Please wait a minute...
Traditional Medicine Research  2018, Vol. 3 Issue (1): 10-21    DOI: 10.12032/TMR201809060
Modernization of Traditional Medicine     
TGF-β signaling in hepatocellular carcinoma suppression and progression
Jian Hao1, Dan Chen2,*()
1Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
2School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Download: HTML     PDF(647KB)
Export: BibTeX | EndNote (RIS)      


This paper evaluates the suppressive and accelerant roles of TGF-β in hepatocellular carcinoma, discusses how a tumor-suppressor pathway can be so radically turned on its head and further provides some new molecular insights that may aid efforts towards targeted antitumor therapies.

Editor’s Summary

This review pays particular attention to the dual role of TGF-β in hepatocellular carcinoma. It also discusses the potential anti-tumor herbs through TGF-β signaling pathways.


Derangements of several cell signaling pathways have been implicated in the initiation, progression, and development of hepatocellular carcinoma (HCC). One of such pathways is the activated TGF-β/Smad pathway. TGF-β inhibits proliferation and induces apoptosis in various cells types in the early tumor, and accumulation of loss-of-function mutations in the TGF-β receptor or Smad genes in tumor classify the pathway as a tumor suppressor. However, in chronic hepatitis, the cytostatic effect of TGF-β for hepatocytes attenuates as liver disease progresses from cirrhosis to HCC under persistent inflammatory microenvironments. In the later cancer period, TGF-β promotes tumor growth by modulating processes such as cell invasion, immune regulation, and microenvironment modification. Here we evaluate the suppressive and accelerant roles of TGF-β in HCC, discuss how a tumor-suppressor pathway can be so radically turned on its head and further provide some new molecular insights that may aid efforts towards targeted antitumor therapies. Moreover, we discussed the potential anti-tumor herbs through TGF-β signaling pathways.

Key wordsTGF-β      Hepatocellular Carcinoma      Suppression      Progression      Anti-tumor herbs     
Published: 05 January 2018
Corresponding Authors: Chen Dan     E-mail:
Cite this article:

Jian Hao, Dan Chen. TGF-β signaling in hepatocellular carcinoma suppression and progression. Traditional Medicine Research, 2018, 3(1): 10-21. doi: 10.12032/TMR201809060

URL:     OR

Figure 1 Smad-dependent and Smad-independent TGF-β pathways

In the Smad-dependent pathway, the three TGF-β ligand isoforms, TGF-β1, TGF-β2, and TGF-β3, are activated and assisted by the membranous TGF-β type III receptor to bind to TGF-β type II receptor (TGF-βRII) with high affinity. TGF-βRII binding allows dimerization with TGF-β type I receptor (TGF-βRI) homodimers, activation of the TGF-βRI kinase domain and signal transduction via phosphorylation of the C-terminus of receptor-regulated SMADs (R-SMAD), SMAD2 and SMAD3. The TGF-βR dimer then forms a heterotrimeric complex with SMAD4 which translocates and accumulates in the nucleus. TGF-β dependent signaling can activate or repress hundreds of target genes through the interaction of SMADs with various transcription factors (TF). SMAD activities are regulated via expression of inhibitory SMAD6 and SMAD7. In the Smad-independent pathway, TGF-β signaling activates other pathways such as PI3K/AKT, MAPK pathways (ERK, JNK, and p38 MAPK) as well as NF-kB, Rho/Rac1, CDC42, FAK, Src, Abl. The TGF-β signaling pathway has pleiotropic functions regulating cell growth, differentiation, apoptosis, cell motility, extracellular matrix production, angiogenesis and cellular immune response.

Figure 2 TGF-β signaling in HCC progression and suppression

Tumor suppressive effects. Cell cycle arrest by increasing tumour suppressing genes and decreasing oncogenes; Induces autophagy, differentiation, senescence and apoptosis; Suppresses angiogenesis through inhibiting VEGF; Inhibits inflammatory cytokine production from lymphocytes and macrophages.

Tumor promoter effects. Growth and migration promotion of HCC cells via inducing the production of growth factors epithelial-mesenchymal transition induction, evasion of immune surveillance, Augments microenvironment-modifying proteases and cytokines; invasion and angiogenesis by inducing expression of genes such as MMP2, MMP9 and CTGF.

