TY - JOUR
T1 - AKR1C3, a crucial androgenic enzyme in prostate cancer, promotes epithelial-mesenchymal transition and metastasis through activating ERK signaling
AU - Wang, Bin
AU - Gu, Yanan
AU - Hui, Ke
AU - Huang, Jun
AU - Xu, Shan
AU - Wu, Shiqi
AU - Li, Lei
AU - Fan, Jinhai
AU - Wang, Xinyang
AU - Hsieh, Jer Tsong
AU - He, Dalin
AU - Wu, Kaijie
N1 - Funding Information:
This work was supported by grants from the National Natural Science Foundation of China ( NSFC 81202014 to KW and NSFC 81130041 to DH), the “New-Star” Young Scientists Program of Shaanxi Province (to KW), the Fundamental Research Funds for the Central Universities (to KW) and the United States Army Grant ( W81XWH-11-1-0491 to JTH). Also, we thank Dr. David Xu for his English edition.
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/10
Y1 - 2018/10
N2 - Background: AKR1C3, as a crucial androgenic enzyme, facilitates intratumoral androgen biosynthesis and androgen receptor activation in castration-resistant prostate cancer (PCa). The data has shown that AKR1C3 expression is significantly elevated in clinical metastatic PCa specimens, indicating a potential role of AKR1C3 in PCa metastasis. Methods: C4-2, 22RV1-T, and PC-3 cells with higher AKR1C3 expression were selected and treated with several specific AKR1C3 shRNAs or small molecule inhibitor, and the cell migration and invasion abilities were detected by wound healing assay and Transwell assay. The expression of several epithelial-mesenchymal transition (EMT) markers (i.e., E-cadherin and vimentin) and the related transcription factors (i.e., ZEB1, TWIST1, and SLUG) was examined by Western blot or quantitative PCR assays, and the phosphorylation of AKT or ERK was detected by Western blot. Also, subcutaneous xenografts with 22RV1-T sublines were used to detect in vivo tumor growth, and the expression of E-cadherin, vimentin, and ZEB1 by immunohistochemical staining. The correlation between AKR1C3 and EMT marker expression in clinical specimens was analyzed. Results: AKR1C3 was overexpressed in more aggressive PCa cell lines regardless of the androgen receptor status. Knockdown of AKR1C3 expression or inhibition of AKR1C3 activity could significantly suppress cell migration and invasion abilities in vitro, and increase E-cadherin expression but decrease vimentin expression, in which the phosphorylation of ERK and the EMT-associated transcription factor expression were specifically down-regulated. Also, knockdown of AKR1C3 could suppress PCa tumorigenesis and reverse EMT in vivo. Moreover, there was a significant correlation between AKR1C3 expression and EMT in human PCa specimens from public tissue microarray. Conclusions: AKR1C3 is a novel EMT driver in PCa metastasis through activating ERK signaling.
AB - Background: AKR1C3, as a crucial androgenic enzyme, facilitates intratumoral androgen biosynthesis and androgen receptor activation in castration-resistant prostate cancer (PCa). The data has shown that AKR1C3 expression is significantly elevated in clinical metastatic PCa specimens, indicating a potential role of AKR1C3 in PCa metastasis. Methods: C4-2, 22RV1-T, and PC-3 cells with higher AKR1C3 expression were selected and treated with several specific AKR1C3 shRNAs or small molecule inhibitor, and the cell migration and invasion abilities were detected by wound healing assay and Transwell assay. The expression of several epithelial-mesenchymal transition (EMT) markers (i.e., E-cadherin and vimentin) and the related transcription factors (i.e., ZEB1, TWIST1, and SLUG) was examined by Western blot or quantitative PCR assays, and the phosphorylation of AKT or ERK was detected by Western blot. Also, subcutaneous xenografts with 22RV1-T sublines were used to detect in vivo tumor growth, and the expression of E-cadherin, vimentin, and ZEB1 by immunohistochemical staining. The correlation between AKR1C3 and EMT marker expression in clinical specimens was analyzed. Results: AKR1C3 was overexpressed in more aggressive PCa cell lines regardless of the androgen receptor status. Knockdown of AKR1C3 expression or inhibition of AKR1C3 activity could significantly suppress cell migration and invasion abilities in vitro, and increase E-cadherin expression but decrease vimentin expression, in which the phosphorylation of ERK and the EMT-associated transcription factor expression were specifically down-regulated. Also, knockdown of AKR1C3 could suppress PCa tumorigenesis and reverse EMT in vivo. Moreover, there was a significant correlation between AKR1C3 expression and EMT in human PCa specimens from public tissue microarray. Conclusions: AKR1C3 is a novel EMT driver in PCa metastasis through activating ERK signaling.
KW - AKR1C3
KW - ERK
KW - Epithelial-to-mesenchymal transition
KW - Metastasis
KW - Prostate cancer
KW - Transcription factor
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U2 - 10.1016/j.urolonc.2018.07.005
DO - 10.1016/j.urolonc.2018.07.005
M3 - Article
C2 - 30139661
AN - SCOPUS:85051722097
SN - 1078-1439
VL - 36
SP - 472.e11-472.e20
JO - Urologic Oncology: Seminars and Original Investigations
JF - Urologic Oncology: Seminars and Original Investigations
IS - 10
ER -