5.9
CiteScore
5.9
Impact Factor
Volume 47 Issue 9
Sep.  2020
Turn off MathJax
Article Contents
Article Navigation >  Journal of Genetics and Genomics  > 2020  >  47(9): 497-512

The dichotomous role of TGF-β in controlling liver cancer cell survival and proliferation

doi: 10.1016/j.jgg.2020.09.005
  • a 

    Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, Nanchang, 330006, China

  • b 

    School of Biological Engineering, Huainan Normal University, Huainan, 232001, China

  • c 

    School of Basic Medical Sciences, Nanchang University, Nanchang 330006, China

  • d 

    Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China

  • e 

    Institute of Biomedical Sciences, Nanchang University Medical College, Nanchang, 330031, China

More Information
    Abstract
  • Hepatocellular carcinoma (HCC) is the major form of primary liver cancer and one of the most prevalent and life-threatening malignancies globally. One of the hallmarks in HCC is the sustained cell survival and proliferative signals, which are determined by the balance between oncogenes and tumor suppressors. Transforming growth factor beta (TGF-β) is an effective growth inhibitor of epithelial cells including hepatocytes, through induction of cell cycle arrest, apoptosis, cellular senescence, or autophagy. The antitumorigenic effects of TGF-β are bypassed during liver tumorigenesis via multiple mechanisms. Furthermore, along with malignant progression, TGF-β switches to promote cancer cell survival and proliferation. This dichotomous nature of TGF-β is one of the barriers to therapeutic targeting in liver cancer. Thereafter, understanding the underlying molecular mechanisms is a prerequisite for discovering novel antitumor drugs that may specifically disable the growth-promoting branch of TGF-β signaling or restore its tumor-suppressive arm. This review summarizes how TGF-β inhibits or promotes liver cancer cell survival and proliferation, highlighting the functional switch mechanisms during the process.
    • These authors contributed equally to the work.
    FullText(HTML)
  • loading
    • References(205)
  • [1]
    Ali, A., Zhang, P., Liangfang, Y., Wenshe, S., Wang, H., Lin, X., Dai, Y., Feng, X.H., Moses, R., Wang, D., Li, X., Xiao, J., 2015. KLF17 empowers TGF-beta/Smad signaling by targeting Smad3-dependent pathway to suppress tumor growth and metastasis during cancer progression. Cell Death Dis. 6, e1681.
    [2]
    Allaire, M., Rautou, P.E., Codogno, P., Lotersztajn, S., 2019. Autophagy in liver diseases: Time for translation? J. Hepatol. 70, 985-998.
    [3]
    Anido, J., Saez-Borderias, A., Gonzalez-Junca, A., Rodon, L., Folch, G., Carmona, M.A., Prieto-Sanchez, R.M., Barba, I., Martinez-Saez, E., Prudkin, L., Cuartas, I., Raventos, C., Martinez-Ricarte, F., Poca, M.A., Garcia-Dorado, D., Lahn, M.M., Yingling, J.M., Rodon, J., Sahuquillo, J., Baselga, J., Seoane, J., 2010. TGF-beta receptor inhibitors target the CD44(high)/Id1(high) glioma-initiating cell population in human glioblastoma. Cancer Cell 18, 655-668.
    [4]
    Arsura, M., Panta, G.R., Bilyeu, J.D., Cavin, L.G., Sovak, M.A., Oliver, A.A., Factor, V., Heuchel, R., Mercurio, F., Thorgeirsson, S.S., Sonenshein, G.E., 2003. Transient activation of NF-kappaB through a TAK1/IKK kinase pathway by TGF-beta1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation. Oncogene 22, 412-425.
    [5]
    Berasain, C., Ujue Latasa, M., Urtasun, R., Goni, S., Elizalde, M., Garcia-Irigoyen, O., Azcona, M., Prieto, J., Avila, M.A., 2011. Epidermal growth factor receptor (EGFR) crosstalks in liver cancer. Cancers 3, 2444-2461.
    [6]
    Bierie, B., Moses, H.L., 2006. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat. Rev. Cancer 6, 506-520.
    [7]
    Bird, T.G., Muller, M., Boulter, L., Vincent, D.F., Ridgway, R.A., Lopez-Guadamillas, E., Lu, W.Y., Jamieson, T., Govaere, O., Campbell, A.D., Ferreira-Gonzalez, S., Cole, A.M., Hay, T., Simpson, K.J., Clark, W., Hedley, A., Clarke, M., Gentaz, P., Nixon, C., Bryce, S., Kiourtis, C., Sprangers, J., Nibbs, R.J.B., Van Rooijen, N., Bartholin, L., McGreal, S.R., Apte, U., Barry, S.T., Iredale, J.P., Clarke, A.R., Serrano, M., Roskams, T.A., Sansom, O.J., Forbes, S.J., 2018. TGFbeta inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence. Sci. Transl. Med. 10, eaan1230.
    [8]
    Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R.L., Torre, L.A., Jemal, A., 2018. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394-424.
    [9]
    Brenner, C., Galluzzi, L., Kepp, O., Kroemer, G., 2013. Decoding cell death signals in liver inflammation. J. Hepatol. 59, 583-594.
    [10]
    Cai, J., Pardali, E., Sanchez-Duffhues, G., ten Dijke, P., 2012. BMP signaling in vascular diseases. FEBS Lett. 586, 1993-2002.
    [11]
    Caja, L., Dituri, F., Mancarella, S., Caballero-Diaz, D., Moustakas, A., Giannelli, G., Fabregat, I., 2018. TGF-beta and the tissue microenvironment: relevance in fibrosis and cancer. Int. J. Mol. Sci. 19, 1294.
    [12]
    Caja, L., Ortiz, C., Bertran, E., Murillo, M.M., Miro-Obradors, M.J., Palacios, E., Fabregat, I., 2007. Differential intracellular signalling induced by TGF-beta in rat adult hepatocytes and hepatoma cells: implications in liver carcinogenesis. Cell Signal. 19, 683-694.
    [13]
    Caja, L., Sancho, P., Bertran, E., Fabregat, I., 2011. Dissecting the effect of targeting the epidermal growth factor receptor on TGF-beta-induced-apoptosis in human hepatocellular carcinoma cells. J. Hepatol. 55, 351-358.
    [14]
    Caja, L., Sancho, P., Bertran, E., Iglesias-Serret, D., Gil, J., Fabregat, I., 2009. Overactivation of the MEK/ERK pathway in liver tumor cells confers resistance to TGF-beta-induced cell death through impairing up-regulation of the NADPH oxidase NOX4. Cancer Res. 69, 7595-7602.
    [15]
    Campisi, J., 2013. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685-705.
    [16]
    Cancer Genome Atlas Research Network. Electronic address, w.b.e., Cancer Genome Atlas Research, N., 2017. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell 169, 1327-1341 e1323.
    [17]
    Carmona-Cuenca, I., Roncero, C., Sancho, P., Caja, L., Fausto, N., Fernandez, M., Fabregat, I., 2008. Upregulation of the NADPH oxidase NOX4 by TGF-beta in hepatocytes is required for its pro-apoptotic activity. J. Hepatol. 49, 965-976.
    [18]
    Cassar, L., Nicholls, C., Pinto, A.R., Chen, R., Wang, L., Li, H., Liu, J.P., 2017. TGF-beta receptor mediated telomerase inhibition, telomere shortening and breast cancer cell senescence. Protein Cell 8, 39-54.
