טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentFares Basem
SubjectPAX8 Plays an Essential Pro-Proliferative Role in Uterine
Serous Papillary Cancer
DepartmentDepartment of Medicine
Supervisors Professor Eyal Gottlieb
Dr. Ruth Perets
Full Thesis textFull thesis text - English Version


Abstract

Endometrial carcinoma (EC) is cancer arising from the epithelial lining of the uterus (endometrium) and is the most common form of gynecological cancer and the fourth-most common cancer in women worldwide. EC subtypes are divided into two groups- namely Type I and Type II. 80% of ECs are Type I ECs, which occur around the time of menopause and are often low-grade, minimally invasive, and estrogen-dependent. Endomtrioid EC is the most common subtype of type I EC. Type II ECs, on the other hand, usually occur in post-menopausal women, and are often high-grade invasive tumors with poorer prognosis. USPC, is the prototypical and most common Type II EC, and it is histologically and molecularly resembling high-grade ovarian cancer. It is characterized by p53 mutations and copy number variations.

PAX8 is an essential transcription factor during embryonic development of the Müllerian duct, which is the embryonic precursor of the female reproductive organs, and it is expressed in nearly 100% of ECs and USPCs. For this reason, PAX8 is used as a marker to distinguish carcinomas of gynecological origin, from other epithelial cancers. This led us to investigate the role of PAX8 in EC cell proliferation. To this end, we used four established USPC cell lines, characterized them with respect to EC markers expression, and used them for in-vitro studies of the role of PAX8 in EC.

Our results show that PAX8 silencing in EC cells decreased cell viability via apoptosis of cancer cells, suggesting an essential anti-apoptotic role for PAX8 in USPC. We show that, similar to our previous findings in ovarian cancer, in USPC PAX8 regulates a mutant GOF p53, and this effect can mediate its pro-proliferative effect. We also show that PAX8 activates p21 in USPC in a p53-independent manner. Similar to our findings in epithelial ovarian cancer, p21 in EC is cytoplasmic and confers a pro-proliferative effect. Our results suggest a novel mechanism for the pro-proliferative role of PAX8 in USPC, mediated by a cytoplasmic p21 similar to its role in HGSC. Similar to our studies conducted with ovarian cancer, these results suggest that PAX8 could be a target for USPC specific therapy.

In addition, high throughput sequencing analysis of USPC following PAX8 KD suggests that PAX8 regulates hallmark cancer processes in USPC such as cell metabolism and angiogenesis. These results would be further validated by biological assays beyond the scope of this thesis. Furthermore, our results suggest several genes that are co-regulated with PAX8 in USPC, and can be further studied as potential mediators of the role of PAX8 in USPC.

To summarize, we show here for the first time that PAX8 plays an essential anti-apoptotic role in USPC and suggest mechanisms for this activity.