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Overexpression of HMGA2 promotes metastasis and impacts survival of colorectal cancers.

ABSTRACT: PURPOSE:This study aims to address the hypothesis that the high-mobility group A2 (HMGA2), an oncofetal protein, relates to survivability and serves as a prognostic biomarker for colorectal cancer (CRC). EXPERIMENTAL DESIGN:This is a retroprospective multiple center study. The HMGA2 expression level was determined by performing immunohistochemistry on surgical tissue samples of 89 CRCs from a training set and 191 CRCs from a validation set. The Kaplan-Meier analysis and COX proportional hazard model were employed to analyze the survivability. RESULTS:Multivariate logistic analysis indicated that the expression of HMGA2 significantly correlates with distant metastasis in training set (odds ratio, OR = 3.53, 95% CI: 1.37-9.70) and validation set (OR = 6.38, 95% CI: 1.47-43.95). Survival analysis revealed that the overexpression of HMGA2 is significantly associated with poor survival of CRC patients (P < 0.05). The adjusted HRs for overall survival were 2.38 (95% CI: 1.30-4.34) and 2.14 (95% CI: 1.21-3.79) in training and validation sets, respectively. Further investigation revealed that HMGA2 delays the clearance of ?-H2AX in HCT-116 and SW480 cells post ?-irradiation, which supports our finding that CRC patients with HMAG2-positive staining in primary tumors had augmented the efficacy of adjuvant radiotherapy (HR = 0.18, 95% CI: 0.04-0.63). CONCLUSION:Overexpression of HMGA2 is associated with metastasis and unequivocally occurred in parallel with reduced survival rates of patients with CRC. Therefore, HMGA2 may potentially serve as a biomarker for predicting aggressive CRC with poor survivability and as an indicator for better response of radiotherapy.

SUBMITTER: Wang X

PROVIDER: S-EPMC3079060 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Overexpression of HMGA2 promotes metastasis and impacts survival of colorectal cancers.

Wang Xiaochen X Liu Xiyong X Li Angela Ying-Jian AY Chen Lirong L Lai Lily L Lin Her Helen HH Hu Shuya S Yao Lifang L Peng Jiaping J Loera Sofia S Xue Lijun L Zhou Bingsen B Zhou Lun L Zheng Shu S Chu Peiguo P Zhang Suzhan S Ann David Kong DK Yen Yun Y

Clinical cancer research : an official journal of the American Association for Cancer Research 20110120 8

<h4>Purpose</h4>This study aims to address the hypothesis that the high-mobility group A2 (HMGA2), an oncofetal protein, relates to survivability and serves as a prognostic biomarker for colorectal cancer (CRC).<h4>Experimental design</h4>This is a retroprospective multiple center study. The HMGA2 expression level was determined by performing immunohistochemistry on surgical tissue samples of 89 CRCs from a training set and 191 CRCs from a validation set. The Kaplan-Meier analysis and COX propor ...[more]

PMID: 21252160

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Project description:IntroductionWomen with HER2(+) or triple negative/basal-like (TN/BL) breast cancers succumb to their cancer rapidly due, in part to acquired Herceptin resistance and lack of TN/BL-targeted therapies. BRCA1-IRIS is a recently discovered, 1399 residue, BRCA1 locus alternative product, which while sharing 1365 residues with the full-length product of this tumor suppressor gene, BRCA1/p220, it has oncoprotein-like properties. Here, we examine whether BRCA1-IRIS is a valuable treatment target for HER2(+) and/or TN/BL tumors.Methodology/principal findingsImmunohistochemical staining of large cohort of human breast tumor samples using new monoclonal anti-BRCA1-IRIS antibody, followed by correlation of BRCA1-IRIS expression with that of AKT1, AKT2, p-AKT, survivin and BRCA1/p220, tumor status and age at diagnosis. Generation of subcutaneous tumors in SCID mice using human mammary epithelial (HME) cells overexpressing TERT/LT/BRCA1-IRIS, followed by comparing AKT, survivin, and BRCA1/p220 expression, tumor status and aggressiveness in these tumors to that in tumors developed using TERT/LT/Ras(V12)-overexpressing HME cells. Induction of primary and invasive rat mammary tumors using the carcinogen N-methyl-N-nitrosourea (NMU), followed by analysis of rat BRCA1-IRIS and ERα mRNA levels in these tumors. High BRCA1-IRIS expression was detected in the majority of human breast tumors analyzed, which was positively correlated with that of AKT1-, AKT2-, p-AKT-, survivin, but negatively with BRCA1/p220 expression. BRCA1-IRIS-positivity induced high-grade, early onset and metastatic HER2(+) or TN/BL tumors. TERT/LT/BRCA1-IRIS overexpressing HME cells formed invasive subcutaneous tumors that express high AKT1, AKT2, p-AKT and vimentin, but no CK19, p63 or BRCA1/p220. NMU-induced primary and invasive rat breast cancers expressed high levels of rat BRCA1-IRIS mRNA but low levels of rat ERα mRNA.Conclusion/significanceBRCA1-IRIS overexpression triggers aggressive breast tumor formation, especially in patients with HER2(+) or TN/BL subtypes. We propose that BRCA1-IRIS inhibition may be pursued as a novel therapeutic option to treat these aggressive breast tumor subtypes.

Dataset Information

Overexpression of HMGA2 promotes metastasis and impacts survival of colorectal cancers.

Publications

Overexpression of HMGA2 promotes metastasis and impacts survival of colorectal cancers.

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