    [19]
    Cavin, L.G., Romieu-Mourez, R., Panta, G.R., Sun, J., Factor, V.M., Thorgeirsson, S.S., Sonenshein, G.E., Arsura, M., 2003. Inhibition of CK2 activity by TGF-beta1 promotes IkappaB-alpha protein stabilization and apoptosis of immortalized hepatocytes. Hepatology 38, 1540-1551.
    [20]
    Chandra, M., Zang, S., Li, H., Zimmerman, L.J., Champer, J., Tsuyada, A., Chow, A., Zhou, W., Yu, Y., Gao, H., Ren, X., Lin, R.J., Wang, S.E., 2012. Nuclear translocation of type I transforming growth factor beta receptor confers a novel function in RNA processing. Mol. Cell Biol. 32, 2183-2195.
    [21]
    Chang, L., Li, C., Guo, T., Wang, H., Ma, W., Yuan, Y., Liu, Q., Ye, Q., Liu, Z., 2016. The human RNA surveillance factor UPF1 regulates tumorigenesis by targeting Smad7 in hepatocellular carcinoma. J Exp. Clin. Cancer Res. 35, 8.
    [22]
    Chen, J., Gingold, J.A., Su, X., 2019. Immunomodulatory TGF-beta signaling in hepatocellular carcinoma. Trends Mol. Med. 25, 1010-1023.
    [23]
    Chen, J., Zaidi, S., Rao, S., Chen, J.S., Phan, L., Farci, P., Su, X., Shetty, K., White, J., Zamboni, F., Wu, X., Rashid, A., Pattabiraman, N., Mazumder, R., Horvath, A., Wu, R.C., Li, S., Xiao, C., Deng, C.X., Wheeler, D.A., Mishra, B., Akbani, R., Mishra, L., 2018. Analysis of genomes and transcriptomes of hepatocellular carcinomas identifies mutations and gene expression changes in the transforming growth factor-beta pathway. Gastroenterology 154, 195-210.
    [24]
    Chen, W., Ten Dijke, P., 2016. Immunoregulation by members of the TGFbeta superfamily. Nat. Rev. Immunol. 16, 723-740.
    [25]
    Chu, J.S., Ge, F.J., Zhang, B., Wang, Y., Silvestris, N., Liu, L.J., Zhao, C.H., Lin, L., Brunetti, A.E., Fu, Y.L., Wang, J., Paradiso, A., Xu, J.M., 2013. Expression and prognostic value of VEGFR-2, PDGFR-beta, and c-Met in advanced hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 32, 16.
    [26]
    Coulouarn, C., Factor, V.M., Thorgeirsson, S.S., 2008. Transforming growth factor-beta gene expression signature in mouse hepatocytes predicts clinical outcome in human cancer. Hepatology 47, 2059-2067.
    [27]
    Damdinsuren, B., Nagano, H., Kondo, M., Natsag, J., Hanada, H., Nakamura, M., Wada, H., Kato, H., Marubashi, S., Miyamoto, A., Takeda, Y., Umeshita, K., Dono, K., Monden, M., 2006. TGF-beta1-induced cell growth arrest and partial differentiation is related to the suppression of Id1 in human hepatoma cells. Oncol. Rep. 15, 401-408.
    [28]
    David, C.J., Massague, J., 2018. Contextual determinants of TGFbeta action in development, immunity and cancer. Nat. Rev. Mol. Cell Biol. 19, 419-435.
    [29]
    Derynck, R., Budi, E.H., 2019. Specificity, versatility, and control of TGF-beta family signaling. Sci. Signal. 12, eaav5183.
    [30]
    Dewidar, B., Meyer, C., Dooley, S., Meindl-Beinker, A.N., 2019. TGF-beta in hepatic stellate cell activation and liver fibrogenesis-updated 2019. Cells 8, 1419.
    [31]
    Di Fazio, P., Matrood, S., 2018. Targeting autophagy in liver cancer. Transl. Gastroenterol. Hepatol. 3, 39.
    [32]
    Ding, L., Wang, Z., Yan, J., Yang, X., Liu, A., Qiu, W., Zhu, J., Han, J., Zhang, H., Lin, J., Cheng, L., Qin, X., Niu, C., Yuan, B., Wang, X., Zhu, C., Zhou, Y., Li, J., Song, H., Huang, C., Ye, Q., 2009. Human four-and-a-half LIM family members suppress tumor cell growth through a TGF-beta-like signaling pathway. J. Clin. Invest. 119, 349-361.
    [33]
    Dituri, F., Mancarella, S., Cigliano, A., Chieti, A., Giannelli, G., 2019. TGF-beta as multifaceted orchestrator in HCC progression: signaling, EMT, immune microenvironment, and novel therapeutic perspectives. Semin. Liver Dis. 39, 53-69.
    [34]
    Dooley, S., ten Dijke, P., 2012. TGF-beta in progression of liver disease. Cell Tissue Res. 347, 245-256.
    [35]
    Dzieran, J., Fabian, J., Feng, T., Coulouarn, C., Ilkavets, I., Kyselova, A., Breuhahn, K., Dooley, S., Meindl-Beinker, N.M., 2013. Comparative analysis of TGF-beta/Smad signaling dependent cytostasis in human hepatocellular carcinoma cell lines. PLoS One 8, e72252.
    [36]
    Eggert, T., Wolter, K., Ji, J., Ma, C., Yevsa, T., Klotz, S., Medina-Echeverz, J., Longerich, T., Forgues, M., Reisinger, F., Heikenwalder, M., Wang, X.W., Zender, L., Greten, T.F., 2016. Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell 30, 533-547.
    [37]
    Eguchi, A., Wree, A., Feldstein, A.E., 2014. Biomarkers of liver cell death. J. Hepatol. 60, 1063-1074.
    [38]
    Fabregat, I., Caballero-Diaz, D., 2018. Transforming growth factor-beta-induced cell plasticity in liver fibrosis and hepatocarcinogenesis. Front. Oncol. 8, 357.
    [39]
    Fabregat, I., Herrera, B., Fernandez, M., Alvarez, A.M., Sanchez, A., Roncero, C., Ventura, J.J., Valverde, A.M., Benito, M., 2000. Epidermal growth factor impairs the cytochrome C/caspase-3 apoptotic pathway induced by transforming growth factor beta in rat fetal hepatocytes via a phosphoinositide 3-kinase-dependent pathway. Hepatology 32, 528-535.
    [40]
    Fabregat, I., Moreno-Caceres, J., Sanchez, A., Dooley, S., Dewidar, B., Giannelli, G., Ten Dijke, P., 2016. TGF-beta signalling and liver disease. FEBS J. 283, 2219-2232.
    [41]
    Fabregat, I., Roncero, C., Fernandez, M., 2007. Survival and apoptosis: a dysregulated balance in liver cancer. Liver Int. 27, 155-162.
    [42]
    Faget, D.V., Ren, Q., Stewart, S.A., 2019. Unmasking senescence: context-dependent effects of SASP in cancer. Nat. Rev. Cancer 19, 439-453.
    [43]
    Farazi, P.A., DePinho, R.A., 2006. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat. Rev. Cancer 6, 674-687.
    [44]
    Feng, T., Dzieran, J., Gu, X., Marhenke, S., Vogel, A., Machida, K., Weiss, T.S., Ruemmele, P., Kollmar, O., Hoffmann, P., Grasser, F., Allgayer, H., Fabian, J., Weng, H.L., Teufel, A., Maass, T., Meyer, C., Lehmann, U., Zhu, C., Mertens, P.R., Gao, C.F., Dooley, S., Meindl-Beinker, N.M., 2015a. Smad7 regulates compensatory hepatocyte proliferation in damaged mouse liver and positively relates to better clinical outcome in human hepatocellular carcinoma. Clin. Sci. (Lond) 128, 761-774.
    [45]
    Feng, X.X., Luo, J., Liu, M., Yan, W., Zhou, Z.Z., Xia, Y.J., Tu, W., Li, P.Y., Feng, Z.H., Tian, D.A., 2015b. Sirtuin 6 promotes transforming growth factor-beta1/H2O2/HOCl-mediated enhancement of hepatocellular carcinoma cell tumorigenicity by suppressing cellular senescence. Cancer Sci. 106, 559-566.
    [46]
