High mobility group A1 enhances tumorigenicity of human cholangiocarcinoma and confers resistance to therapy.

ABSTRACT

High mobility group A1 (HMGA1) protein has been described to play an important role in numerous types of human carcinoma. By the modulation of several target genes HMGA1 promotes proliferation and epithelial-mesenchymal transition of tumor cells. However, its role in cholangiocarcinoma (CCA) has not been addressed yet. Therefore, we determined HMGA1 mRNA expression in CCA samples in a transcriptome array (n = 104) and a smaller cohort (n = 13) by qRT-PCR. Protein expression was evaluated by immunohistochemistry in a tissue microarray (n = 67). In addition, we analyzed changes in cell proliferation, colony formation, response to gemcitabine treatment, and target gene expression after modulation of HMGA1 expression in CCA cell lines. mRNA levels of HMGA1 were found to be upregulated in 15-62% depending on the cohort analyzed. Immunohistochemistry showed HMGA1 overexpression in 51% of CCA specimens. Integration with clinico-pathological data revealed that high HMGA1 expression was associated with reduced time to recurrence and a positive lymph node status in extrahepatic cholangiocellular carcinoma. In vitro experiments showed that overexpression of HMGA1 in CCA cell lines promoted cell proliferation, whereas its suppression reduced growth rate. HMGA1 further promoted colony formation in an anchorage independent growth and conferred resistance to gemcitabine treatment. Finally, HMGA1 modulated the expression of two genes involved in CCA carcinogenesis, iNOS and ERBB2. In conclusion, our findings indicate that HMGA1 expression is increased in a substantial number of CCA specimens. HMGA1 further promotes CCA tumorigenicity and confers resistance to chemotherapy.