Transforming growth factor β1 promotes migration and invasion in HepG2 cells: Epithelial‑to‑mesenchymal transition via JAK/STAT3 signaling

Lin,Xiao‑Long; Liu,Mihua; Liu,Yuanbo; Hu,Huijun; Pan,Yongquan; Zou,Weiwen; Fan,Xiaojuan; Hu,Xuemei

doi:10.3892/ijmm.2017.3228

Transforming growth factor β1 promotes migration and invasion in HepG2 cells: Epithelial‑to‑mesenchymal transition via JAK/STAT3 signaling

Authors:
- Xiao‑Long Lin
- Mihua Liu
- Yuanbo Liu
- Huijun Hu
- Yongquan Pan
- Weiwen Zou
- Xiaojuan Fan
- Xuemei Hu
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Affiliations: Department of Pathology, Huizhou Third People's Hospital, Guangzhou Medical University, Huizhou, Guangdong 516002, P.R. China, Department of Clinical Laboratory, Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421001, P.R. China, Department of Neurology, The Sixth People's Hospital of Huizhou, Huizhou, Guangdong 516211, P.R. China
Published online on: November 1, 2017 https://doi.org/10.3892/ijmm.2017.3228
Pages: 129-136
Copyright: © Lin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Transforming growth factor β1 (TGFβ1) is a cytokine with multiple functions. TGFβ1 significantly induces migration and invasion of liver cancer cells. However, the molecular mechanisms underlying this effect remain unclear. Epithelial‑to‑mesenchymal transition (EMT) is crucial for the development of invasion and metastasis in human cancers. The aim of the present study was to determine whether TGFβ1‑induced EMT promoted migration and invasion in HepG2 cells. The underlying mechanism and the effect of EMT on HepG2 cells were also investigated. The results demonstrated that TGFβ1 may induce EMT to promote migration and invasion of HepG2 cells, and this effect depends on activation of the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway. JAK/STAT3 signaling is involved in human malignancies, including lung cancer, and is implicated in cell transformation, tumorigenicity, EMT and metastasis. In the present study, TGFβ1 also activated JAK/STAT3 signaling in HepG2 cells and promoted Twist expression, but these events were abolished by treatment with the STAT3 inhibitor AG490. Additionally, Twist siRNA blocked TGFβ1‑induced EMT. Thus, TGFβ1 was shown to induce EMT, thereby promoting the migration and invasion of HepG2 cells via JAK/STAT3/Twist signaling.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Huang HC, Hu CH, Tang MC, Wang WS, Chen PM and Su Y: Thymosin beta4 triggers an epithelial-mesenchymal transition in colorectal carcinoma by upregulating integrin-linked kinase. Oncogene. 26:2781–2790. 2007. View Article : Google Scholar
3	Gjerdrum C, Tiron C, Høiby T, Stefansson I, Haugen H, Sandal T, Collett K, Li S, McCormack E, Gjertsen BT, et al: Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proc Natl Acad Sci USA. 107:1124–1129. 2010. View Article : Google Scholar : PubMed/NCBI
4	Song Y, Washington MK and Crawford HC: Loss of FOXA1/2 is essential for the epithelial-to-mesenchymal transition in pancreatic cancer. Cancer Res. 70:2115–2125. 2010. View Article : Google Scholar : PubMed/NCBI
5	Lee TK, Poon RT, Yuen AP, Ling MT, Kwok WK, Wang XH, Wong YC, Guan XY, Man K, Chau KL, et al: Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res. 12:5369–5376. 2006. View Article : Google Scholar : PubMed/NCBI
6	Giannelli G, Fransvea E, Bergamini C, Marinosci F and Antonaci S: Laminin-5 chains are expressed differentially in metastatic and nonmetastatic hepatocellular carcinoma. Clin Cancer Res. 9:3684–3691. 2003.PubMed/NCBI
7	Lee J, Choi JH and Joo CK: TGF-β1 regulates cell fate during epithelial-mesenchymal transition by upregulating survivin. Cell Death Dis. 4:e7142013. View Article : Google Scholar
