High-mobility-group A2 overexpression provokes a poor prognosis of gastric cancer through the epithelial-mesenchymal transition

Lee,Junhyun; Ha,Shinjung; Jung,Chan-Kwon; Lee,Han Hong

doi:10.3892/ijo.2015.2947

High-mobility-group A2 overexpression provokes a poor prognosis of gastric cancer through the epithelial-mesenchymal transition

Authors:
- Junhyun Lee
- Shinjung Ha
- Chan-Kwon Jung
- Han Hong Lee
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Affiliations: Division of Gastrointestinal Surgery, Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea, Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
Published online on: April 1, 2015 https://doi.org/10.3892/ijo.2015.2947
Pages: 2431-2438

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Abstract

Tumor metastases are the ultimate target in cancer therapy. In epithelial malignancies, the expression of high-mobility-group A2 (HMGA2) is associated with disease progression and the epithelial-mesenchymal transition (EMT), which is involved in the metastatic process. The present study assessed the clinical and molecular effects of HMGA2 with the malignant tissues of 170 patients with gastric cancer and gastric cancer cells expressing HMGA2. HMGA2 expression was determined using immunohistochemistry and analyzed with respect to the clinicopathological data of patients with this tumor. In the gastric cancer cell line MKN28, in which HMGA2 was knocked down by two different short-hairpin RNAs, Transwell migration and invasion assays were conducted and western blotting was used to detect the altered expression of EMT markers. In patients with gastric cancer, HMGA2 overexpression correlated with tumor progression and was indicative of a significantly worse overall survival. Migration and invasion assays using HMGA2-knocked down MKN28 cells showed a reduction in cell migration and invasion. The upregulation of E-cadherin, an epithelial marker, and the downregulation of N-cadherin, a mesenchymal marker were observed in HMGA2-knocked down cells. In addition, expression of the transcriptional factors Snail and Zeb1 and of the EMT-pathway molecule β-catenin were decreased. HMGA2 overexpression, through its relationship to EMT, thus seems to aggravate invasion and metastasis in gastric cancer. It may therefore serve as a predictive marker in determining the clinical outcome of patients with gastric cancer and offer a promising therapeutic target.

