Impact of high-mobility-group A2 overexpression on epithelial-mesenchymal transition in pancreatic cancer

Background: Tumor metastasis causes high mortality in patients with malignancies. In carcinomas, overexpression of high-mobility-group A2 (HMGA2) in cancer cells would lead to tumor development and epithelial to mesenchymal transition (EMT), promoting metastasis. This study evaluated HMGA2 overexpression for its effects on pancreatic cancer (PC). Methods: HMGA2 protein levels were immunohistochemically assessed in human PC tissue specimens and evaluated for associations with patients' clinicopathological findings. In human PC CAPAN 1 cells after HMGA2 expression was silenced or overexpressed, Transwell migration and invasion assays were performed, and EMT marker levels (E-cadherin, N-cadherin and Vimentin) were determined by immunoblot. Results: HMGA2 and Vimentin were found in 43% and 45% of PC tissue samples, respectively, while E-cadherin was absent in 60%. HMGA2 expression, loss of E-cadherin and Vimentin expression were significantly associated with clinical stage, tumor differentiation and lymph node metastasis. More importantly, univariate and multivariate analysis demonstrated that HMGA2 expression is an independent prognostic factor for patients with pancreatic cancer. Meanwhile, HMGA2-silenced CAPAN 1 cells showed reduced migration and invasion ability while HMGA2-overexpressed CAPAN 1 cells showed increased migration and invasion ability. Increased E-cadherin (epithelial marker) and reduced N-cadherin and Vimentin (mesenchymal markers) were found in HMGA2-silenced cells, while reduced E-cadherin and increased N-cadherin and Vimentin were found in HMGA2-overexpressed cells. Furthermore, Snail and Zeb1 (transcriptional factors) were reduced in HMGA2-silenced cells and increased in HMGA2-overexpressed cells. Conclusion: Our findings demonstrate that HMGA2 expression correlates with advanced tumor grades, lymph node metastasis and poor prognosis and may be a novel prognosis/therapeutic marker for PC.