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

다국어 초록 (Multilingual Abstract)

<P><B>Abstract</B></P> <P><B>Objective</B></P> <P>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).</P> <P><B>Methods</B></P> <P>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 <I>in vitro</I> and <I>in vivo</I> experiments using CDK7 siRNA or a covalent CDK7 inhibitor (THZ1) to elucidate the effect of CDK7 inhibition on tumorigenesis in EOC cells.</P> <P><B>Results</B></P> <P>The patient incidence of high CDK7 expression (CDK7<SUP>High</SUP>) gradually increased from normal ovarian epithelium to EOC (<I>P</I> < 0.001). Moreover, CDK7<SUP>High</SUP> was associated with an advanced stage and high-grade histology (<I>P</I> = 0.035 and <I>P</I> = 0.011, respectively) in EOC patients and had an independent prognostic significance in EOC recurrence (<I>P</I> = 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 G0/G1 cell cycle arrest. In <I>in vivo</I> therapeutic experiments using cell-line xenograft and PDX models, CDK7 inhibition significantly decreased the tumor weight, which was mediated by cell proliferation and apoptosis.</P> <P><B>Conclusion</B></P> <P>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.</P> <P><B>Highlights</B></P> <P> <UL> <LI> CDK7 inhibition has an anti-cancer effect on platinum-sensitive EOC. </LI> <LI> CDK7 inhibition could induce responsiveness to platinum chemotherapy in platinum-resistant EOC. </LI> <LI> CDK7 overexpression had independent negative prognostic value for disease recurrence of EOC. </LI> <LI> CDK7 might play a critical role in EOC tumorigenesis, and it also serves as a possible therapeutic target in EOC. </LI> </UL> </P>