8	O'Connor JW and Gomez EW: Cell adhesion and shape regulate TGF-beta1-induced epithelial-myofibroblast transition via MRTF-A signaling. PLoS One. 8:e831882013. View Article : Google Scholar : PubMed/NCBI
9	Wendt MK, Balanis N, Carlin CR and Schiemann WP: STAT3 and epithelial-mesenchymal transitions in carcinomas. JAK-STAT. 3:e289752014. View Article : Google Scholar : PubMed/NCBI
10	Kamran MZ, Patil P and Gude RP: Role of STAT3 in cancer metastasis and translational advances. Biomed Res Int. 421821:2013. View Article : Google Scholar : PubMed/NCBI
11	Hills CE and Squires PE: The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy. Cytokine Growth Factor Rev. 22:131–139. 2011.PubMed/NCBI
12	Książkiewicz M, Markiewicz A and Zaczek AJ: Epithelial-mesenchymal transition: A hallmark in metastasis formation linking circulating tumor cells and cancer stem cells. Pathobiology. 79:195–208. 2012. View Article : Google Scholar
13	Levy DE and Darnell JE Jr: Stats: transcriptional control and biological irnpact. Nat Rev Mol Cell Biol. 3:651–662. 2002. View Article : Google Scholar : PubMed/NCBI
14	Wu Y, Sarkissyan M and Vadgama JV: Epithelial-Mesenchymal Transition and Breast Cancer. J Clin Med. 5:2–18. 2016. View Article : Google Scholar
15	Brivio S, Cadamuro M, Fabris L and Strazzabosco M: Epithelial-to-mesenchymal transition and cancer invasiveness: What can we learn from cholangiocarcinoma. J Clin Med. 4:2028–2041. 2015. View Article : Google Scholar : PubMed/NCBI
16	Nalluri SM, O'Connor JW and Gomez EW: Cytoskeletal signaling in TGFβ-induced epithelial-mesenchymal transition. Cytoskeleton. 72:557–569. 2015. View Article : Google Scholar
17	Cheng GZ, Zhang WZ, Sun M, Wang Q, Coppola D, Mansour M, Xu LM, Costanzo C, Cheng JQ and Wang LH: Twist is transcriptionally induced by activation of STAT3 and mediates STAT3 oncogenic function. J Biol Chem. 283:14665–14673. 2008. View Article : Google Scholar : PubMed/NCBI
18	Zhang S, Sun WY, Wu JJ, Gu YJ and Wei W: Decreased expression of the type III TGF-β receptor enhances metastasis and invasion in hepatocellullar carcinoma progression. Oncol Rep. 35:2373–2381. 2016. View Article : Google Scholar : PubMed/NCBI
19	Yeh YH, Wang SW, Yeh YC, Hsiao HF and Li TK: Rhapontigenin inhibits TGF-β-mediated epithelial mesenchymal transition via the I3K/AKT/mTOR pathway and is not associated with HIF-1α degradation. Oncol Rep. 35:2887–2895. 2016. View Article : Google Scholar : PubMed/NCBI
20	Piccirillo R and Giavazzi R: Inactivating STAT3: Bad for tumor, good for muscle. Cell Cycle. 14:939–940. 2015. View Article : Google Scholar : PubMed/NCBI
21	Wake MS and Watson CJ: STAT3 the oncogene - still eluding therapy. FEBS J. 282:2600–2611. 2015. View Article : Google Scholar : PubMed/NCBI
22	Colomiere M, Ward AC, Riley C, Trenerry MK, Cameron-Smith D, Findlay J, Ackland L and Ahmed N: Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial-mesenchymal transition in ovarian carcinomas. Br J Cancer. 100:134–144. 2009. View Article : Google Scholar
23	Li CJ, Li YC, Zhang DR and Pan JH: Signal transducers and activators of transcription 3 function in lung cancer. J Cancer Res Ther. 9(Suppl 2): S67–S73. 2013. View Article : Google Scholar : PubMed/NCBI
24	Liu A, Zhao F, Wang J, Zhao Y, Luo Z, Gao Y and Shi J: Regulation of TRPM7 function by IL-6 through the JAK2 STAT3 signaling pathway. PLoS One. 11:e0152120–e0152132. 2016. View Article : Google Scholar
25	Xiong H, Zhang ZG, Tian XQ, Sun DF, Liang QC, Zhang YJ, Lu R, Chen YX and Fang JY: Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells. Neoplasia. 10:287–297. 2008. View Article : Google Scholar : PubMed/NCBI
26	Liu RY, Zeng Y, Lei Z, Wang L, Yang H, Liu Z, Zhao J and Zhang HT: JAK/STAT3 signaling is required for TGF-β-induced epithelial-mesenchymal transition in lung cancer cells. Int J Oncol. 44:1643–1651. 2014. View Article : Google Scholar : PubMed/NCBI