Cytochrome P450 17 (CYP17) encodes cytochrome P450c17α, an enzyme with 17α-hydroxylase and 17, 20-lyase activities involved in estradiol biosynthesis. Here we examine the role of CYP17 gene in endometrial carcinogenesis. Immunohistochemistry staining of endometrial carcinoma and corresponding uninvolved tissues showed that CYP17 is upregulated in endometrial cancers (15 of 24, 62.5%). To understand the functional significance of this upregulation, we silenced CYP17 gene by introduction of siRNA into endometrial cancer cell line KLE followed by functional studies. Further, to understand the molecular basis of the role of CYP17, we profiled the expression of key pathway-specific genes and identified several components of the apoptosis and invasion pathways that are potentially regulated by CYP17. Silencing of CYP17 caused decreased cell proliferation and induced apoptosis. Significantly, CYP17 depletion leads to downregulation of anti-apoptotic genes B cell lymphoma 2 (Bcl-2) and telomerase reverse transcriptase (TERT), indicating induced apoptosis. Also, attenuation of CYP17 decreased the cellular invasion ability and regulated expression of several invasion pathway components such as melanoma cell adhesion molecule (MCAM), matrix metallopeptidase 2 and 9 (MMP-2 and MMP-9), and tissue inhibitor of metalloproteinase 3 (TIMP3). In conclusion, this is the first report documenting that upregulation of CYP17 in endometrial cancers play a crucial role in endometrial carcinogenesis by targeting multiple components of apoptosis and invasion pathways. Further studies are required to understand the detailed mechanisms underlying CYP17-mediated regulation of these components.
© 2010 Wiley-Liss, Inc.