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1	Fidler IJ: Critical determinants of metastasis. Semin Cancer Biol. 12:89–96. 2002. View Article : Google Scholar : PubMed/NCBI
2	Steeg PS: Tumor metastasis: Mechanistic insights and clinical challenges. Nat Med. 12:895–904. 2006. View Article : Google Scholar : PubMed/NCBI
3	Yoon JH, Choi WS, Kim O and Park WS: The role of gastrokine 1 in gastric cancer. J Gastric Cancer. 14:147–155. 2014. View Article : Google Scholar : PubMed/NCBI
4	Reeves R and Nissen MS: The A.T-DNA-binding domain of mammalian high mobility group I chromosomal proteins. A novel peptide motif for recognizing DNA structure. J Biol Chem. 265:8573–8582. 1990.PubMed/NCBI
5	Sgarra R, Rustighi A, Tessari MA, Di Bernardo J, Altamura S, Fusco A, Manfioletti G and Giancotti V: Nuclear phospho-proteins HMGA and their relationship with chromatin structure and cancer. FEBS Lett. 574:1–8. 2004. View Article : Google Scholar : PubMed/NCBI
6	Reeves R: Structure and function of the HMGI(Y) family of architectural transcription factors. Environ Health Perspect. 108(Suppl 5): 803–809. 2000. View Article : Google Scholar : PubMed/NCBI
7	Rogalla P, Drechsler K, Frey G, Hennig Y, Helmke B, Bonk U and Bullerdiek J: HMGI-C expression patterns in human tissues. Implications for the genesis of frequent mesenchymal tumors. Am J Pathol. 149:775–779. 1996.PubMed/NCBI
8	Chiappetta G, Avantaggiato V, Visconti R, Fedele M, Battista S, Trapasso F, Merciai BM, Fidanza V, Giancotti V, Santoro M, et al: High level expression of the HMGI (Y) gene during embryonic development. Oncogene. 13:2439–2446. 1996.PubMed/NCBI
9	Thuault S, Valcourt U, Petersen M, Manfioletti G, Heldin CH and Moustakas A: Transforming growth factor-beta employs HMGA2 to elicit epithelial-mesenchymal transition. J Cell Biol. 174:175–183. 2006. View Article : Google Scholar : PubMed/NCBI
10	Watanabe S, Ueda Y, Akaboshi S, Hino Y, Sekita Y and Nakao M: HMGA2 maintains oncogenic RAS-induced epithelial-mesen-chymal transition in human pancreatic cancer cells. Am J Pathol. 174:854–868. 2009. View Article : Google Scholar : PubMed/NCBI
11	Wei CH, Wei LX, Lai MY, Chen JZ and Mo XJ: Effect of silencing of high mobility group A2 gene on gastric cancer MKN-45 cells. World J Gastroenterol. 19:1239–1246. 2013. View Article : Google Scholar : PubMed/NCBI
12	Zha L, Zhang J, Tang W, Zhang N, He M, Guo Y and Wang Z: HMGA2 elicits EMT by activating the Wnt/β-catenin pathway in gastric cancer. Dig Dis Sci. 58:724–733. 2013. View Article : Google Scholar
13	Joo YE, Chung IJ, Park YK, Koh YS, Lee JH, Park CH, Lee WS, Kim HS, Choi SK, Rew JS, et al: Expression of cyclooxygenase-2, p53 and Ki-67 in gastric cancer. J Korean Med Sci. 21:871–876. 2006. View Article : Google Scholar : PubMed/NCBI
14	Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI
15	Jing Y, Han Z, Zhang S, Liu Y and Wei L: Epithelial-mesenchymal transition in tumor microenvironment. Cell Biosci. 1:292011. View Article : Google Scholar : PubMed/NCBI
16	Rogalla P, Drechsler K, Kazmierczak B, Rippe V, Bonk U and Bullerdiek J: Expression of HMGI-C, a member of the high mobility group protein family, in a subset of breast cancers: Relationship to histologic grade. Mol Carcinog. 19:153–156. 1997. View Article : Google Scholar : PubMed/NCBI
17	Meyer B, Loeschke S, Schultze A, Weigel T, Sandkamp M, Goldmann T, Vollmer E and Bullerdiek J: HMGA2 overexpression in non-small cell lung cancer. Mol Carcinog. 46:503–511. 2007. View Article : Google Scholar : PubMed/NCBI
18	Miyazawa J, Mitoro A, Kawashiri S, Chada KK and Imai K: Expression of mesenchyme-specific gene HMGA2 in squamous cell carcinomas of the oral cavity. Cancer Res. 64:2024–2029. 2004. View Article : Google Scholar : PubMed/NCBI
19	Abe N, Watanabe T, Suzuki Y, Matsumoto N, Masaki T, Mori T, Sugiyama M, Chiappetta G, Fusco A and Atomi Y: An increased high-mobility group A2 expression level is associated with malignant phenotype in pancreatic exocrine tissue. Br J Cancer. 89:2104–2109. 2003. View Article : Google Scholar : PubMed/NCBI
