Abstract
The poor prognosis of hepatocellular carcinoma (HCC) is mainly due to tumor recurrence and metastases. Recently, epithelial–mesenchymal transition (EMT) has been implicated in tumor invasion and metastasis. However, the underlying molecular mechanisms are yet to be elucidated. Here, we show that 30-kDa Tat-interacting protein (TIP30), also called CC3, is significantly downregulated during transforming growth factor-β-induced EMT. In our in vitro and in vivo studies, we show that decreased TIP30 expression leads to EMT, as well as enhanced motility and invasion of HCC cells. Also, increased self-renewal ability and chemotherapeutic resistance are observed with TIP30 depletion. Moreover, Snail is one of the key transcription factors promoting EMT, and overexpression of TIP30 greatly decreased nucleic accumulation in Snail through the regulation of intracellular localization. Small interfering RNAs targeting Snail attenuated EMT and tumor-initiating properties induced by TIP30 deficiency. We further confirmed that TIP30 competitively interrupted the interaction of Snail with importin-β2 to block the nuclear import of Snail. Consistently, TIP30 expression significantly correlates with E-cadherin expression in HCC patients. TIP30 or combination of E-cadherin is a powerful marker in predicting the prognosis of HCC. Taken together, our results suggest a novel and critical role of TIP30 involved in HCC progression and aggressiveness.
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References
He J, Gu D, Wu X, Reynolds K, Duan X, Yao C et al. Major causes of death among men and women in China. New Engl J Med 2005; 353: 1124–1134.
Coleman WB . Mechanisms of human hepatocarcinogenesis. Curr Mol Med 2003; 3: 573–588.
Shtivelman E . A link between metastasis and resistance to apoptosis of variant small cell lung carcinoma. Oncogene 1997; 14: 2167–2173.
Ito M, Jiang C, Krumm K, Zhang X, Pecha J, Zhao J et al. TIP30 deficiency increases susceptibility to tumorigenesis. Cancer Res 2003; 63: 8763–8767.
Zhao J, Ni H, Ma Y, Dong L, Dai J, Zhao F et al. TIP30/CC3 expression in breast carcinoma: relation to metastasis, clinicopathologic parameters, and P53 expression. Hum Pathol 2007; 38: 293–298.
Tong X, Li K, Luo Z, Lu B, Liu X, Wang T et al. Decreased TIP30 expression promotes tumor metastasis in lung cancer. Am J Pathol 2009; 174: 1931–1939.
Chen X, Cao X, Dong W, Luo S, Suo Z, Jin Y . Expression of TIP30 tumor suppressor gene is down-regulated in human colorectal carcinoma. Dig Dis Sci 2010; 55: 2219–2226.
Lu B, Ma Y, Wu G, Tong X, Guo H, Liang A et al. Methylation of Tip30 promoter is associated with poor prognosis in human hepatocellular carcinoma. Clin Cancer Res 2008; 14: 7405–7412.
Zhao J, Lu B, Xu H, Tong X, Wu G, Zhang X et al. Thirty-kilodalton Tat-interacting protein suppresses tumor metastasis by inhibition of osteopontin transcription in human hepatocellular carcinoma. Hepatology 2008; 48: 265–275.
Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC et al. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med 2003; 9: 416–423.
Huber MA, Kraut N, Beug H . Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 2005; 17: 548–558.
Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY et al. The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133: 704–715.
Morel AP, Lievre M, Thomas C, Hinkal G, Ansieau S, Puisieux A . Generation of breast cancer stem cells through epithelial–mesenchymal transition. PLoS One 2008; 3: e2888.
Yang J, Weinberg RA . Epithelial–mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 2008; 14: 818–829.
Massague J . TGFbeta in Cancer. Cell 2008; 134: 215–230.
Jiang C, Pecha J, Hoshino I, Ankrapp D, Xiao H . TIP30 mutant derived from hepatocellular carcinoma specimens promotes growth of HepG2 cells through up-regulation of N-cadherin. Cancer Res 2007; 67: 3574–3582.
