Soriano, Amata Amy (2018) PAX8 in ovarian carcinoma: identification of new downstream networks and target genes. [Tesi di dottorato]


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Item Type: Tesi di dottorato
Resource language: English
Title: PAX8 in ovarian carcinoma: identification of new downstream networks and target genes
Soriano, Amata
Date: 7 December 2018
Number of Pages: 67
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Molecolare e Biotecnologie Mediche
Dottorato: Medicina molecolare e biotecnologie mediche
Ciclo di dottorato: 31
Coordinatore del Corso di dottorato:
Avvedimento, Vittorio
Date: 7 December 2018
Number of Pages: 67
Keywords: PAX8; RNA-seq; ovarian cancer; fallopian tube secretory epithelial cells; Integrin β3, migration, adhesion, metastasis, transcriptional networks
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/03 - Genetica medica
Date Deposited: 09 Jan 2019 12:47
Last Modified: 29 Jun 2020 10:59

Collection description

PAX8 is a transcription factor involved in the tissue-specific expression of several genes during development, tissue homeostasis and cancer. Recently, PAX8 has been reported to be an important marker for the diagnosis of ovarian carcinoma with a pivotal function in the tumorigenic phenotype of ovarian cancer cells. PAX8 is normally expressed in Fallopian tube secretory cells but not in ovarian surface epithelial cells; however, its expression is detected in the majority of high-grade serous ovarian carcinoma (HGSC) supporting the tubal origin of this cancer. To determine whether PAX8 contributes to ovarian cancer development, we initially conducted a transcriptome analyses to determine the distinctive molecular profiles of the Fallopian tube epithelial secretory cell line (FT194) and the ovarian cancer cell line (SKOV3), before and after PAX8 silencing. The bioinformatics analysis revealed several GO categories enriched in both PAX8-silenced FT-194 and SKOV3 cells. Among those categories, the results showed that both “cell migration” and the “positive regulation of cell migration” bioprocess displayed transcriptional change of 5% in SKOV3 cells and the adhesion category shows change of about 16% in SKOV3 and 14% in FT-194 cells. With respect to specific pathways, the highest differential changes upon PAX8 silencing were found in angiogenesis, Wnt, cadherin and integrin signalling pathways, in both cell types. Since migration and adhesion are important biological processes in both physiological and pathological conditions, migration and adhesion assays were performed using a primary human fallopian tube secretory cells (Primary hFTSECs) and a panel of ovarian cancer cell lines (SKOV3, KURAMOCHI, OVSAHO and PEA1). Interestingly, our results show that inhibition of PAX8 expression in Primary hFTSEC and in epithelial ovarian cancer cell lines significantly reduces the ability of the cells to migrate and adhere on Fibronectin and/or Collagen I substrates. Integrins are reported to be the major regulators of cellular attachment with the extracellular matrix and are required for cellular migration. In our transcriptome analysis, Integrin β3 was significantly downregulated after PAX8 silencing in SKOV3 cells. Therefore, we performed qRT-PCR on Primary hFTSEC and our panel of ovarian cancer cell lines and the results show a strong reduction of Integrin β3 expression in all ovarian cancer cell lines after PAX8 silencing, respect to the control cells. In parallel, we also show that loss of PAX8 does not affect the expression of Integrin αv, the ligand of Integrin β3 involved in ovarian cancer tumorigenesis. The Immunofluorescences assays of the functional heterodimer αvβ3 was tested in Primary hFTSEC and KURAMOCHI cell lines and in PAX8 silenced cells the signal was decreased. In conclusion, we believe that it is of great relevance to further study and decipher the link between PAX8 and Integrin β3 because it could help uncover the role of PAX8 in HGSC development.


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