20	Sarhadi VK, Wikman H, Salmenkivi K, Kuosma E, Sioris T, Salo J, Karjalainen A, Knuutila S and Anttila S: Increased expression of high mobility group A proteins in lung cancer. J Pathol. 209:206–212. 2006. View Article : Google Scholar : PubMed/NCBI
21	Shell S, Park SM, Radjabi AR, Schickel R, Kistner EO, Jewell DA, Feig C, Lengyel E and Peter ME: Let-7 expression defines two differentiation stages of cancer. Proc Natl Acad Sci USA. 104:11400–11405. 2007. View Article : Google Scholar : PubMed/NCBI
22	Langelotz C, Schmid P, Jakob C, Heider U, Wernecke KD, Possinger K and Sezer O: Expression of high-mobility-group-protein HMGI-C mRNA in the peripheral blood is an independent poor prognostic indicator for survival in metastatic breast cancer. Br J Cancer. 88:1406–1410. 2003. View Article : Google Scholar : PubMed/NCBI
23	Wang X, Liu X, Li AY, Chen L, Lai L, Lin HH, Hu S, Yao L, Peng J, Loera S, et al: Overexpression of HMGA2 promotes metastasis and impacts survival of colorectal cancers. Clin Cancer Res. 17:2570–2580. 2011. View Article : Google Scholar : PubMed/NCBI
24	Motoyama K, Inoue H, Nakamura Y, Uetake H, Sugihara K and Mori M: Clinical significance of high mobility group A2 in human gastric cancer and its relationship to let-7 microRNA family. Clin Cancer Res. 14:2334–2340. 2008. View Article : Google Scholar : PubMed/NCBI
25	Murai T, Yamada S, Fuchs BC, Fujii T, Nakayama G, Sugimoto H, Koike M, Fujiwara M, Tanabe KK and Kodera Y: Epithelial-to-mesenchymal transition predicts prognosis in clinical gastric cancer. J Surg Oncol. 109:684–689. 2014. View Article : Google Scholar : PubMed/NCBI
26	Ryu HS, Park J, Kim HH, Kim WH and Lee HS: Combination of epithelial-mesenchymal transition and cancer stem cell-like phenotypes has independent prognostic value in gastric cancer. Hum Pathol. 43:520–528. 2012. View Article : Google Scholar
27	Peng Z, Wang CX, Fang EH, Wang GB and Tong Q: Role of epithelial-mesenchymal transition in gastric cancer initiation and progression. World J Gastroenterol. 20:5403–5410. 2014. View Article : Google Scholar : PubMed/NCBI
28	Wu J, Liu Z, Shao C, Gong Y, Hernando E, Lee P, Narita M, Muller W, Liu J and Wei JJ: HMGA2 overexpression-induced ovarian surface epithelial transformation is mediated through regulation of EMT genes. Cancer Res. 71:349–359. 2011. View Article : Google Scholar : PubMed/NCBI
29	Morishita A, Zaidi MR, Mitoro A, Sankarasharma D, Szabolcs M, Okada Y, D’Armiento J and Chada K: HMGA2 is a driver of tumor metastasis. Cancer Res. 73:4289–4299. 2013. View Article : Google Scholar : PubMed/NCBI
30	Liu X, Lai L, Wang X, Xue L, Leora S, Wu J, Hu S, Zhang K, Kuo ML, Zhou L, et al: Ribonucleotide reductase small subunit M2B prognoses better survival in colorectal cancer. Cancer Res. 71:3202–3213. 2011. View Article : Google Scholar : PubMed/NCBI
31	Sánchez-Tilló E, Liu Y, de Barrios O, Siles L, Fanlo L, Cuatrecasas M, Darling DS, Dean DC, Castells A and Postigo A: EMT-activating transcription factors in cancer: Beyond EMT and tumor invasiveness. Cell Mol Life Sci. 69:3429–3456. 2012. View Article : Google Scholar : PubMed/NCBI
32	Rosivatz E, Becker I, Specht K, Fricke E, Luber B, Busch R, Höfler H and Becker KF: Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. Am J Pathol. 161:1881–1891. 2002. View Article : Google Scholar : PubMed/NCBI
33	Castro Alves C, Rosivatz E, Schott C, Hollweck R, Becker I, Sarbia M, Carneiro F and Becker KF: Slug is overexpressed in gastric carcinomas and may act synergistically with SIP1 and Snail in the down-regulation of E-cadherin. J Pathol. 211:507–515. 2007. View Article : Google Scholar : PubMed/NCBI
34	Stemmer V, de Craene B, Berx G and Behrens J: Snail promotes Wnt target gene expression and interacts with beta-catenin. Oncogene. 27:5075–5080. 2008. View Article : Google Scholar : PubMed/NCBI