1.   European Association For The Study Of The Liver. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012, 56: 908-943.
doi: 10.1016/j.jhep.2011.12.001 pmid: 22424438
2.   Bissell DM.Chronic liver injury, TGF-β, and cancer. Exp Mol Med 2001, 33: 179-190.
doi: 10.1038/emm.2001.31
3.   Inagaki Y, Okazaki I.Emerging insights into transforming growth factor β Smad signal in hepatic fibrogenesis. Gut 2007, 56: 284-292.
doi: 10.1136/gut.2005.088690 pmid: 1856752
4.   Tian M, Neil JR, Schiemann WP.Transforming growth factor-β and the hallmarks of cancer. Cell Signal 2011, 23: 951-962.
doi: 10.1016/j.cellsig.2010.10.015 pmid: 20940046
5.   Gold LI.The role for transforming growth factor-beta (TGF-beta) in human cancer. Crit Rev Oncogenesis 1998, 10: 303-360.
doi: 10.1046/j.1365-313x.1998.00236.x pmid: 10654929
6.   Jakowlew SB.Transforming growth factor-β in cancer and metastasis. Cancer Metast Rev 2006, 25: 435-457.
doi: 10.1007/s10555-006-9006-2
7.   Groppe J, Hinck CS, Samavarchi-Tehrani P, et al.Cooperative assembly of TGF-β superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding. Moll Cell 2008, 29: 157-168.
doi: 10.1016/j.molcel.2007.11.039 pmid: 18243111
8.   Shi Y, Massagué J.Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 2003, 113: 685-700.
doi: 10.1016/S0092-8674(03)00432-X
9.   De Robertis EM, Kuroda H.Dorsal-ventral patterning and neural induction in Xenopus embryos. Annu Rev Cell Dev Bi 2004, 20: 285.
doi: 10.1146/annurev.cellbio.20.011403.154124 pmid: 15473842
10.   Rodgarkia-Dara C, Vejda S, Erlach N, et al.The activin axis in liver biology and disease. Mutat Res-Rev Mutat 2006, 613: 123-137.
doi: 10.1016/j.mrrev.2006.07.002 pmid: 16997617
11.   De Caestecker MP, Parks WT, Frank CJ, et al.Smad2 transduces common signals from receptor serine-threonine and tyrosine kinases. Gene Dev 1998, 12: 1587-1592.
doi: 10.1101/gad.12.11.1587 pmid: 9620846
12.   Kretzschmar M, Doody J, Timokhina I, et al.A mechanism of repression of TGFβ/Smad signaling by oncogenic Ras. Gene Dev 1999, 13: 804-816.
doi: 10.1101/gad.13.7.804 pmid: 10197981
13.   Funaba M, Zimmerman CM, Mathews LS.Modulation of Smad2-mediated signaling by extracellular signal-regulated kinase. J Biol Chem 2002, 277: 41361-41368.
doi: 10.1074/jbc.M204597200 pmid: 12193595
14.   Engel ME, McDonnell MA, Law BK, et al. Interdependent SMAD and JNK signaling in transforming growth factor-β-mediated transcription. J Biol Chem 1999, 274: 37413-37420.
doi: 10.1074/jbc.274.52.37413
15.   Yu L, Hébert MC, Zhang YE.TGF-β receptor-activated p38 MAP kinase mediates Smad-independent TGF-β responses. Embo J 2002, 21: 3749-3759.
doi: 10.1093/emboj/cdf366 pmid: 12110587
16.   Yue J, Mulder KM.Activation of the Mitogen-Activated Protein Kinase Pathway by TGFβ //Transforming Growth Factor-Beta Protocols. Humana Press 2000, 125-131.
17.   Yamaguchi K, Nagai S, Ninomiya-Tsuji J, et al.XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway. EMBO J 1999, 18: 179-187.
doi: 10.1093/emboj/18.1.179 pmid: 9878061
18.   Rich JN, Zhang M, Datto MB, et al.Transforming Growth Factor-β-mediated p15INK4B Induction and Growth Inhibition in Astrocytes Is SMAD3-dependent and a Pathway Prominently Altered in Human Glioma Cell Lines. J Biol Chem 1999, 274: 35053-35058.
doi: 10.1074/jbc.274.49.35053
19.   Im YH, Kim HT, Kim IY, et al.Heterozygous mice for the transforming growth factor-β type II receptor gene have increased susceptibility to hepatocellular carcinogenesis. Cancer Res 2001, 61: 6665-6668.
20.   Nguyen LN, Furuya MH, Wolfraim LA, et al.Transforming growth factor-beta differentially regulates oval cell and hepatocyte proliferation. Hepatology 2007, 45: 31-41.
