The transcription factor PAX8 promotes angiogenesis in ovarian cancer through interaction with SOX17

Abstract

PAX8 is a master transcription factor that is essential during embryogenesis and promotes neoplastic growth. It is expressed by the secretory cells lining the female reproductive tract, and its deletion during development results in atresia of reproductive tract organs. Nearly all ovarian carcinomas express PAX8, and its knockdown results in apoptosis of ovarian cancer cells. To explore the role of PAX8 in these tissues, we purified the PAX8 protein complex from nonmalignant fallopian tube cells and high-grade serous ovarian carcinoma cell lines. We found that PAX8 was a member of a large chromatin remodeling complex and preferentially interacted with SOX17, another developmental transcription factor. Depleting either PAX8 or SOX17 from cancer cells altered the expression of factors involved in angiogenesis and functionally disrupted tubule and capillary formation in cell culture and mouse models. PAX8 and SOX17 in ovarian cancer cells promoted the secretion of angiogenic factors by suppressing the expression of SERPINE1 , which encodes a proteinase inhibitor with anti a ngiogenic effects. The findings reveal a non–cell-autonomous function of these transcription factors in regulating angiogenesis in ovarian cancer.

SOX17: a highly sensitive and specific marker for ovarian and endometrial carcinomas

“…Recent studies indicated that SOX17 may be involved in tumorigenesis, and TCGA has recently classi ed SOX17 as a mutated cancer driver gene in endometrial carcinoma (29)(30)(31)(32). Both SOX17 and PAX8 might be involved in tumorigenesis from ovarian and endometrial origins, and PAX8 promotes angiogenesis in ovarian cancer through interaction with SOX17 (33,34). Interestingly, multiple studies show SOX17 may function as a tumor suppressor in endometrial cancer and many other cancer types through inhibiting the WNT/beta-catenin oncogenic pathway, and hypermethylation of SOX17 has been linked to it repression in breast, colon, stomach, liver, and lung cancer (35)(36)(37)(38)(39)(40).…”

PAX8 in the Junction between Development and Tumorigenesis

“…Another role for PAX8 is binding of YAP1/TEAD proteins and transcriptional activation of the Hippo/YAP signaling pathway [128], known to regulate pro-survival genes [129]. Taken together, the information regarding the role of PAX8 in HGSCs fits its definition as a master regulator transcription factor of HGSCs, regulating about 30,000 genes and governing many hallmarks of cancer such as evading apoptosis, angiogenesis, and migration [2,3,17,18,127].…”

“…A recent study suggests that PAX8 has a pro-angiogenic role in HGSCs via its interaction with another developmental factor, SOX17. PAX8 and SOX17 are co-expressed in ovarian cancer cells [126] and together inhibit the expression of SERPINE1, an anti-angiogenic factor, thereby promoting angiogenesis [18]. The PAX8 and SOX17 complex was also shown to regulate other genes involved in the cell cycle and morphogenesis.…”

“…Therefore, targeting of key cancer cell drivers affects not only the proliferation of cancer cells, but also curbs the supporting tumor microenvironment [12]. Examples of key intracellular drivers that also affect the microenvironment are KRAS [14], the ERK pathway, and intracellular transcription factors such as MYC [15], HIF-1 [16], and PAX8 [17,18]. Nevertheless, it is important to note that while these factors influence embryos to differentiate in an organized fashion, cancer progression is disorganized and includes dedifferentiation [6].…”

PAX8 as a Potential Target for Ovarian Cancer: What We Know so Far

“…Recently, it has been demonstrated that the protein complex PAX8/SOX17 promotes angiogenesis in OC through inhibition of SERPINE1, that is a potent suppressor of VEGF pathway. 69 Bleu et al 70 have examined in detail the mechanistic interaction between PAX8 and MECOM. They demonstrated that PAX8 and MECOM are part of the same transcriptional complex and determined a PAX8-MECOM gene signature featuring patients of OC with poor prognosis.…”