<i>STAT3/PIAS3</i> Levels Serve as "Early Signature" Genes in the Development of High-Grade Serous Carcinoma from the Fallopian Tube.

Abstract

The initial molecular events that lead to malignant transformation of the fimbria of the fallopian tube (FT) through high-grade serous ovarian carcinoma (HGSC) remain poorly understood. In this study, we report that increased expression of signal transducer and activator of transcription 3 (<i>pSTAT3 Tyr705</i>) and suppression or loss of protein inhibitor of activated STAT3 (<i>PIAS3</i>) in FT likely drive HGSC. We evaluated human tissues-benign normal FT, tubal-peritoneal junction (TPJ), p53 signature FT tissue, tubal intraepithelial lesion in transition (TILT), serous tubal intraepithelial carcinoma (STIC) without ovarian cancer, and HGSC for expression of <i>STAT3/PIAS3</i> (compared with their known <i>TP53</i> signature) and their target proliferation genes. We observed constitutive activation of <i>STAT3</i> and low levels or loss of <i>PIAS3</i> in the TPJ, p53 signature, TILT, and STIC through advanced stage IV (HGSC) tissues. Elevated expression of <i>pSTAT3 Tyr705</i> and decreased levels of <i>PIAS3</i> appeared as early as TPJ and the trend continued until very advanced stage HGSC (compared with high <i>PIAS3</i> and low <i>pSTAT3</i> expression in normal benign FT). Exogenous expression of <i>STAT3</i> in FT cells mediated translocation of <i>pSTAT3</i> and <i>c-Myc</i> into the nucleus. <i>In vivo</i> experiments demonstrated that overexpression of <i>STAT3</i> in FT secretory epithelial cells promoted tumor progression and metastasis, mimicking the clinical disease observed in patients with HGSC. Thus, we conclude that the <i>STAT3</i> pathway plays a role in the development and progression of HGSC from its earliest premalignant states.<b>Significance:</b> Concomitant gain of pSTAT3 Tyr705 and loss of PIAS3 appear critical for initiation and development of high-grade serous carcinoma. <i>Cancer Res; 78(7); 1739-50. ©2018 AACR</i>.