    Fischer, A.N., Fuchs, E., Mikula, M., Huber, H., Beug, H., Mikulits, W., 2007. PDGF essentially links TGF-beta signaling to nuclear beta-catenin accumulation in hepatocellular carcinoma progression. Oncogene 26, 3395-3405.
    [47]
    Franco, D.L., Mainez, J., Vega, S., Sancho, P., Murillo, M.M., de Frutos, C.A., del Castillo, G., Lopez-Blau, C., Fabregat, I., Nieto, M.A., 2010. Snail1 suppresses TGF-beta-induced apoptosis and is sufficient to trigger EMT in hepatocytes. J. Cell Sci. 123, 3467-3477.
    [48]
    Fu, H., He, Y., Qi, L., Chen, L., Luo, Y., Chen, L., Li, Y., Zhang, N., Guo, H., 2017. cPLA2alpha activates PI3K/AKT and inhibits Smad2/3 during epithelial-mesenchymal transition of hepatocellular carcinoma cells. Cancer Lett. 403, 260-270.
    [49]
    Furuta, K., Misao, S., Takahashi, K., Tagaya, T., Fukuzawa, Y., Ishikawa, T., Yoshioka, K., Kakumu, S., 1999. Gene mutation of transforming growth factor beta1 type II receptor in hepatocellular carcinoma. Int. J. Cancer 81, 851-853.
    [50]
    Gingold, J.A., Zhu, D., Lee, D.F., Kaseb, A., Chen, J., 2018. Genomic profiling and metabolic homeostasis in primary liver cancers. Trends Mol. Med. 24, 395-411.
    [51]
    Godoy, P., Hengstler, J.G., Ilkavets, I., Meyer, C., Bachmann, A., Muller, A., Tuschl, G., Mueller, S.O., Dooley, S., 2009. Extracellular matrix modulates sensitivity of hepatocytes to fibroblastoid dedifferentiation and transforming growth factor beta-induced apoptosis. Hepatology 49, 2031-2043.
    [52]
    Gomez, G.G., Wykosky, J., Zanca, C., Furnari, F.B., Cavenee, W.K., 2013. Therapeutic resistance in cancer: microRNA regulation of EGFR signaling networks. Cancer Biol. Med. 10, 192-205.
    [53]
    Gotzmann, J., Fischer, A.N., Zojer, M., Mikula, M., Proell, V., Huber, H., Jechlinger, M., Waerner, T., Weith, A., Beug, H., Mikulits, W., 2006. A crucial function of PDGF in TGF-beta-mediated cancer progression of hepatocytes. Oncogene 25, 3170-3185.
    [54]
    Gracia-Sancho, J., Guixe-Muntet, S., 2018. The many-faced role of autophagy in liver diseases. J. Hepatol. 68, 593-594.
    [55]
    Gudey, S.K., Sundar, R., Mu, Y., Wallenius, A., Zang, G., Bergh, A., Heldin, C.H., Landstrom, M., 2014. TRAF6 stimulates the tumor-promoting effects of TGFbeta type I receptor through polyubiquitination and activation of presenilin 1. Sci. Signal. 7, ra2.
    [56]
    Hamajima, H., Ozaki, I., Zhang, H., Iwane, S., Kawaguchi, Y., Eguchi, Y., Matsuhashi, S., Mizuta, T., Matsuzaki, K., Fujimoto, K., 2009. Modulation of the transforming growth factor-beta1-induced Smad phosphorylation by the extracellular matrix receptor beta1-integrin. Int. J. Oncol. 35, 1441-1447.
    [57]
    Hamidi, A., Song, J., Thakur, N., Itoh, S., Marcusson, A., Bergh, A., Heldin, C.H., Landstrom, M., 2017. TGF-beta promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85alpha. Sci. Signal. 10.
    [58]
    Han, C., Bowen, W.C., Li, G., Demetris, A.J., Michalopoulos, G.K., Wu, T., 2010. Cytosolic phospholipase A2alpha and peroxisome proliferator-activated receptor gamma signaling pathway counteracts transforming growth factor beta-mediated inhibition of primary and transformed hepatocyte growth. Hepatology 52, 644-655.
    [59]
    Hanahan, D., Weinberg, R.A., 2011. Hallmarks of cancer: the next generation. Cell 144, 646-674.
    [60]
    Hardy, S.D., Shinde, A., Wang, W.H., Wendt, M.K., Geahlen, R.L., 2017. Regulation of epithelial-mesenchymal transition and metastasis by TGF-beta, P-bodies, and autophagy. Oncotarget 8, 103302-103314.
    [61]
    Hashimoto, O., Ueno, T., Kimura, R., Ohtsubo, M., Nakamura, T., Koga, H., Torimura, T., Uchida, S., Yamashita, K., Sata, M., 2003. Inhibition of proteasome-dependent degradation of Wee1 in G2-arrested Hep3B cells by TGF beta 1. Mol. Carcinogen. 36, 171-182.
    [62]
    Hata, A., Chen, Y.G., 2016. TGF-beta signaling from receptors to Smads. Cold Spring Harb. Perspect. Biol. 8, a022061.
    [63]
    Hayflick, L., Moorhead, P.S., 1961. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585-621.
    [64]
    Heldin, C.H., Moustakas, A., 2016. Signaling receptors for TGF-beta family members. Cold Spring Harb. Perspect. Biol. 8, a022053.
    [65]
    Herrera, B., Fernandez, M., Alvarez, A.M., Roncero, C., Benito, M., Gil, J., Fabregat, I., 2001. Activation of caspases occurs downstream from radical oxygen species production, Bcl-xL down-regulation, and early cytochrome C release in apoptosis induced by transforming growth factor beta in rat fetal hepatocytes. Hepatology 34, 548-556.
    [66]
    Herzer, K., Ganten, T.M., Schulze-Bergkamen, H., Grosse-Wilde, A., Koschny, R., Krammer, P.H., Walczak, H., 2005. Transforming growth factor beta can mediate apoptosis via the expression of TRAIL in human hepatoma cells. Hepatology 42, 183-192.
    [67]
    Herzer, K., Grosse-Wilde, A., Krammer, P.H., Galle, P.R., Kanzler, S., 2008. Transforming growth factor-beta-mediated tumor necrosis factor-related apoptosis-inducing ligand expression and apoptosis in hepatoma cells requires functional cooperation between Smad proteins and activator protein-1. Mol. Cancer Res. 6, 1169-1177.
    [68]
    Hill, C.S., 2016. Transcriptional Control by the SMADs. Cold Spring Harb. Perspect. Biol. 8, a022079.
    [69]
    Ho, J., Cocolakis, E., Dumas, V.M., Posner, B.I., Laporte, S.A., Lebrun, J.J., 2005. The G protein-coupled receptor kinase-2 is a TGFbeta-inducible antagonist of TGFbeta signal transduction. EMBO J. 24, 3247-3258.
    [70]
    Hofmann, T.G., Stollberg, N., Schmitz, M.L., Will, H., 2003. HIPK2 regulates transforming growth factor-beta-induced c-Jun NH(2)-terminal kinase activation and apoptosis in human hepatoma cells. Cancer Res. 63, 8271-8277.
    [71]
    Hoshida, Y., Nijman, S.M., Kobayashi, M., Chan, J.A., Brunet, J.P., Chiang, D.Y., Villanueva, A., Newell, P., Ikeda, K., Hashimoto, M., Watanabe, G., Gabriel, S., Friedman, S.L., Kumada, H., Llovet, J.M., Golub, T.R., 2009. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 69, 7385-7392.
    [72]
    Huang, Y.H., Hu, J., Chen, F., Lecomte, N., Basnet, H., David, C.J., Witkin, M.D., Allen, P.J., Leach, S.D., Hollmann, T.J., Iacobuzio-Donahue, C.A., Massague, J., 2020. ID1 mediates escape from TGFbeta tumor suppression in pancreatic cancer. Cancer Discov. 10, 142-157.
    [73]
    Hujie, G., Zhou, S.H., Zhang, H., Qu, J., Xiong, X.W., Hujie, O., Liao, C.G., Yang, S.E., 2018. MicroRNA-10b regulates epithelial-mesenchymal transition by modulating KLF4/KLF11/Smads in hepatocellular carcinoma. Cancer Cell Int. 18, 10.
