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


METHODS
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 γ-H2AX in HCT-116 and SW480 cells post γ-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).


CONCLUSIONS
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.
Departments of Surgical Oncology and Pathology, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Xiaochen
X
Wang
Xiyong
X
Liu
Angela Ying-Jian
AY
Li
Lirong
L
Chen
Lily
L
Lai
Her Helen
HH
Lin
Shuya
S
Hu
Lifang
L
Yao
Jiaping
J
Peng
Sofia
S
Loera
Lijun
L
Xue
Bingsen
B
Zhou
Lun
L
Zhou
Shu
S
Zheng
Peiguo
P
Chu
Suzhan
S
Zhang
David Kong
DK
Ann
Yun
Y
Yen
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003106:Colon / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D045325:HCT116 Cells; D057809:HEK293 Cells; D025743:HMGA2 Protein / Q000096:biosynthesis* / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000706:statistics & numerical data; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies
D014408:Biomarkers, Tumor; C468783:H2AX protein, human; D025743:HMGA2 Protein; D006657:Histones
Cell. 2007 Dec 14;131(6):1109-23
18083101
Science. 2007 Mar 16;315(5818):1576-9
17322030
Biochim Biophys Acta. 2010 Jan-Feb;1799(1-2):55-61
20123068
Cancer Cell. 2006 Jul;10(1):13-24
16843262
Clin Cancer Res. 2008 Apr 15;14(8):2334-40
18413822
Clin Cancer Res. 2006 Nov 1;12(21):6337-44
17085643
Genes Chromosomes Cancer. 2010 Aug;49(8):661-8
20544840
Lancet. 2010 Mar 20;375(9719):1030-47
20304247
Br J Cancer. 2003 May 6;88(9):1406-10
12778070
J Biol Chem. 2000 May 12;275(19):14394-400
10747931
Oncol Rep. 2005 Sep;14(3):737-41
16077985
Nat Rev Cancer. 2007 Dec;7(12):899-910
18004397
FEBS Lett. 2004 Sep 10;574(1-3):1-8
15358530
Surg Oncol Clin N Am. 2007 Jul;16(3):493-506, vii-viii
17606190
Cancer Res. 1999 Oct 1;59(19):4793-7
10519386
Cancer Res. 2009 Jul 15;69(14):5699-706
19549901
Oncogene. 2002 May 9;21(20):3190-8
12082634
Cancer Res. 2004 Mar 15;64(6):2024-9
15026339
Int J Oncol. 2008 Feb;32(2):289-305
18202751
Nat Cell Biol. 2008 May;10(5):567-74
18425117
Carcinogenesis. 2001 Oct;22(10):1583-91
11576996
Eur J Cancer. 2005 Sep;41(14):2060-70
16125380
Zhonghua Zhong Liu Za Zhi. 2009 Jun;31(6):428-33
19950551
Nucleic Acids Res. 2009 Jul;37(13):4371-84
19465398
Cancer. 2010 Sep 1;116(17):4178-86
20549764
Cell. 2008 Oct 17;135(2):227-39
18957199
Int J Colorectal Dis. 2009 Nov;24(11):1281-6
19609535
Cancer Genet Cytogenet. 1998 Jun;103(2):175-7
9614921
Br J Cancer. 2009 Oct 20;101(8):1282-9
19773751
Cancer Cell. 2006 Jun;9(6):459-71
16766265
CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108
15761078
Cancer Genet Cytogenet. 1996 Aug;90(1):88-90
8780755
CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300
20610543
J Pathol. 2006 Jun;209(2):206-12
16521118
Genes Dev. 2007 May 1;21(9):1025-30
17437991
Mol Carcinog. 1997 Jul;19(3):153-6
9254881
Am J Pathol. 2006 May;168(5):1452-63
16651613
Cancer Res. 2005 Aug 1;65(15):6622-30
16061642
Cancer Genet Cytogenet. 1997 Jun;95(2):198-205
9169041
Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11400-5
17600087