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CDK7 is a reliable prognostic factor and novel therapeutic target in epithelial ovarian cancer

Authors
 Jihye Kim  ;  Young-Jae Cho  ;  Ji-Yoon Ryu  ;  Ilseon Hwang  ;  Hee Dong Han  ;  Hyung Jun Ahn  ;  Woo Young Kim  ;  Hanbyoul Cho  ;  Joon-Yong Chung  ;  Stephen M Hewitt  ;  Jae-Hoon Kim  ;  Byoung-Gie Kim  ;  Duk-Soo Bae  ;  Chel Hun Choi  ;  Jeong-Won Lee 
Citation
 GYNECOLOGIC ONCOLOGY, Vol.156(1) : 211-221, 2020-01 
Journal Title
GYNECOLOGIC ONCOLOGY
ISSN
 0090-8258 
Issue Date
2020-01
MeSH
Animals ; Biomarkers, Tumor / antagonists & inhibitors ; Biomarkers, Tumor / biosynthesis ; Carcinoma, Ovarian Epithelial / drug therapy ; Carcinoma, Ovarian Epithelial / enzymology* ; Carcinoma, Ovarian Epithelial / pathology ; Cell Line, Tumor ; Cell Proliferation / drug effects ; Cyclin-Dependent Kinases / antagonists & inhibitors ; Cyclin-Dependent Kinases / biosynthesis* ; Female ; Heterografts ; Humans ; Immunohistochemistry ; Mice ; Mice, Inbred BALB C ; Middle Aged ; Neoplasm Recurrence, Local / enzymology ; Ovarian Neoplasms / drug therapy ; Ovarian Neoplasms / enzymology* ; Ovarian Neoplasms / pathology ; Phenylenediamines / pharmacology ; Prognosis ; Protein Kinase Inhibitors / pharmacology ; Pyrimidines / pharmacology
Keywords
Cyclin-dependent kinase 7 ; Epithelial ovarian cancer ; Prognosis ; THZ1 ; Therapeutic target
Abstract
Objective: Cyclin-dependent kinase 7 (CDK7) engages tumor growth by acting as a direct link between the regulation of transcription and the cell cycle. Here, we investigated the clinical significance of CDK7 expression and its potential as a therapeutic target in epithelial ovarian cancer (EOC). Methods: CDK7 expression was examined in 436 ovarian tissues including normal to metastatic ovarian tumors using immunohistochemistry, and its clinical implications were analyzed. Furthermore, we performed in vitro and in vivo experiments using CDK7 siRNA or a covalent CDK7 inhibitor (THZ1) to elucidate the effect of CDK7 inhibition on tumorigenesis in EOC cells. Results: The patient incidence of high CDK7 expression (CDK7(High)) gradually increased from normal ovarian epithelium to EOC (P < 0.001). Moreover, CDK7(High) was associated with an advanced stage and high-grade histology (P = 0.035 and P = 0.011, respectively) in EOC patients and had an independent prognostic significance in EOC recurrence (P = 0.034). CDK7 inhibition with siRNA or THZ1 decreased cell proliferation and migration, and increased apoptosis in EOC cells, and this anti-cancer mechanism is caused by GO/G1 cell cycle arrest. In in vivo therapeutic experiments using cell-line xenograft and PDX models, CDK7 inhibition significantly decreased the tumor weight, which was mediated by cell proliferation and apoptosis. Conclusion: Mechanistic interrogation of CDK7 revealed that it is significantly associated with an aggressive phenotype of EOC, and it has independent prognostic power for EOC recurrence. Furthermore, CDK7 may be a potential therapeutic target for patients with EOC, whether platinum sensitive or resistant.
DOI
10.1016/j.ygyno.2019.11.004
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Obstetrics and Gynecology (산부인과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jae Hoon(김재훈) ORCID logo https://orcid.org/0000-0001-6599-7065
Cho, Hanbyoul(조한별) ORCID logo https://orcid.org/0000-0002-6177-1648
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/190296
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