doi: 10.1002/hep.21466 pmid: 17187411
21.   Siegel PM, Massagué J.Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer. Nat Rev Cancer 2003, 3: 807-820.
doi: 10.1038/nrc1208 pmid: 14557817
22.   Gressner AM, Lahme B, Mannherz HG, et al.TGF-β-mediated hepatocellular apoptosis by rat and human hepatoma cells and primary rat hepatocytes. J hepatol 1997, 26: 1079-1092.
doi: 10.1016/S0168-8278(97)80117-1 pmid: 9186839
23.   Takekawa M, Tatebayashi K, Itoh F, et al.Smad-dependent GADD45β expression mediates delayed activation of p38 MAP kinase by TGF-β. EMBO J 2002, 21: 6473-6482.
doi: 10.1093/emboj/cdf643 pmid: 12456654
24.   Tachibana I, Imoto M, Adjei PN, et al.Overexpression of the TGFbeta-regulated zinc finger encoding gene, TIEG, induces apoptosis in pancreatic epithelial cells. J Clin Invest 1997, 99: 2365.
doi: 10.1172/JCI119418 pmid: 9153278
25.   Chalaux E, López-Rovira T, Rosa JL, et al.A zinc-finger transcription factor induced by TGF-β promotes apoptotic cell death in epithelial Mv1Lu cells. FEBS Lett 1999, 457: 478-482.
doi: 10.1016/S0014-5793(99)01051-0 pmid: 10471833
26.   Kim BC, Mamura M, Choi KS, et al.Transforming growth factor β1 induces apoptosis through cleavage of BAD in a Smad3-dependent mechanism in FaO hepatoma cells. Mol Cellular Bio 2002, 22: 1369-1378.
doi: 10.1128/MCB.22.5.1369-1378.2002 pmid: 11839804
27.   Ohgushi M, Kuroki S, Fukamachi H, et al.Transforming growth factor β-dependent sequential activation of Smad, Bim, and caspase-9 mediates physiological apoptosis in gastric epithelial cells. Mol Cellular Bio 2005, 25: 10017-10028.
doi: 10.1128/MCB.25.22.10017-10028.2005 pmid: 1280259
28.   Kim KY, Kim BC, Xu Z, et al.Mixed lineage kinase 3 (MLK3)-activated p38 MAP kinase mediates transforming growth factor-β-induced apoptosis in hepatoma cells. J Bio Chem 2004, 279: 29478-29484.
doi: 10.1074/jbc.M313947200 pmid: 15069087
29.   Kogiso T, Nagahara H, Hashimoto E, et al.Efficient Induction of Apoptosis by Wee1 Kinase Inhibition in Hepatocellular Carcinoma Cells. PloS one 2014, 9: e100495.
doi: 10.1371/journal.pone.0100495 pmid: 4069002
30.   Kuo KK, Jian SF, Li YJ, et al.Epigenetic inactivation of transforming growth factor-β1 target gene HEYL, a novel tumor suppressor, is involved in the P53-induced apoptotic pathway in hepatocellular carcinoma. Hepatol Res 2014, 45: 782-793.
doi: 10.1111/hepr.12414 pmid: 25179429
31.   Wang F, Kaur S, Cavin LG, et al.Nuclear-factor-κB (NF-κB) and radical oxygen species play contrary roles in transforming growth factor-β1 (TGF-β1)-induced apoptosis in hepatocellular carcinoma (HCC) cells. Biochem bioph Res Co 2008, 377: 1107-1112.
doi: 10.1016/j.bbrc.2008.10.130
32.   Senturk S, Mumcuoglu M, Gursoy-Yuzugullu O, et al.Transforming growth factor-beta induces senescence in hepatocellular carcinoma cells and inhibits tumor growth. Hepatology 2010, 52: 966-974.
doi: 10.1002/hep.23769 pmid: 20583212
33.   Suzuki HI, Kiyono K, Miyazono K.Regulation of autophagy by transforming growth factor-β (TGF-β) signaling. Autophagy 2010, 6: 645-647.
doi: 10.4161/auto.6.5.12046
34.   Kim KY, Jeong SY, Won J, et al.Induction of angiogenesis by expression of soluble type II transforming growth factor-β receptor in mouse hepatoma. J Bio Chemi 2001, 276: 38781-38786.
doi: 10.1074/jbc.M104944200
35.   Ito N, Kawata S, Tamura S, et al.Elevated levels of transforming growth factor β messenger RNA and its polypeptide in human hepatocellular carcinoma. Cancer Res 1991, 51: 4080-4083.
36.   Ito N, Kawata S, Tamura S, et al.Positive correlation of plasma transforming growth factor-β1 levels with tumor vascularity in hepatocellular carcinoma. Cancer lett 1995, 89: 45-48.
