A role for PAX8 in the tumorigenic phenotype of ovarian cancer cells

Abstract

BackgroundPAX8 is a member of the paired box (Pax) multigene family of transcription factors, which are involved in the developmental and tissue-specific control of the expression of several genes in both vertebrates and invertebrates. Previously, several studies reported that PAX8 is expressed at high levels in specific types of tumors. In particular, PAX8 has been recently reported to be conspicuously expressed in human ovarian cancer, but the functional role of PAX8 in the carcinogenesis of this type of tumor has not been addressed. In this study, we investigated the contribution of PAX8 in ovarian cancer progression.MethodsStable PAX8 depleted ovarian cancer cells were generated using short hairpin RNA (shRNA) constructs. PAX8 mRNA and protein were detected by RT-PCR, immunoblot and immunofluorescence. Cell proliferation, motility and invasion potential of PAX8 silenced cells were analyzed by means of growth curves, wound healing and Matrigel assays. In addition, PAX8 knockdown and control cells were injected into nude mice for xenograft tumorigenicity assays. Finally, qPCR was used to detect the expression levels of EMT markers in PAX8-overexpressing and control cells.ResultsHere, we show that PAX8 plays a critical role in the migration, invasion and tumorigenic ability of ovarian cancer cells. Our results show that RNA interference-mediated knockdown of PAX8 expression in SKOV-3 ovarian cancer cells produces a significant reduction of cell proliferation, migration ability and invasion activity compared with control parental SKOV-3 cells. Moreover, PAX8 silencing strongly suppresses anchorage-independent growth in vitro. Notably, tumorigenesis in vivo in a nude mouse xenograft model is also significantly inhibited.ConclusionsOverall, our results indicate that PAX8 plays an important role in the tumorigenic phenotype of ovarian cancer cells and identifies PAX8 as a potential new target for the treatment of ovarian cancer.

Loss of PAX8 in high-grade serous ovarian cancer reduces cell survival despite unique modes of action in the fallopian tube and ovarian surface epithelium

“…E-cadherin was not tested in this system as OSE cells lack expression of E-cadherin [20]. Fibronectin is associated with both EMT and migration, and was analyzed by Di Palma and colleagues in their study of PAX8 in SV40 immortalized human IOSE 80 cells [19]. N-cadherin and Fibronectin protein levels were significantly increased in MOSE-PAX8 cells compared to MOSE-Neo control (Figure 1D).…”

“…Despite its ubiquitous expression and role in other tumor types, little is known about what PAX8 regulates in HGSC. Previous research has shown that PAX8 knockdown in HGSC leads to apoptosis as well as an increase in migration, anchorage independent growth, and tumor suppression [18, 19]. The pathways involved in these phenotypic changes, however, remain unknown.…”

Epigenetic remodeling regulates transcriptional changes between ovarian cancer and benign precursors

“…Interestingly, PAX8 is the single most differentially expressed gene when comparing ovarian cancer cell lines with all other cancer cell lines in the Cancer Cell Line Encyclopedia (24). Loss of PAX8 in most, but not all, serous ovarian cancer cell lines leads to apoptosis and decreased tumorigenicity, while cancer cell lines from other organ sites are unaffected (24, 33). Together, these findings have led to substantial interest in PAX8 as a lineage-defining gene for Müllerian cancers in humans.…”

PAX8 expression in ovarian surface epithelial cells

“…This is supported by functional evidence showing that PAX8 knockdown in ovarian carcinoma cell lines induces growth arrest, apoptosis, and decreases tumorigenesis [14-16]. The observation of PAX8 expression in fallopian tube secretory epithelial cells (FTSECs) and in many CICs but not OSECs could suggest that the epithelial lining of CICs is derived from the fallopian tube and that most, if not all HGSOCs likely originate from FTSECs.…”