = "English",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",

}

TY - JOUR

T1 - Leukemia Inhibitory Factor Promotes Castration-resistant Prostate Cancer and Neuroendocrine Differentiation by Activated ZBTB46

AU - Liu, Yen-Nien

AU - Niu, Shaoxi

AU - Chen, Wei-Yu

AU - Zhang, Qingfu

AU - Tao, Yulei

AU - Chen, Wei-Hao

AU - Jiang, Kuo-Ching

AU - Chen, Xufeng

AU - Shi, Huaiyin

AU - Liu, Aijun

AU - Li, Jinhang

AU - Li, Yanjing

AU - Lee, Yi-Chao

AU - Zhang, Xu

AU - Huang, Jiaoti

N1 - ©2019 American Association for Cancer Research.

PY - 2019/4/8

Y1 - 2019/4/8

N2 - 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.

AB - 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.

U2 - 10.1158/1078-0432.CCR-18-3239

DO - 10.1158/1078-0432.CCR-18-3239

M3 - Article

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

ER -