Kalluri R, Weinberg RA . The basics of epithelial–mesenchymal transition. J Clin Invest 2009; 119: 1420–1428.
Li A, Zhang C, Gao S, Chen F, Yang C, Luo R et al. TIP30 loss enhances cytoplasmic and nuclear EGFR signaling and promotes lung adenocarcinogenesis in mice. Oncogene 2013; 32: 2273–2281.
Zhang C, Mori M, Gao S, Li A, Hoshino I, Aupperlee MD et al. Tip30 deletion in MMTV-Neu mice leads to enhanced EGFR signaling and development of estrogen receptor-positive and progesterone receptor-negative mammary tumors. Cancer Res 2010; 70: 10224–10233.
Wang H, Zhou X, Huang J, Mu N, Guo Z, Wen Q et al. The role of Akt/FoxO3a in the protective effect of venlafaxine against corticosterone-induced cell death in PC12 cells. Psychopharmacology (Berl) 2013; 228: 129–141.
Fujiki K, Inamura H, Matsuoka M . Phosphorylation of FOXO3a by PI3K/Akt pathway in HK-2 renal proximal tubular epithelial cells exposed to cadmium. Arch Toxicol 2013; 87: 2119–2127.
Julien S, Puig I, Caretti E, Bonaventure J, Nelles L, van Roy F et al. Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. Oncogene 2007; 26: 7445–7456.
Kim MS, Kim GM, Choi YJ, Kim HJ, Kim YJ, Jin W . TrkC promotes survival and growth of leukemia cells through Akt-mTOR-dependent up-regulation of PLK-1 and Twist-1. Mol Cells 2013; 36: 177–184.
Xue G, Restuccia DF, Lan Q, Hynx D, Dirnhofer S, Hess D et al. Akt/PKB-mediated phosphorylation of Twist1 promotes tumor metastasis via mediating cross-talk between PI3K/Akt and TGF-beta signaling axes. Cancer Discov 2012; 2: 248–259.
Wu K, Fan J, Zhang L, Ning Z, Zeng J, Zhou J et al. PI3K/Akt to GSK3beta/beta-catenin signaling cascade coordinates cell colonization for bladder cancer bone metastasis through regulating ZEB1 transcription. Cell Signal 2012; 24: 2273–2282.
Barrallo-Gimeno A, Nieto MA . The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development 2005; 132: 3151–3161.
Peinado H, Olmeda D, Snail Cano A . Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 2007; 7: 415–428.
Medici D, Hay ED, Olsen BR . Snail and Slug promote epithelial-mesenchymal transition through beta-catenin-T-cell factor-4-dependent expression of transforming growth factor-beta3. Mol Biol Cell 2008; 19: 4875–4887.
Hwang WL, Yang MH, Tsai ML, Lan HY, Su SH, Chang SC et al. SNAIL regulates interleukin-8 expression, stem cell-like activity, and tumorigenicity of human colorectal carcinoma cells. Gastroenterology 2011; 141: 279–291.
Yamasaki H, Sekimoto T, Ohkubo T, Douchi T, Nagata Y, Ozawa M et al. Zinc finger domain of Snail functions as a nuclear localization signal for importin beta-mediated nuclear import pathway. Genes Cells 2005; 10: 455–464.
King FW, Shtivelman E . Inhibition of nuclear import by the proapoptotic protein CC3. Mol Cell Biol 2004; 24: 7091–7101.
Zhao J, Chen J, Lu B, Dong L, Wang H, Bi C et al. TIP30 induces apoptosis under oxidative stress through stabilization of p53 messenger RNA in human hepatocellular carcinoma. Cancer Res 2008; 68: 4133–4141.
Nakahara J, Kanekura K, Nawa M, Aiso S, Suzuki N . Abnormal expression of TIP30 and arrested nucleocytoplasmic transport within oligodendrocyte precursor cells in multiple sclerosis. J Clin Invest 2009; 119: 169–181.