    [74]
    Im, Y.H., Kim, H.T., Kim, I.Y., Factor, V.M., Hahm, K.B., Anzano, M., Jang, J.J., Flanders, K., Haines, D.C., Thorgeirsson, S.S., Sizeland, A., Kim, S.J., 2001. Heterozygous mice for the transforming growth factor-beta type II receptor gene have increased susceptibility to hepatocellular carcinogenesis. Cancer Res. 61, 6665-6668.
    [75]
    Jang, C.W., Chen, C.H., Chen, C.C., Chen, J.Y., Su, Y.H., Chen, R.H., 2002. TGF-beta induces apoptosis through Smad-mediated expression of DAP-kinase. Nat. Cell Biol. 4, 51-58.
    [76]
    Jiang, Y., Sun, A., Zhao, Y., Ying, W., Sun, H., Yang, X., Xing, B., Sun, W., Ren, L., Hu, B., Li, C., Zhang, L., Qin, G., Zhang, M., Chen, N., Zhang, M., Huang, Y., Zhou, J., Zhao, Y., Liu, M., Zhu, X., Qiu, Y., Sun, Y., Huang, C., Yan, M., Wang, M., Liu, W., Tian, F., Xu, H., Zhou, J., Wu, Z., Shi, T., Zhu, W., Qin, J., Xie, L., Fan, J., Qian, X., He, F., Chinese Human Proteome Project, C., 2019. Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma. Nature 567, 257-261.
    [77]
    Kang, T.W., Yevsa, T., Woller, N., Hoenicke, L., Wuestefeld, T., Dauch, D., Hohmeyer, A., Gereke, M., Rudalska, R., Potapova, A., Iken, M., Vucur, M., Weiss, S., Heikenwalder, M., Khan, S., Gil, J., Bruder, D., Manns, M., Schirmacher, P., Tacke, F., Ott, M., Luedde, T., Longerich, T., Kubicka, S., Zender, L., 2011. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547-551.
    [78]
    Kang, Y., Chen, C.R., Massague, J., 2003. A self-enabling TGFbeta response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells. Mol. Cell 11, 915-926.
    [79]
    Katakura, Y., 2006. Molecular basis for the cellular senescence program and its application to anticancer therapy. Biosci. Biotechnol. Biochem. 70, 1076-1081.
    [80]
    Kaur, S., Wang, F., Venkatraman, M., Arsura, M., 2005. X-linked inhibitor of apoptosis (XIAP) inhibits c-Jun N-terminal kinase 1 (JNK1) activation by transforming growth factor beta1 (TGF-beta1) through ubiquitin-mediated proteosomal degradation of the TGF-beta1-activated kinase 1 (TAK1). J. Biol. Chem. 280, 38599-38608.
    [81]
    Khambu, B., Huda, N., Chen, X., Antoine, D.J., Li, Y., Dai, G., Kohler, U.A., Zong, W.X., Waguri, S., Werner, S., Oury, T.D., Dong, Z., Yin, X.M., 2018. HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers. J. Clin. Invest. 128, 2419-2435.
    [82]
    Kim, K.Y., Kim, B.C., Xu, Z., Kim, S.J., 2004. Mixed lineage kinase 3 (MLK3)-activated p38 MAP kinase mediates transforming growth factor-beta-induced apoptosis in hepatoma cells. J. Biol. Chem. 279, 29478-29484.
    [83]
    Kitisin, K., Ganesan, N., Tang, Y., Jogunoori, W., Volpe, E.A., Kim, S.S., Katuri, V., Kallakury, B., Pishvaian, M., Albanese, C., Mendelson, J., Zasloff, M., Rashid, A., Fishbein, T., Evans, S.R., Sidawy, A., Reddy, E.P., Mishra, B., Johnson, L.B., Shetty, K., Mishra, L., 2007. Disruption of transforming growth factor-beta signaling through beta-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation. Oncogene 26, 7103-7110.
    [84]
    Kiyono, K., Suzuki, H.I., Matsuyama, H., Morishita, Y., Komuro, A., Kano, M.R., Sugimoto, K., Miyazono, K., 2009. Autophagy is activated by TGF-beta and potentiates TGF-beta-mediated growth inhibition in human hepatocellular carcinoma cells. Cancer Res. 69, 8844-8852.
    [85]
    Korkut, A., Zaidi, S., Kanchi, R.S., Rao, S., Gough, N.R., Schultz, A., Li, X., Lorenzi, P.L., Berger, A.C., Robertson, G., Kwong, L.N., Datto, M., Roszik, J., Ling, S., Ravikumar, V., Manyam, G., Rao, A., Shelley, S., Liu, Y., Ju, Z., Hansel, D., de Velasco, G., Pennathur, A., Andersen, J.B., O'Rourke, C.J., Ohshiro, K., Jogunoori, W., Nguyen, B.N., Li, S., Osmanbeyoglu, H.U., Ajani, J.A., Mani, S.A., Houseman, A., Wiznerowicz, M., Chen, J., Gu, S., Ma, W., Zhang, J., Tong, P., Cherniack, A.D., Deng, C., Resar, L., Cancer Genome Atlas Research, N., Weinstein, J.N., Mishra, L., Akbani, R., 2018. A Pan-cancer analysis reveals high-frequency genetic alterations in mediators of signaling by the TGF-beta superfamily. Cell Syst. 7, 422-437 e427.
    [86]
    Kotsafti, A., Farinati, F., Cardin, R., Cillo, U., Nitti, D., Bortolami, M., 2012. Autophagy and apoptosis-related genes in chronic liver disease and hepatocellular carcinoma. BMC Gastroenterol. 12, 118.
    [87]
    Krstic, J., Trivanovic, D., Mojsilovic, S., Santibanez, J.F., 2015. Transforming growth factor-beta and oxidative stress interplay: implications in tumorigenesis and cancer progression. Oxid. Med. Cell Longev. 2015, 654594.
    [88]
    Lan, S.H., Wu, S.Y., Zuchini, R., Lin, X.Z., Su, I.J., Tsai, T.F., Lin, Y.J., Wu, C.T., Liu, H.S., 2014. Autophagy suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of microRNA-224. Hepatology 59, 505-517.
    [89]
    Lee, M.K., Pardoux, C., Hall, M.C., Lee, P.S., Warburton, D., Qing, J., Smith, S.M., Derynck, R., 2007. TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA. EMBO J. 26, 3957-3967.
    [90]
    Li, H., Liu, J.P., 2007. Mechanisms of action of TGF-beta in cancer: evidence for Smad3 as a repressor of the hTERT gene. Ann. N. Y. Acad. Sci. 1114, 56-68.
    [91]
    Li, J., Yang, B., Zhou, Q., Wu, Y., Shang, D., Guo, Y., Song, Z., Zheng, Q., Xiong, J., 2013. Autophagy promotes hepatocellular carcinoma cell invasion through activation of epithelial-mesenchymal transition. Carcinogenesis 34, 1343-1351.
    [92]
    Li, P., Du, Q., Cao, Z., Guo, Z., Evankovich, J., Yan, W., Chang, Y., Shao, L., Stolz, D.B., Tsung, A., Geller, D.A., 2012. Interferon-gamma induces autophagy with growth inhibition and cell death in human hepatocellular carcinoma (HCC) cells through interferon-regulatory factor-1 (IRF-1). Cancer Lett. 314, 213-222.
    [93]
    Li, Q., Liu, G., Yuan, H., Wang, J., Guo, Y., Chen, T., Zhai, R., Shao, D., Ni, W., Tai, G., 2015. Mucin1 shifts Smad3 signaling from the tumor-suppressive pSmad3C/p21(WAF1) pathway to the oncogenic pSmad3L/c-Myc pathway by activating JNK in human hepatocellular carcinoma cells. Oncotarget 6, 4253-4265.
    [94]
    Li, X., Feng, X.H., 2020. SMAD-oncoprotein interplay: potential determining factors in targeted therapies. Biochem. Pharmacol. 180, 114155.
    [95]
    Li, Y., Tu, S., Zeng, Y., Zhang, C., Deng, T., Luo, W., Lian, L., Chen, L., Xiong, X., Yan, X., 2020. KLF2 inhibits TGF-beta-mediated cancer cell motility in hepatocellular carcinoma. Acta Biochim. Biophys. Sin. (Shanghai) 52, 485-494.
    [96]
    Liang, Y.Y., Brunicardi, F.C., Lin, X., 2009. Smad3 mediates immediate early induction of Id1 by TGF-beta. Cell Res. 19, 140-148.
