STAT3/PIAS3 levels serve as "early signature" genes in the development of high-grade serous carcinoma from the fallopian tube

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 (pSTAT3 Tyr705) and suppression or loss of protein inhibitor of activated STAT3 (PIAS3) in FT likely drive HGSC. We evaluated human tissues-benign normal FT, tubal peritoneal junction (TPJ), p53 signature fallopian tube tissue, tubal intraepithelial lesion in transition (TILT), serous tubal intraepithelial carcinoma (STIC) without ovarian cancer, and HGSC for expression of STAT3/PIAS3 (compared with their known TP53 signature) and their target proliferation genes. We observed constitutive activation of STAT3 and low levels or loss of PIAS3 in the TPJ, p53 signature, TILT, and STIC through advanced stage IV (HGSC) tissues. Elevated expression of pSTAT3 Tyr705 and decreased levels of PIAS3 appeared as early as TPJ and the trend continued until very advanced stage HGSC (compared to high PIAS3 and low pSTAT3 expression in normal benign FT). Exogenous expression of STAT3 in FT cells mediated translocation of pSTAT3 and c-Myc into the nucleus. In vivo experiments demonstrated that overexpression of STAT3 in fallopian tube secretory epithelial cells (FTSEC) promoted tumor progression and metastasis, mimicking the clinical disease observed in patients with HGSC. Thus we conclude that the STAT3 pathway plays a role in the development and progression of HGSC from its earliest pre-malignant states.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2B7h51w