Acloque H, Adams MS, Fishwick K, Bronner-Fraser M, Nieto MA . Epithelial–mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Invest 2009; 119: 1438–1449.
Thiery JP, Sleeman JP . Complex networks orchestrate epithelial–mesenchymal transitions. Nat Rev Mol Cell Biol 2006; 7: 131–142.
Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG et al. The transcription factor snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2000; 2: 76–83.
Chua HL, Bhat-Nakshatri P, Clare SE, Morimiya A, Badve S, Nakshatri H . NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2. Oncogene 2007; 26: 711–724.
Nieto MA . The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 2002; 3: 155–166.
Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004; 117: 927–939.
Fujita Y, Krause G, Scheffner M, Zechner D, Leddy HE, Behrens J et al. Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex. Nat Cell Biol 2002; 4: 222–231.
Pecha J, Ankrapp D, Jiang C, Tang W, Hoshino I, Bruck K et al. Deletion of Tip30 leads to rapid immortalization of murine mammary epithelial cells and ductal hyperplasia in the mammary gland. Oncogene 2007; 26: 7423–7431.
NicAmhlaoibh R, Shtivelman E . Metastasis suppressor CC3 inhibits angiogenic properties of tumor cells in vitro. Oncogene 2001; 20: 270–275.
Banerjee SK, Banerjee S . CCN5/WISP-2: a micromanager of breast cancer progression. J Cell Commun Signal 2012; 6: 63–71.
Graham TR, Zhau HE, Odero-Marah VA, Osunkoya AO, Kimbro KS, Tighiouart M et al. Insulin-like growth factor-I-dependent up-regulation of ZEB1 drives epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Res 2008; 68: 2479–2488.
Zhang W, Sun HC, Wang WQ, Zhang QB, Zhuang PY, Xiong YQ et al. Sorafenib down-regulates expression of HTATIP2 to promote invasiveness and metastasis of orthotopic hepatocellular carcinoma tumors in mice. Gastroenterology 2012; 143: 1641–1649.
Taura K, Miura K, Iwaisako K, Osterreicher CH, Kodama Y, Penz-Osterreicher M et al. Hepatocytes do not undergo epithelial–mesenchymal transition in liver fibrosis in mice. Hepatology 2010; 51: 1027–1036.
Kurrey NK, Jalgaonkar SP, Joglekar AV, Ghanate AD, Chaskar PD, Doiphode RY et al. Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells 2009; 27: 2059–2068.
Dang H, Ding W, Emerson D, Rountree CB . Snail1 induces epithelial-to-mesenchymal transition and tumor initiating stem cell characteristics. BMC Cancer 2011; 11: 396.
Poon RT, Ng IO, Fan ST, Lai EC, Lo CM, Liu CL et al. Clinicopathologic features of long-term survivors and disease-free survivors after resection of hepatocellular carcinoma: a study of a prospective cohort. J Clin Oncol 2001; 19: 3037–3044.
Yang XR, Xu Y, Yu B, Zhou J, Li JC, Qiu SJ et al. CD24 is a novel predictor for poor prognosis of hepatocellular carcinoma after surgery. Clin Cancer Res 2009; 15: 5518–5527.
Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 2007; 25: 2586–2593.
Acknowledgements
This work is supported in part by grants from Ministry of Science and Technology of China '973' and '863' programs (2010CB945600, 2010CB833600, 2011CB966200), National Nature Science Foundation of China, State Key Project for Infection Disease and New Drug Development and Programs of Shanghai Subject Chief Scientists, Municipal Commission of Education and Municipal Commission of Science and Technology.
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Zhu, M., Yin, F., Fan, X. et al. Decreased TIP30 promotes Snail-mediated epithelial–mesenchymal transition and tumor-initiating properties in hepatocellular carcinoma. Oncogene 34, 1420–1431 (2015). https://doi.org/10.1038/onc.2014.73
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DOI: https://doi.org/10.1038/onc.2014.73
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