    [97]
    Liu, L., Liao, J.Z., He, X.X., Li, P.Y., 2017. The role of autophagy in hepatocellular carcinoma: friend or foe. Oncotarget 8, 57707-57722.
    [98]
    Llovet, J.M., Montal, R., Sia, D., Finn, R.S., 2018. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat. Rev. Clin. Oncol. 15, 599-616.
    [99]
    Luedde, T., Kaplowitz, N., Schwabe, R.F., 2014. Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology 147, 765-783 e764.
    [100]
    Majumdar, A., Curley, S.A., Wu, X., Brown, P., Hwang, J.P., Shetty, K., Yao, Z.X., He, A.R., Li, S., Katz, L., Farci, P., Mishra, L., 2012. Hepatic stem cells and transforming growth factor beta in hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 9, 530-538.
    [101]
    Mamiya, T., Yamazaki, K., Masugi, Y., Mori, T., Effendi, K., Du, W., Hibi, T., Tanabe, M., Ueda, M., Takayama, T., Sakamoto, M., 2010. Reduced transforming growth factor-beta receptor II expression in hepatocellular carcinoma correlates with intrahepatic metastasis. Lab Invest. 90, 1339-1345.
    [102]
    Marquardt, J.U., Andersen, J.B., Thorgeirsson, S.S., 2015. Functional and genetic deconstruction of the cellular origin in liver cancer. Nat. Rev. Cancer 15, 653-667.
    [103]
    Marquardt, J.U., Edlich, F., 2019. Predisposition to apoptosis in hepatocellular carcinoma: from mechanistic insights to therapeutic strategies. Front. Oncol. 9, 1421.
    [104]
    Massague, J., 2008. TGFbeta in Cancer. Cell 134, 215-230.
    [105]
    Massague, J., 2012. TGFbeta signalling in context. Nat. Rev. Mol. Cell Biol. 13, 616-630.
    [106]
    Mathew, R., Karp, C.M., Beaudoin, B., Vuong, N., Chen, G., Chen, H.Y., Bray, K., Reddy, A., Bhanot, G., Gelinas, C., Dipaola, R.S., Karantza-Wadsworth, V., White, E., 2009. Autophagy suppresses tumorigenesis through elimination of p62. Cell 137, 1062-1075.
    [107]
    Matsuzaki, K., Date, M., Furukawa, F., Tahashi, Y., Matsushita, M., Sakitani, K., Yamashiki, N., Seki, T., Saito, H., Nishizawa, M., Fujisawa, J., Inoue, K., 2000. Autocrine stimulatory mechanism by transforming growth factor beta in human hepatocellular carcinoma. Cancer Res. 60, 1394-1402.
    [108]
    Meyer, C., Liu, Y., Kaul, A., Peipe, I., Dooley, S., 2013. Caveolin-1 abrogates TGF-beta mediated hepatocyte apoptosis. Cell Death Dis. 4, e466.
    [109]
    Miyazawa, K., Miyazono, K., 2017. Regulation of TGF-beta family signaling by inhibitory Smads. Cold Spring Harb. Perspect. Biol. 9, a022095.
    [110]
    Moon, H., Ju, H.L., Chung, S.I., Cho, K.J., Eun, J.W., Nam, S.W., Han, K.H., Calvisi, D.F., Ro, S.W., 2017. Transforming growth factor-beta promotes liver tumorigenesis in mice via up-regulation of Snail. Gastroenterology 153, 1378-1391 e1376.
    [111]
    Moreno-Caceres, J., Caballero-Diaz, D., Nwosu, Z.C., Meyer, C., Lopez-Luque, J., Malfettone, A., Lastra, R., Serrano, T., Ramos, E., Dooley, S., Fabregat, I., 2017. The level of caveolin-1 expression determines response to TGF-beta as a tumour suppressor in hepatocellular carcinoma cells. Cell Death Dis. 8, e3098.
    [112]
    Moreno-Caceres, J., Caja, L., Mainez, J., Mayoral, R., Martin-Sanz, P., Moreno-Vicente, R., Del Pozo, M.A., Dooley, S., Egea, G., Fabregat, I., 2014. Caveolin-1 is required for TGF-beta-induced transactivation of the EGF receptor pathway in hepatocytes through the activation of the metalloprotease TACE/ADAM17. Cell Death Dis. 5, e1326.
    [113]
    Moreno-Caceres, J., Fabregat, I., 2015. Apoptosis in liver carcinogenesis and chemotherapy. Hepat Oncol. 2, 381-397.
    [114]
    Moreno-Caceres, J., Mainez, J., Mayoral, R., Martin-Sanz, P., Egea, G., Fabregat, I., 2016. Caveolin-1-dependent activation of the metalloprotease TACE/ADAM17 by TGF-beta in hepatocytes requires activation of Src and the NADPH oxidase NOX1. FEBS J. 283, 1300-1310.
    [115]
    Mori, S., Matsuzaki, K., Yoshida, K., Furukawa, F., Tahashi, Y., Yamagata, H., Sekimoto, G., Seki, T., Matsui, H., Nishizawa, M., Fujisawa, J., Okazaki, K., 2004. TGF-beta and HGF transmit the signals through JNK-dependent Smad2/3 phosphorylation at the linker regions. Oncogene 23, 7416-7429.
    [116]
    Morikawa, M., Derynck, R., Miyazono, K., 2016. TGF-beta and the TGF-beta family: context-dependent roles in cell and tissue physiology. Cold Spring Harb. Perspect. Biol 8, a021873.
    [117]
    Moses, H.L., Roberts, A.B., Derynck, R., 2016. The Discovery and Early Days of TGF-beta: A Historical Perspective. Cold Spring Harb Perspect Biol. 8, a021865.
    [118]
    Moustakas, A., Kardassis, D., 1998. Regulation of the human p21/WAF1/Cip1 promoter in hepatic cells by functional interactions between Sp1 and Smad family members. Proc. Natl. Acad. Sci U. S. A. 95, 6733-6738.
    [119]
    Mu, Y., Sundar, R., Thakur, N., Ekman, M., Gudey, S.K., Yakymovych, M., Hermansson, A., Dimitriou, H., Bengoechea-Alonso, M.T., Ericsson, J., Heldin, C.H., Landstrom, M., 2011. TRAF6 ubiquitinates TGFbeta type I receptor to promote its cleavage and nuclear translocation in cancer. Nat. Commun. 2, 330.
    [120]
    Mudbhary, R., Hoshida, Y., Chernyavskaya, Y., Jacob, V., Villanueva, A., Fiel, M.I., Chen, X., Kojima, K., Thung, S., Bronson, R.T., Lachenmayer, A., Revill, K., Alsinet, C., Sachidanandam, R., Desai, A., SenBanerjee, S., Ukomadu, C., Llovet, J.M., Sadler, K.C., 2014. UHRF1 overexpression drives DNA hypomethylation and hepatocellular carcinoma. Cancer Cell 25, 196-209.
    [121]
    Munoz-Espin, D., Canamero, M., Maraver, A., Gomez-Lopez, G., Contreras, J., Murillo-Cuesta, S., Rodriguez-Baeza, A., Varela-Nieto, I., Ruberte, J., Collado, M., Serrano, M., 2013. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104-1118.
    [122]
    Munoz-Espin, D., Serrano, M., 2014. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482-496.
    [123]
    Murata, M., Matsuzaki, K., Yoshida, K., Sekimoto, G., Tahashi, Y., Mori, S., Uemura, Y., Sakaida, N., Fujisawa, J., Seki, T., Kobayashi, K., Yokote, K., Koike, K., Okazaki, K., 2009. Hepatitis B virus X protein shifts human hepatic transforming growth factor (TGF)-beta signaling from tumor suppression to oncogenesis in early chronic hepatitis B. Hepatology 49, 1203-1217.
    [124]
    Murillo, M.M., Carmona-Cuenca, I., Del Castillo, G., Ortiz, C., Roncero, C., Sanchez, A., Fernandez, M., Fabregat, I., 2007. Activation of NADPH oxidase by transforming growth factor-beta in hepatocytes mediates up-regulation of epidermal growth factor receptor ligands through a nuclear factor-kappaB-dependent mechanism. Biochem. J. 405, 251-259.
