TGF-β1 induces HMGA1 expression in human breast cancer cells: Implications of the involvement of HMGA1 in TGF-β signaling

Zu,Xuyu; Zhong,Jing; Tan,Jingjing; Tan,Li; Yang,Dong; Zhang,Qinghai; Ding,Wenjun; Liu,Wen; Wen,Gebo; Liu,Jianghua; Cao,Renxian; Jiang,Yuyang

doi:10.3892/ijmm.2015.2062

TGF-β1 induces HMGA1 expression in human breast cancer cells: Implications of the involvement of HMGA1 in TGF-β signaling

Authors:
- Xuyu Zu
- Jing Zhong
- Jingjing Tan
- Li Tan
- Dong Yang
- Qinghai Zhang
- Wenjun Ding
- Wen Liu
- Gebo Wen
- Jianghua Liu
- Renxian Cao
- Yuyang Jiang
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Affiliations: Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China, Guangdong Provincial Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen, Guangdong 518055, P.R. China
Published online on: January 5, 2015 https://doi.org/10.3892/ijmm.2015.2062
Pages: 693-701
Copyright: © Zu et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Transforming growth factor-β1 (TGF-β1) signaling and high mobility group A (HMGA1) are known to play essential roles in the progression of breast cancer by inducing epithelial-mesenchymal transition. However, the correlation between TGF-β1 and HMGA1 in breast cancer cell is not yet well understood. In this study, we determined the effects of TGF-β1 on HMGA1 expression in breast cancer cells and examined the role of HMGA1 in breast cancer progression. Our results demonstrated that TGF-β1 induced the expression of HMGA1 in both MCF-7 and MDA-MB-231 breast cancer cells, as shown by RT-qPCR and immunofluorescence staining; however, the TGF-β1-induced expression of HMGA was blocked by treatment of the cells with phosphatidylinositol-3 kinase (PI3K) signaling inhibitors. Moreover, the HMGA1 promoter activity was found to be activated by TGF-β1 in the MCF-7 and MDA-MB-231 cells and we found that specificity protein 1 (Sp1) was involved in the TGF-β1-induced HMGA1 promoter activity, as shown by luciferase activity assay. Furthermore, the enforced expression of HMGA1 by transfection with a HMGA1 promoter enhanced cellular oncogenic properties, including proliferation, migration and invasion, and a tissue microarray revealed that breast tumors expressing human epidermal growth factor receptor 2 (HER2) showed higher expression levels of HMGA1 (P=0.007). In addition, higher HMGA1 expression levels were also observed in the ductal breast cancer cases compared with the lobular breast cancer cases (P=0.000). These findings establish the first link between HMGA1 and TGF-β1 in breast cancer, providing further evidence of the pivotal role of HMGA1 in breast cancer progression.

