Transient Sox9 Expression Facilitates Resistance to Androgen-Targeted Therapy in Prostate Cancer

被引：35

作者：

Nouri, Mannan ^{[1
,2
,4
]}

Massah, Shabnam ^{[1
,2
]}

Caradec, Josselin ^{[1
,2
]}

Lubik, Amy A. ^{[1
,2
]}

Li, Na ^{[1
,2
]}

Truong, Sarah ^{[1
]}

Lee, Ahn R. ^{[1
,2
]}

Fazli, Ladan ^{[1
]}

Ramnarine, Varune R. ^{[1
,2
]}

Lovnicki, Jessica M. ^{[1
,2
]}

Moore, Jackson ^{[1
]}

Wang, Mike ^{[1
]}

Foo, Jane ^{[1
]}

Gleave, Martin E. ^{[1
,2
]}

Hollier, Brett G. ^{[3
]}

Nelson, Colleen ^{[1
,2
,3
]}

Collins, Colin ^{[1
,2
]}

Dong, Xuesen ^{[1
,2
]}

Buttyan, Ralph ^{[1
,2
]}

机构：

[1] Vancouver Prostate Ctr, 2660 Oak St, Vancouver, BC V6H 3Z6, Canada

[2] Univ British Columbia, Dept Urol Sci, Vancouver, BC, Canada

[3] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia

[4] Harvard Med Sch, Ctr Life Sci, Beth Israel Deaconess Med Ctr, 3 Blackfan Circle, Boston, MA 02115 USA

来源：

CLINICAL CANCER RESEARCH | 2020年 / 26卷 / 07期

基金：

加拿大健康研究院;

关键词：

KAPPA-B; MOLECULAR CHARACTERIZATION; LINEAGE PLASTICITY; CELLS; RECEPTOR; CASTRATION; TRANSDIFFERENTIATION; PROGRESSION; PHENOTYPE; GENE;

D O I：

10.1158/1078-0432.CCR-19-0098

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: Patients with metastatic prostate cancer are increasingly presenting with treatment-resistant, androgen receptor-negative/low (AR(-/Low)) tumors, with or without neuroendocrine characteristics, in processes attributed to tumor cell plasticity. This plasticity has been modeled by Rb1/p53 knockdown/knockout and is accompanied by overexpression of the pluripotency factor, Sox2. Here, we explore the role of the developmental transcription factor Sox9 in the process of prostate cancer therapy response and tumor progression. Experimental Design: Unique prostate cancer cell models that capture AR(-/Low) stem cell-like intermediates were analyzed for features of plasticity and the functional role of Sox9. Human prostate cancer xenografts and tissue microarrays were evaluated for temporal alterations in Sox9 expression. The role of NF-kappa B pathway activity in Sox9 overexpression was explored. Results: Prostate cancer stemcell-like intermediates have reduced Rb1 and p53 protein expression and overexpress Sox2 as well as Sox9. Sox9 was required for spheroid growth, and overexpression increased invasiveness and neural features of prostate cancer cells. Sox9 was transiently upregulated in castration-induced progression of prostate cancer xenografts and was specifically overexpressed in neoadjuvant hormone therapy (NHT)-treated patient tumors. High Sox9 expression in NHT-treated patients predicts biochemical recurrence. Finally, we link Sox9 induction to NF-kappa B dimer activation in prostate cancer cells. Conclusions: Developmentally reprogrammed prostate cancer cell models recapitulate features of clinically advanced prostate tumors, including downregulated Rb1/p53 and overexpression of Sox2 with Sox9. Sox9 is a marker of a transitional state that identifies prostate cancer cells under the stress of therapeutic assault and facilitates progression to therapy resistance. Its expression may index the relative activity of the NF-kappa B pathway.

引用

页码：1678 / 1689

页数：12

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