    [125]
    Murillo, M.M., del Castillo, G., Sanchez, A., Fernandez, M., Fabregat, I., 2005. Involvement of EGF receptor and c-Src in the survival signals induced by TGF-beta1 in hepatocytes. Oncogene 24, 4580-4587.
    [126]
    Nardella, C., Clohessy, J.G., Alimonti, A., Pandolfi, P.P., 2011. Pro-senescence therapy for cancer treatment. Nat. Rev. Cancer 11, 503-511.
    [127]
    Ozaki, I., Hamajima, H., Matsuhashi, S., Mizuta, T., 2011. Regulation of TGF-beta1-induced pro-apoptotic signaling by growth factor receptors and extracellular matrix receptor integrins in the liver. Front. Physiol. 2, 78.
    [128]
    Park, J., Lee, J., Kang, W., Chang, S., Shin, E.C., Choi, C., 2013. TGF-beta1 and hypoxia-dependent expression of MKP-1 leads tumor resistance to death receptor-mediated cell death. Cell Death Dis. 4, e521.
    [129]
    Perlman, R., Schiemann, W.P., Brooks, M.W., Lodish, H.F., Weinberg, R.A., 2001. TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nat. Cell Biol. 3, 708-714.
    [130]
    Ramesh, S., Qi, X.J., Wildey, G.M., Robinson, J., Molkentin, J., Letterio, J., Howe, P.H., 2008. TGF beta-mediated BIM expression and apoptosis are regulated through SMAD3-dependent expression of the MAPK phosphatase MKP2. EMBO Rep. 9, 990-997.
    [131]
    Ramjaun, A.R., Tomlinson, S., Eddaoudi, A., Downward, J., 2007. Upregulation of two BH3-only proteins, Bmf and Bim, during TGF beta-induced apoptosis. Oncogene 26, 970-981.
    [132]
    Rao, S., Mishra, L., 2019. Targeting transforming growth factor beta signaling in liver cancer. Hepatology 69, 1375-1378.
    [133]
    Roberts, R.A., James, N.H., Cosulich, S.C., 2000. The role of protein kinase B and mitogen-activated protein kinase in epidermal growth factor and tumor necrosis factor alpha-mediated rat hepatocyte survival and apoptosis. Hepatology 31, 420-427.
    [134]
    Robertson, I.B., Rifkin, D.B., 2016. Regulation of the bioavailability of TGF-beta and TGF-beta-related proteins. Cold Spring Harb. Perspect. Biol. 8, a021907.
    [135]
    Rojas, A., Zhang, P., Wang, Y., Foo, W.C., Munoz, N.M., Xiao, L., Wang, J., Gores, G.J., Hung, M.C., Blechacz, B., 2016. A positive TGF-beta/c-KIT feedback loop drives tumor progression in advanced primary liver cancer. Neoplasia (New York, N.Y.) 18, 371-386.
    [136]
    Schulze, K., Imbeaud, S., Letouze, E., Alexandrov, L.B., Calderaro, J., Rebouissou, S., Couchy, G., Meiller, C., Shinde, J., Soysouvanh, F., Calatayud, A.L., Pinyol, R., Pelletier, L., Balabaud, C., Laurent, A., Blanc, J.F., Mazzaferro, V., Calvo, F., Villanueva, A., Nault, J.C., Bioulac-Sage, P., Stratton, M.R., Llovet, J.M., Zucman-Rossi, J., 2015. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet. 47, 505-511.
    [137]
    Schwabe, R.F., Luedde, T., 2018. Apoptosis and necroptosis in the liver: a matter of life and death. Nat. Rev. Gastroenterol. Hepatol. 15, 738-752.
    [138]
    Senturk, S., Mumcuoglu, M., Gursoy-Yuzugullu, O., Cingoz, B., Akcali, K.C., Ozturk, M., 2010. Transforming growth factor-beta induces senescence in hepatocellular carcinoma cells and inhibits tumor growth. Hepatology 52, 966-974.
    [139]
    Seoane, J., Gomis, R.R., 2017. TGF-beta family signaling in tumor suppression and cancer progression. Cold Spring Harb. Perspect. Biol. 9, a022277.
    [140]
    Shi, C., Cai, Y., Li, Y., Li, Y., Hu, N., Ma, S., Hu, S., Zhu, P., Wang, W., Zhou, H., 2018. Yap promotes hepatocellular carcinoma metastasis and mobilization via governing cofilin/F-actin/lamellipodium axis by regulation of JNK/Bnip3/SERCA/CaMKII pathways. Redox Biol. 14, 59-71.
    [141]
    Shima, Y., Nakao, K., Nakashima, T., Kawakami, A., Nakata, K., Hamasaki, K., Kato, Y., Eguchi, K., Ishii, N., 1999. Activation of caspase-8 in transforming growth factor-beta-induced apoptosis of human hepatoma cells. Hepatology 30, 1215-1222.
    [142]
    Sohn, B.H., Park, I.Y., Lee, J.J., Yang, S.J., Jang, Y.J., Park, K.C., Kim, D.J., Lee, D.C., Sohn, H.A., Kim, T.W., Yoo, H.S., Choi, J.Y., Bae, Y.S., Yeom, Y.I., 2010. Functional switching of TGF-beta1 signaling in liver cancer via epigenetic modulation of a single CpG site in TTP promoter. Gastroenterology 138, 1898-1908.
    [143]
    Sorrentino, A., Thakur, N., Grimsby, S., Marcusson, A., von Bulow, V., Schuster, N., Zhang, S., Heldin, C.H., Landstrom, M., 2008a. The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat. Cell Biol. 10, 1199-1207.
    [144]
    Sorrentino, A., Thakur, N., Grimsby, S., Marcusson, A., von Bulow, V., Schuster, N., Zhang, S., Heldin, C.H., Landstrom, M., 2008b. The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat. Cell Biol. 10, 1199-1207.
    [145]
    Stankic, M., Pavlovic, S., Chin, Y., Brogi, E., Padua, D., Norton, L., Massague, J., Benezra, R., 2013. TGF-beta-Id1 signaling opposes Twist1 and promotes metastatic colonization via a mesenchymal-to-epithelial transition. Cell Rep. 5, 1228-1242.
    [146]
    Stolfi, C., De Simone, V., Colantoni, A., Franze, E., Ribichini, E., Fantini, M.C., Caruso, R., Monteleone, I., Sica, G.S., Sileri, P., MacDonald, T.T., Pallone, F., Monteleone, G., 2014. A functional role for Smad7 in sustaining colon cancer cell growth and survival. Cell Death Dis. 5, e1073.
    [147]
    Stolfi, C., Marafini, I., De Simone, V., Pallone, F., Monteleone, G., 2013. The dual role of Smad7 in the control of cancer growth and metastasis. Int. J. Mol. Sci. 14, 23774-23790.
    [148]
    Storer, M., Mas, A., Robert-Moreno, A., Pecoraro, M., Ortells, M.C., Di Giacomo, V., Yosef, R., Pilpel, N., Krizhanovsky, V., Sharpe, J., Keyes, W.M., 2013. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155, 1119-1130.
    [149]
    Sugiyama, A., Nagaki, M., Shidoji, Y., Moriwaki, H., Muto, Y., 1997. Regulation of cell cycle-related genes in rat hepatocytes by transforming growth factor beta1. Biochem. Biophys. Res. Commun. 238, 539-543.
    [150]
    Sun, C.K., Chua, M.S., He, J., So, S.K., 2011. Suppression of glypican 3 inhibits growth of hepatocellular carcinoma cells through up-regulation of TGF-beta 2. Neoplasia (New York, N.Y.) 13, 735-U111.
    [151]
    Sun, H., Peng, Z., Tang, H., Xie, D., Jia, Z., Zhong, L., Zhao, S., Ma, Z., Gao, Y., Zeng, L., Luo, R., Xie, K., 2017. Loss of KLF4 and consequential downregulation of Smad7 exacerbate oncogenic TGF-beta signaling in and promote progression of hepatocellular carcinoma. Oncogene 36, 2957-2968.
    [152]
    Suzuki, H.I., Kiyono, K., Miyazono, K., 2010. Regulation of autophagy by transforming growth factor-beta (TGF-beta) signaling. Autophagy 6, 645-647.
