SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma

Abstract

Background & aims Cholangiocarcinoma (CCA) is a biliary malignancy linked to genetic and epigenetic abnormalities, such as hypermethylation of SOX17 promoter. Here, the role of SOX17 in cholangiocyte differentiation and cholangiocarcinogenesis was studied. Methods SOX17 expression/function was evaluated along the differentiation of human induced pluripotent stem cells (iPSC) into cholangiocytes, in the dedifferentiation process of normal human cholangiocytes (NHC) in culture and in cholangiocarcinogenesis. Lentiviruses for SOX17 overexpression or knock-down were used. Gene expression and DNA methylation profiling were performed. Results SOX17 expression is induced in the last stage of cholangiocyte differentiation from iPSC and regulates the acquisition of biliary markers. SOX17 becomes downregulated in NHC undergoing dedifferentiation; experimental SOX17 knock-down in differentiated NHC downregulated biliary markers and promoted baseline and Wnt-dependent proliferation. SOX17 expression is lower in human CCA than in healthy tissue, which correlates with worse survival after tumor resection. In CCA cells, SOX17 overexpression decreased their tumorigenic capacity in murine xenograft models, which was related to increased oxidative stress and apoptosis. In contrast, SOX17 overexpression in NHC did not affect their survival but inhibited their baseline proliferation. In CCA cells, SOX17 inhibited migration, anchorage-independent growth and Wnt/β-catenin-dependent proliferation, and restored the expression of biliary markers and primary cilium length. In human CCA, SOX17 promoter was found hypermethylated and its expression inversely correlates with the methylation grade. In NHC, Wnt3a decreased SOX17 expression in a DNMT-dependent manner, whereas in CCA, DNMT1 inhibition or silencing upregulated SOX17. Conclusions SOX17 regulates the differentiation and maintenance of the biliary phenotype and functions as a tumor suppressor for CCA, being a potential prognostic marker and a promising therapeutic target.

Signalling networks in cholangiocarcinoma: Molecular pathogenesis, targeted therapies and drug resistance

“…Downregulation of SOX17 during CCA development promotes cholangiocyte dedifferentiation and is correlated with worse outcomes after tumour resection. Additionally, overexpression of SOX17 in CCA cells decreased their tumorigenic capacity by increasing oxidative stress and apoptosis, also inhibiting cell migration and Wnt/β‐catenin‐dependent proliferation …”

Oncogenic activity of SOX1 in glioblastoma

“…For example, SOX2, SOX4, SOX9 or SOX10 display oncogenic functions in different types of cancers including glioblastoma111213141516. In contrast, SOX17 and SOX11 have been shown to act as tumor suppressors in certain types of cancer such as gastrointestinal tumors, mantle cell lymphomas, and also glioblastomas1718192021.…”

Cancer‐associated missense mutations enhance the pluripotency reprogramming activity of OCT4 and SOX17

“…Interestingly, position 403 is close to a previously mapped b-catenin interaction site [67,68] that is critical for the reprogramming activity of the rationally designed high-performance factor SOX17EK [34]. If SOX17 is indeed a tumor suppressor as asserted for a variety of tumors [66,[69][70][71][72][73][74][75][76][77][78], the acquisition of the pluripotency reprogramming activity of factors such as SOX17EK and SOX17FL-V118M is counterintuitive. Conventional wisdom predicts that tumor-promoting factors such as KLF4, SOX2 and c-MYC facilitate reprogramming, while tumor suppressors such p53 impede reprogramming [79][80][81][82].…”