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1	Porter PL: Global trends in breast cancer incidence and mortality. Salud Publica Mex. 51(Suppl 2): s141–s146. 2009. View Article : Google Scholar
2	Yang L, Pang Y and Moses HL: TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 31:220–227. 2010. View Article : Google Scholar : PubMed/NCBI
3	Smith AL, Robin TP and Ford HL: Molecular pathways: targeting the TGF-β pathway for cancer therapy. Clin Cancer Res. 18:4514–4521. 2012. View Article : Google Scholar : PubMed/NCBI
4	Derynck R, Akhurst RJ and Balmain A: TGF-beta signaling in tumor suppression and cancer progression. Nat Genet. 29:117–129. 2001. View Article : Google Scholar : PubMed/NCBI
5	Reeves R: Nuclear functions of the HMG proteins. Biochim Biophys Acta. 1799:3–14. 2010. View Article : Google Scholar
6	Resar LM: The high mobility group A1 gene: transforming inflammatory signals into cancer? Cancer Res. 70:436–439. 2010. View Article : Google Scholar : PubMed/NCBI
7	Fusco A and Fedele M: Roles of HMGA proteins in cancer. Nat Rev Cancer. 7:899–910. 2007. View Article : Google Scholar : PubMed/NCBI
8	Ben-Porath I, Thomson MW, Carey VJ, et al: An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet. 40:499–507. 2008. View Article : Google Scholar : PubMed/NCBI
9	Chou BK, Mali P, Huang X, et al: Efficient human iPS cell derivation by a non-integrating plasmid from blood cells with unique epigenetic and gene expression signatures. Cell Res. 21:518–529. 2011. View Article : Google Scholar : PubMed/NCBI
10	Karp JE, Smith BD, Resar LS, et al: Phase 1 and pharmacokinetic study of bolus-infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias. Blood. 117:3302–3310. 2011. View Article : Google Scholar : PubMed/NCBI
11	Nelson DM, Joseph B, Hillion J, Segal J, Karp JE and Resar LM: Flavopiridol induces BCL-2 expression and represses oncogenic transcription factors in leukemic blasts from adults with refractory acute myeloid leukemia. Leuk Lymphoma. 52:1999–2006. 2011. View Article : Google Scholar : PubMed/NCBI
12	Schuldenfrei A, Belton A, Kowalski J, et al: HMGA1 drives stem cell, inflammatory pathway, and cell cycle progression genes during lymphoid tumorigenesis. BMC Genomics. 12(549): 2011
13	Belton A, Gabrovsky A, Bae YK, et al: HMGA1 induces intestinal polyposis in transgenic mice and drives tumor progression and stem cell properties in colon cancer cells. PLoS One. 7:e300342012. View Article : Google Scholar : PubMed/NCBI
14	Shah SN and Resar LM: High mobility group A1 and cancer: potential biomarker and therapeutic target. Histol Histopathol. 27:567–579. 2012.PubMed/NCBI
15	Abe N, Watanabe T, Masaki T, et al: Pancreatic duct cell carcinomas express high levels of high mobility group I(Y) proteins. Cancer Res. 60:3117–3122. 2000.PubMed/NCBI
16	Chiappetta G, Tallini G, De Biasio MC, et al: Detection of high mobility group I HMGI(Y) protein in the diagnosis of thyroid tumors: HMGI(Y) expression represents a potential diagnostic indicator of carcinoma. Cancer Res. 58:4193–4198. 1998.PubMed/NCBI
17	Chiappetta G, Manfioletti G, Pentimalli F, et al: High mobility group HMGI(Y) protein expression in human colorectal hyperplastic and neoplastic diseases. Int J Cancer. 91:147–151. 2001. View Article : Google Scholar : PubMed/NCBI
18	Chiappetta G, Botti G, Monaco M, et al: HMGA1 protein over-expression in human breast carcinomas: correlation with ErbB2 expression. Clin Cancer Res. 10:7637–7644. 2004. View Article : Google Scholar : PubMed/NCBI
19	Meyer B, Loeschke S, Schultze A, et al: HMGA2 overexpression in non-small cell lung cancer. Mol Carcinog. 46:503–511. 2007. View Article : Google Scholar : PubMed/NCBI
20	Masciullo V, Baldassarre G, Pentimalli F, et al: HMGA1 protein over-expression is a frequent feature of epithelial ovarian carcinomas. Carcinogenesis. 24:1191–1198. 2003. View Article : Google Scholar : PubMed/NCBI
21	Tamimi Y, van der Poel HG, Denyn MM, et al: Increased expression of high mobility group protein I(Y) in high grade prostatic cancer determined by in situ hybridization. Cancer Res. 53:5512–5516. 1993.PubMed/NCBI
22	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
23	Rho YS, Lim YC, Park IS, et al: High mobility group HMGI(Y) protein expression in head and neck squamous cell carcinoma. Acta Otolaryngol. 127:76–81. 2007. View Article : Google Scholar : PubMed/NCBI
24	Dolde CE, Mukherjee M, Cho C and Resar LM: HMG-I/Y in human breast cancer cell lines. Breast Cancer Res Treat. 71:181–191. 2002. View Article : Google Scholar : PubMed/NCBI
25	Zhong J, Cao RX, Zu XY, et al: Identification and characterization of novel spliced variants of PRMT2 in breast carcinoma. FEBS J. 279:316–335. 2012. View Article : Google Scholar
26	Welch DR, Fabra A and Nakajima M: Transforming growth factor beta stimulates mammary adenocarcinoma cell invasion and metastatic potential. Proc Natl Acad Sci USA. 87:7678–7682. 1990. View Article : Google Scholar : PubMed/NCBI
27	Derynck R and Zhang YE: Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature. 425:577–584. 2003. View Article : Google Scholar : PubMed/NCBI
28	Moustakas A and Heldin CH: Non-Smad TGF-β signals. J Cell Sci. 118:3573–3584. 2005. View Article : Google Scholar : PubMed/NCBI
29	Massimi I, Guerrieri F, Petroni M, Veschi V, Truffa S, Screpanti I, Frati L, Levrero M, Gulino A and Giannini G: The HMGA1 protoncogene frequently deregulated in cancer is a transcriptional target of E2F1. Mol Carcinog. 52:526–534. 2013. View Article : Google Scholar
30	Abe N, Watanabe T, Izumisato Y, et al: High mobility group A1 is expressed in metastatic adenocarcinoma to the liver and intrahepatic cholangiocarcinoma, but not in hepatocellular carcinoma: its potential use in the diagnosis of liver neoplasms. J Gastroenterol. 38:1144–1149. 2003. View Article : Google Scholar
31	Shah SN, Kerr C, Cope L, et al: HMGA1 reprograms somatic cells into pluripotent stem cells by inducing stem cell transcriptional networks. PLoS One. 7:e485332012. View Article : Google Scholar : PubMed/NCBI
32	Wang Q, Ji Y, Wang X and Evers BM: Isolation and molecular characterization of the 5′-upstream region of the human TRAIL gene. Biochem Biophys Res Commun. 276:466–471. 2000. View Article : Google Scholar : PubMed/NCBI
33	Chan J, Prado-Lourenco L, Khachigian LM, Bennett MR, Di Bartolo BA and Kavurma MM: TRAIL promotes VSMC proliferation and neointima formation in a FGF-2-, Sp1 phosphorylation-, and NFkappaB-dependent manner. Circ Res. 106:1061–1071. 2010. View Article : Google Scholar : PubMed/NCBI
34	Flohr AM, Rogalla P, Bonk U, et al: High mobility group protein HMGA1 expression in breast cancer reveals a positive correlation with tumour grade. Histol Histopathol. 18:999–1004. 2003.PubMed/NCBI