    [153]
    Takamura, A., Komatsu, M., Hara, T., Sakamoto, A., Kishi, C., Waguri, S., Eishi, Y., Hino, O., Tanaka, K., Mizushima, N., 2011. Autophagy-deficient mice develop multiple liver tumors. Genes Dev. 25, 795-800.
    [154]
    Tang, B., Bottinger, E.P., Jakowlew, S.B., Bagnall, K.M., Mariano, J., Anver, M.R., Letterio, J.J., Wakefield, L.M., 1998. Transforming growth factor-beta1 is a new form of tumor suppressor with true haploid insufficiency. Nat. Med. 4, 802-807.
    [155]
    Tang, Y., Katuri, V., Dillner, A., Mishra, B., Deng, C.X., Mishra, L., 2003. Disruption of transforming growth factor-beta signaling in ELF beta-spectrin-deficient mice. Science 299, 574-577.
    [156]
    Tominaga, K., Suzuki, H.I., 2019. TGF-beta signaling in cellular senescence and aging-related pathology. Int. J. Mol. Sci. 20, 5002.
    [157]
    Tse, E.Y., Ko, F.C., Tung, E.K., Chan, L.K., Lee, T.K., Ngan, E.S., Man, K., Wong, A.S., Ng, I.O., Yam, J.W., 2012. Caveolin-1 overexpression is associated with hepatocellular carcinoma tumourigenesis and metastasis. J. Pathol. 226, 645-653.
    [158]
    Tu, S., Huang, W., Huang, C., Luo, Z., Yan, X., 2019. Contextual regulation of TGF-beta signaling in liver cancer. Cells 8, 1235.
    [159]
    Ullmann, P., Rodriguez, F., Schmitz, M., Meurer, S.K., Qureshi-Baig, K., Felten, P., Ginolhac, A., Antunes, L., Frasquilho, S., Zugel, N., Weiskirchen, R., Haan, S., Letellier, E., 2018. The miR-371 approximately 373 cluster represses colon cancer initiation and metastatic colonization by inhibiting the TGFBR2/ID1 signaling axis. Cancer Res. 78, 3793-3808.
    [160]
    Valdes, F., Alvarez, A.M., Locascio, A., Vega, S., Herrera, B., Fernandez, M., Benito, M., Nieto, M.A., Fabregat, I., 2002. The epithelial mesenchymal transition confers resistance to the apoptotic effects of transforming growth factor beta in fetal rat hepatocytes. Mol. Cancer Res. 1, 68-78.
    [161]
    Villanueva, A., 2019. Hepatocellular carcinoma. N. Engl. J. Med. 380, 1450-1462.
    [162]
    Wakefield, L.M., Hill, C.S., 2013. Beyond TGFbeta: roles of other TGFbeta superfamily members in cancer. Nat. Rev. Cancer 13, 328-341.
    [163]
    Wang, C., Li, L., Duan, Q., Wang, Q., Chen, J., 2017. Kruppel-like factor 2 suppresses human gastric tumorigenesis through inhibiting PTEN/AKT signaling. Oncotarget 8, 100358-100370.
    [164]
    Wildey, G.M., Howe, P.H., 2009. Runx1 is a co-activator with FOXO3 to mediate transforming growth factor beta (TGFbeta)-induced Bim transcription in hepatic cells. J. Biol. Chem. 284, 20227-20239.
    [165]
    Wilkes, M.C., Repellin, C.E., Hong, M., Bracamonte, M., Penheiter, S.G., Borg, J.P., Leof, E.B., 2009. Erbin and the NF2 tumor suppressor Merlin cooperatively regulate cell-type-specific activation of PAK2 by TGF-beta. Dev. Cell 16, 433-444.
    [166]
    Wu, J., Lu, M., Li, Y., Shang, Y.K., Wang, S.J., Meng, Y., Wang, Z., Li, Z.S., Chen, H., Chen, Z.N., Bian, H., 2016. Regulation of a TGF-beta1-CD147 self-sustaining network in the differentiation plasticity of hepatocellular carcinoma cells. Oncogene 35, 5468-5479.
    [167]
    Wu, S.Y., Lan, S.H., Wu, S.R., Chiu, Y.C., Lin, X.Z., Su, I.J., Tsai, T.F., Yen, C.J., Lu, T.H., Liang, F.W., Li, C.Y., Su, H.J., Su, C.L., Liu, H.S., 2018. Hepatocellular carcinoma-related cyclin D1 is selectively regulated by autophagy degradation system. Hepatology 68, 141-154.
    [168]
    Xiong, X., Tu, S., Wang, J., Luo, S., Yan, X., 2019. CXXC5: A novel regulator and coordinator of TGF-beta, BMP and Wnt signaling. J. Cell Mol. Med. 23, 740-749.
    [169]
    Xue, W., Zender, L., Miething, C., Dickins, R.A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., Lowe, S.W., 2007. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656-660.
    [170]
    Yamaguchi, T., Matsuzaki, K., Inokuchi, R., Kawamura, R., Yoshida, K., Murata, M., Fujisawa, J., Fukushima, N., Sata, M., Kage, M., Nakashima, O., Tamori, A., Kawada, N., Tsuneyama, K., Dooley, S., Seki, T., Okazaki, K., 2013. Phosphorylated Smad2 and Smad3 signaling: shifting between tumor suppression and fibro-carcinogenesis in chronic hepatitis C. Hepatol Res. 43, 1327-1342.
    [171]
    Yamamoto, M., Fukuda, K., Miura, N., Suzuki, R., Kido, T., Komatsu, Y., 1998. Inhibition by dexamethasone of transforming growth factor beta1-induced apoptosis in rat hepatoma cells: a possible association with Bcl-xL induction. Hepatology 27, 959-966.
    [172]
    Yamashita, M., Fatyol, K., Jin, C.Y., Wang, X.C., Liu, Z.G., Zhang, Y.E., 2008. TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta. Mol. Cell 31, 918-924.
    [173]
    Yan, X., Chen, Y.G., 2011. Smad7: not only a regulator, but also a cross-talk mediator of TGF-beta signalling. Biochem J. 434, 1-10.
    [174]
    Yan, X., Liao, H., Cheng, M., Shi, X., Lin, X., Feng, X.H., Chen, Y.G., 2016. Smad7 protein interacts with receptor-regulated Smads (R-Smads) to inhibit transforming growth factor-beta (TGF-beta)/Smad signaling. J. Biol. Chem. 291, 382-392.
    [175]
    Yan, X., Liu, Z., Chen, Y., 2009. Regulation of TGF-beta signaling by Smad7. Acta Biochim. Biophys. Sin. (Shanghai) 41, 263-272.
    [176]
    Yan, X., Wu, J., Jiang, Q., Cheng, H., Han, J.J., Chen, Y.G., 2018a. CXXC5 suppresses hepatocellular carcinoma by promoting TGF-beta-induced cell cycle arrest and apoptosis. J. Mol. Cell Biol. 10, 48-59.
    [177]
    Yan, X., Xiong, X., Chen, Y.G., 2018b. Feedback regulation of TGF-beta signaling. Acta Biochim. Biophys. Sin. (Shanghai) 50, 37-50.
    [178]
    Yan, X., Zhang, J., Pan, L., Wang, P., Xue, H., Zhang, L., Gao, X., Zhao, X., Ning, Y., Chen, Y.G., 2011. TSC-22 promotes transforming growth factor beta-mediated cardiac myofibroblast differentiation by antagonizing Smad7 activity. Mol. Cell Biol. 31, 3700-3709.
    [179]
    Yan, X., Zhang, J., Sun, Q., Tuazon, P.T., Wu, X., Traugh, J.A., Chen, Y.G., 2012. p21-Activated kinase 2 (PAK2) inhibits TGF-beta signaling in Madin-Darby canine kidney (MDCK) epithelial cells by interfering with the receptor-Smad interaction. J. Biol. Chem. 287, 13705-13712.
    [180]
    Yang, P., Markowitz, G.J., Wang, X.F., 2014. The hepatitis B virus-associated tumor microenvironment in hepatocellular carcinoma. Natl. Sci. Rev. 1, 396-412.
    [181]
    Yang, Y.A., Zhang, G.M., Feigenbaum, L., Zhang, Y.E., 2006. Smad3 reduces susceptibility to hepatocarcinoma by sensitizing hepatocytes to apoptosis through downregulation of Bcl-2. Cancer Cell 9, 445-457.
