HMGA1 is associated with unfavorable outcome and accelerates the aggressiveness of cholangiocarcinoma.

Abstract

Introduction: Cholangiocarcinoma (CCA) is a highly metastatic bile duct cancer with the highest global incidence in Northeastern Thailand. Most patients are diagnosed at advanced stages, necessitating the identification of novel prognostic markers and therapeutic targets. High mobility group A1 (HMGA1) is a non-histone chromosomal protein that orchestrates the transcription of genes involved in tumor progression, and its overexpression has been implicated in multiple malignancies. Aims: This study aimed to investigate the clinical significance and oncogenic roles of HMGA1 in CCA progression.

Methods: HMGA1 expression was evaluated in a hamster CCA model and human CCA tissues using immunohistochemistry. The functional effects of HMGA1 on cell growth, migration, and invasion, along with the underlying molecular mechanisms were investigated in vitro using human CCA cell lines.

Results: HMGA1 upregulation was detected as an early event in the cholangiocarcinogenesis of a hamster model. In the human cohort (n = 81), high HMGA1 expression significantly correlated with histological type (p=0.014), metastatic stage (p=0.004) and shorter overall survival (p=0.024). In vitro, siRNA-mediated suppression of HMGA1 remarkably inhibited cell proliferation. While HMGA1 silencing increased cleaved caspase-3, it resulted in only a modest increase in the apoptotic cells. Instead, this caspase activation was primarily associated with a marked reduction in cell migration and invasion through the modulation of epithelial-mesenchymal transition (EMT) markers, and cytoskeletal remodeling in a cell line-specific manner. Conclusions: These retrospective and preclinical findings suggest that HMGA1 is a critical driver of CCA progression and a valuable prognostic indicator. HMGA1 promotes neoplastic transformation and aggressiveness of CCA. Targeting HMGA1 may serve as a potential therapeutic strategy to attenuate CCA progression, warranting further clinical validation.