High mobility group AT‐hook 1 (HMGA1) is an independent prognostic factor and novel therapeutic target in pancreatic adenocarcinoma

Abstract

BACKGROUND. High mobility group AT‐hook 1 (HMGA1) proteins are architectural transcription factors that are overexpressed by pancreatic adenocarcinomas. The authors hypothesized that tumor HMGA1 status represents a novel prognostic marker in pancreatic adenocarcinoma. They also tested the hypothesis that HMGA1 promotes anchorage‐independent cellular proliferation and in vivo tumorigenicity. METHODS. Tumor HMGA1 expression was examined by immunohistochemical analysis of tissues from 89 consecutive patients who underwent resection for pancreatic adenocarcinoma. Short‐hairpin RNA (shRNA)‐mediated RNA interference was used to silence HMGA1 expression in MiaPaCa2 and PANC1 pancreatic cancer cells. Anchorage‐independent proliferation was assessed by using soft agar assays. The roles of phosphatidylinositol 3‐kinase (PI3‐K)/Akt and extracellular signal‐regulated kinase (ERK) signaling were investigated by using specific inhibitors and adenoviral dominant‐negative/active Akt constructs. In vivo tumorigenicity was assessed by using a nude mouse xenograft model. RESULTS. Tumor HMGA1 expression was detected in 93% of patients with pancreatic adenocarcinoma. Patients with HMGA1‐negative tumors had a significantly longer median survival than patients with HMGA1‐expressing cancers in univariate analysis (P = .0028) and in multivariate analysis (P<.05). shRNA‐mediated HMGA1 silencing resulted in significant reductions in anchorage‐independent proliferation in soft agar. Forced HMGA1 overexpression promoted proliferation in soft agar through a process that was dependent on PI3‐K/Akt‐activited signaling, but not on mitogen‐activated protein kinase (MEK)/ERK signaling. Targeted silencing of HMGA1 reduced tumor growth in vivo through reduced proliferation (Ki‐67 index) and increased apoptosis (terminal deoxynucleotidyl transferase nick‐end labeling). CONCLUSIONS. The current findings suggested that HMGA1 is an independent predictor of poor postoperative survival in patients with pancreatic adenocarcinoma. Furthermore, HMGA1 promotes tumorigenicity through a PI3‐K/Akt‐dependent mechanism. HMGA1 warrants further evaluation as a prognostic marker and therapeutic target in pancreatic cancer. Cancer 2008. © 2008 American Cancer Society.