    [182]
    Yasui, K., Konishi, C., Gen, Y., Endo, M., Dohi, O., Tomie, A., Kitaichi, T., Yamada, N., Iwai, N., Nishikawa, T., Yamaguchi, K., Moriguchi, M., Sumida, Y., Mitsuyoshi, H., Tanaka, S., Arii, S., Itoh, Y., 2015. EVI1, a target gene for amplification at 3q26, antagonizes transforming growth factor-beta-mediated growth inhibition in hepatocellular carcinoma. Cancer Sci. 106, 929-937.
    [183]
    Yazdani, H.O., Huang, H., Tsung, A., 2019. Autophagy: dual response in the development of hepatocellular carcinoma. Cells 8, 91.
    [184]
    Yewale, C., Baradia, D., Vhora, I., Patil, S., Misra, A., 2013. Epidermal growth factor receptor targeting in cancer: a review of trends and strategies. Biomaterials 34, 8690-8707.
    [185]
    Yoo, J., Ghiassi, M., Jirmanova, L., Balliet, A.G., Hoffman, B., Fornace, A.J., Jr., Liebermann, D.A., Bottinger, E.P., Roberts, A.B., 2003. Transforming growth factor-beta-induced apoptosis is mediated by Smad-dependent expression of GADD45b through p38 activation. J. Biol. Chem. 278, 43001-43007.
    [186]
    Yoon, G., Kim, H.J., Yoon, Y.S., Cho, H., Lim, I.K., Lee, J.H., 2002. Iron chelation-induced senescence-like growth arrest in hepatocyte cell lines: association of transforming growth factor beta1 (TGF-beta1)-mediated p27Kip1 expression. Biochem. J. 366, 613-621.
    [187]
    Yoshida, K., Matsuzaki, K., Murata, M., Yamaguchi, T., Suwa, K., Okazaki, K., 2018. Clinico-pathological importance of TGF-beta/phospho-Smad signaling during human hepatic fibrocarcinogenesis. Cancers (Basel) 10, 183.
    [188]
    Yoshimoto, S., Loo, T.M., Atarashi, K., Kanda, H., Sato, S., Oyadomari, S., Iwakura, Y., Oshima, K., Morita, H., Hattori, M., Honda, K., Ishikawa, Y., Hara, E., Ohtani, N., 2013. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97-101.
    [189]
    Yu, J., Zhang, L., Chen, A., Xiang, G., Wang, Y., Wu, J., Mitchelson, K., Cheng, J., Zhou, Y., 2008. Identification of the gene transcription and apoptosis mediated by TGF-beta-Smad2/3-Smad4 signaling. J. Cell Physiol. 215, 422-433.
    [190]
    Yu, Y., Feng, X.H., 2019. TGF-beta signaling in cell fate control and cancer. Curr. Opin. Cell Biol. 61, 56-63.
    [191]
    Yu, Y., Gu, S., Li, W., Sun, C., Chen, F., Xiao, M., Wang, L., Xu, D., Li, Y., Ding, C., Xia, Z., Li, Y., Ye, S., Xu, P., Zhao, B., Qin, J., Chen, Y.G., Lin, X., Feng, X.H., 2017. Smad7 enables STAT3 activation and promotes pluripotency independent of TGF-beta signaling. Proc. Natl. Acad. Sci. U. S. A. 114, 10113-10118.
    [192]
    Yuan, B., Liu, J., Cao, J., Yu, Y., Zhang, H., Wang, F., Zhu, Y., Xiao, M., Liu, S., Ye, Y., Ma, L., Xu, D., Xu, N., Li, Y., Zhao, B., Xu, P., Jin, J., Xu, J., Chen, X., Shen, L., Lin, X., Feng, X.H., 2019. PTPN3 acts as a tumor suppressor and boosts TGF-beta signaling independent of its phosphatase activity. EMBO J. 38, e99945.
    [193]
    Yue, Z., Jin, S., Yang, C., Levine, A.J., Heintz, N., 2003. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl. Acad. Sci. U. S. A. 100, 15077-15082.
    [194]
    Zhang, H., Ozaki, I., Mizuta, T., Hamajima, H., Yasutake, T., Eguchi, Y., Ideguchi, H., Yamamoto, K., Matsuhashi, S., 2006. Involvement of programmed cell death 4 in transforming growth factor-beta1-induced apoptosis in human hepatocellular carcinoma. Oncogene 25, 6101-6112.
    [195]
    Zhang, H., Ozaki, I., Mizuta, T., Yoshimura, T., Matsuhashi, S., Eguchi, Y., Yasutake, T., Hisatomi, A., Sakai, T., Yamamoto, K., 2004. Transforming growth factor-beta 1-induced apoptosis is blocked by beta 1-integrin-mediated mitogen-activated protein kinase activation in human hepatoma cells. Cancer Sci. 95, 878-886.
    [196]
    Zhang, L., Zhou, F., ten Dijke, P., 2013a. Signaling interplay between transforming growth factor-beta receptor and PI3K/AKT pathways in cancer. Trends Biochem. Sci. 38, 612-620.
    [197]
    Zhang, L., Zhou, F.F., de Vinuesa, A.G., de Kruijf, E.M., Mesker, W.E., Hui, L., Drabsch, Y., Li, Y.H., Bauer, A., Rousseau, A., Sheppard, K.A., Mickanin, C., Kuppen, P.J.K., Lu, C.X., ten Dijke, P., 2013b. TRAF4 promotes TGF-beta receptor signaling and drives breast cancer metastasis. Mol. Cell 51, 559-572.
    [198]
    Zhang, Q., Xiao, M., Gu, S., Xu, Y., Liu, T., Li, H., Yu, Y., Qin, L., Zhu, Y., Chen, F., Wang, Y., Ding, C., Wu, H., Ji, H., Chen, Z., Zu, Y., Malkoski, S., Li, Y., Liang, T., Ji, J., Qin, J., Xu, P., Zhao, B., Shen, L., Lin, X., Feng, X.H., 2019. ALK phosphorylates SMAD4 on tyrosine to disable TGF-beta tumour suppressor functions. Nat. Cell Biol. 21, 179-189.
    [199]
    Zhang, X., Fan, Q., Li, Y., Yang, Z., Yang, L., Zong, Z., Wang, B., Meng, X., Li, Q., Liu, J., Li, H., 2017a. Transforming growth factor-beta1 suppresses hepatocellular carcinoma proliferation via activation of Hippo signaling. Oncotarget 8, 29785-29794.
    [200]
    Zhang, Y., Alexander, P.B., Wang, X.F., 2017b. TGF-beta family signaling in the control of cell proliferation and survival. Cold Spring Harb. Perspect. Biol. 9, a022145.
    [201]
    Zhang, Y.E., 2017. Non-Smad signaling pathways of the TGF-beta family. Cold Spring Harb. Perspect. Biol. 9, a022129.
    [202]
    Zhang, Y.E., 2018. Mechanistic insight into contextual TGF-beta signaling. Curr. Opin. Cell Biol. 51, 1-7.
    [203]
    Zhao, X., Liu, Y., Du, L., He, L., Ni, B., Hu, J., Zhu, D., Chen, Q., 2015. Threonine 32 (Thr32) of FoxO3 is critical for TGF-beta-induced apoptosis via Bim in hepatocarcinoma cells. Protein Cell 6, 127-138.
    [204]
    Zhu, H., Wu, K., Yan, W., Hu, L., Yuan, J., Dong, Y., Li, Y., Jing, K., Yang, Y., Guo, M., 2013. Epigenetic silencing of DACH1 induces loss of transforming growth factor-beta1 antiproliferative response in human hepatocellular carcinoma. Hepatology (Baltimore, Md.) 58, 2012-2022.
    [205]
    Zucman-Rossi, J., Villanueva, A., Nault, J.C., Llovet, J.M., 2015. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology 149, 1226-1239 e1224.
    • Relative Articles
    • Supplements(0)
    • Cited By
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures (5)

    Get Citation
    PDF

    Article Metrics

    Article views (118) PDF downloads (4) Cited by ()
    Proportional views
    Related

    Editorial Office

    Journal of Genetics and Genomics

    京ICP备09063187号-7

    No.1, West Beichen Road, Chaoyang District, Beijing 100101, P.R.China

    +86-10-64806528+86-10-64807786jgg@genetics.ac.cn

    Supported by: Beijing Renhe Information Technology Co. Ltd  

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return