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.

Overexpression of HMGA1 deregulates tumor growth via cdc25A and alters migration/invasion through a cdc25A-independent pathway in medulloblastoma

“…Regarding clinical outcomes, high levels of HMGA1 mRNA/protein in the cancers were associated with shorter survival in patients with pancreatic ductal adenocarcinoma [24] and periampullary cancer but not those with pancreatic head cancer [47]. Liau et al [30] demonstrated that HMGA1 expression was an independent predictor of poor postoperative survival in patients with pancreatic adenocarcinoma. In addition, patients with lung cancer [43] and hepatocellular carcinoma [7] also showed the association with worse prognosis.…”

“…Overexpression of HMGA1 is a common phenomenon in many cancer types [1,2,5,7,9,10,17,24,30,43,47]. Roles of HMGA1 in carcinogenesis were implicated because HMGA1 overexpression induced tumor formation and metastasis in human breast epithelial cells in nude mice and transformation of Rat-1 fibroblast and CB33 human lymphoblastoid cells [40,50,51].…”

“…High expression of HMGA1 was generally associated with increased degree of malignancy, metastatic potential, and/or survival in various human cancers [2,5,7,24,30,43,47]. In colorectal carcinoma, associations of high HMGA1 expression with lymphatic and/or venous involvement, lymph node metastasis, and advanced stage according to Dukes' classification, which are known to be indicative of poor prognosis, were reported [2,47]; however, Kim's study [28] showed no correlation with stage, tumor size, lymph node metastasis, and histologic grade.…”

Tissue Biomarkers for Prognosis in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-analysis

“…In 68 of the 81 studies, IHC was carried out on individual whole-slide tissue sections. In the remaining 15 studies, TMAs were created by using 2-mm (44, 85, 100, 103), 1.5-mm (46,48,84), 1.0-mm (74), or 0.6-mm (61,64,69,75,83) diameter cores from representative tissue regions; one study provided no core size details (116). For 2 studies, only automated scoring techniques were used (42,48).…”

Polyetheylenimine-Polyplexes of Spiegelmer NOX-A50 Directed against Intracellular High Mobility Group Protein A1 (HMGA1) Reduce Tumor Growth in Vivo

“…These PSN-1 cells pretreated with HMGA1 antisense oligodeoxynucleotides failed to form xenograft tumors in nude mice (33). Liau et al showed that down-regulation of HMGA1 in pancreatic cancer cells by stably transfected shRNA vectors reduced proliferation in vitro and tumor growth in vivo (49). They hypothesized that tumor HMGA1 status represents an independent prognostic marker and HMGA1 proteins are therapeutic targets in pancreatic adenocarcinoma.…”