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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.

journal_name

Cancer

journal_title

Cancer

authors

Liau SS,Rocha F,Matros E,Redston M,Whang E

doi

10.1002/cncr.23560

subject

Has Abstract

pub_date

2008-07-15 00:00:00

pages

302-14

issue

eissn

0008-543X

issn

1097-0142

journal_volume

113

pub_type

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