doi: 10.1016/0304-3835(95)90156-6 pmid: 7882301
37.   Inagaki M, Moustakas A, Lin HY, et al.Growth inhibition by transforming growth factor beta (TGF-beta) type I is restored in TGF-beta-resistant hepatoma cells after expression of TGF-beta receptor type II cDNA. P Natl Acad Sci 1993, 90: 5359-5363.
doi: 10.1073/pnas.90.11.5359
38.   Markowitz S, Wang J, Myeroff L, et al.Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Sci 1995, 268: 1336-1338.
doi: 10.1126/science.7761852
39.   Myeroff LL, Parsons R, Kim SJ, et al.A transforming growth factor β receptor type II gene mutation common in colon and gastric but rare in endometrial cancers with microsatellite instability. Cancer Res 1995, 55: 5545-5547.
doi: 10.1002/pen.760290110 pmid: 7585631
40.   Park K, Kim SJ, Bang YJ, et al. Genetic changes in the transforming growth factor beta (TGF-beta) type II receptor gene in human gastric cancer cells: correlation with sensitivity to growth inhibition by TGF-beta. Proc Natl Acad Sci USA. 1994, 91: 8772-8776.
doi: 10.1073/pnas.91.19.8772
41.   Izumoto S, Arita N, Ohnishi T, et al.Microsatellite instability and mutated type II transforming growth factor-β receptor gene in gliomas. Cancer lett 1997, 112: 251-256.
doi: 10.1016/S0304-3835(96)04583-1 pmid: 9066736
42.   Kawate S, Takenoshita S, Ohwada S, et al.Mutation analysis of transforming growth factor beta type II receptor, Smad2, and Smad4 in hepatocellular carcinoma. Int J oncol 1999, 14: 127-158.
doi: 10.1016/S0016-5085(00)81721-7 pmid: 9863018
43.   Yakicier MC, Irmak MB, Romano A, et al.Smad2 and Smad4 gene mutations in hepatocellular carcinoma. Oncogene 1999, 18: 4879-4883.
doi: 10.1038/sj.onc.1202866 pmid: 10490821
44.   Kiss A, Wang NJ, Xie JP, et al.Analysis of transforming growth factor (TGF)-alpha/epidermal growth factor receptor, hepatocyte growth Factor/c-met, TGF-beta receptor type II, and p53 expression in human hepatocellular carcinomas. Clin Cancer Res 1997, 3: 1059-1066.
45.   Mamiya T, Yamazaki K, Masugi Y, et al.Reduced transforming growth factor-β receptor II expression in hepatocellular carcinoma correlates with intrahepatic metastasis. Lab Invest 2010, 90: 1339-1345.
doi: 10.1038/labinvest.2010.105 pmid: 20531292
46.   Kanzler S, Meyer E, Lohse AW, et al.Hepatocellular expression of a dominant-negative mutant TGF-beta type II receptor accelerates chemically induced hepatocarcinogenesis. Oncogene 2001, 20: 5015-5024.
doi: 10.1038/sj.onc.1204544 pmid: 11526486
47.   Sekimoto G, Matsuzaki K, Yoshida K, et al.Reversible Smad-dependent signaling between tumor suppression and oncogenesis. Cancer Res 2007, 67: 5090-5096.
doi: 10.1158/0008-5472.CAN-06-4629 pmid: 17545585
48.   Matsuzaki K, Murata M, Yoshida K, et al.Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor β signaling, promoting cirrhosis and hepatocellular carcinoma. Hepatology 2007, 46: 48-57.
doi: 10.1002/hep.21672 pmid: 17596875
49.   Murata M, Matsuzaki K, Yoshida K, et al.Hepatitis B virus X protein shifts human hepatic transforming growth factor (TGF)-β signaling from tumor suppression to oncogenesis in early chronic hepatitis B. Hepatology 2009, 49: 1203-1217.
doi: 10.1002/hep.22765 pmid: 19263472
50.   Li Q, Liu G, Shao D, et al.Mucin1 mediates autocrine transforming growth factor beta signaling through activating the c-Jun N-terminal kinase/activator protein 1 pathway in human hepatocellular carcinoma cells. Int J Biochem Cell B 2015, 59: 116-125.
doi: 10.1016/j.biocel.2014.11.012 pmid: 25526895
51.   Hernanda PY, Chen K, Das AM, et al.SMAD4 exerts a tumor-promoting role in hepatocellular carcinoma. Oncogene 2014, 34: 5055-5068.
doi: 10.1038/onc.2014.425 pmid: 25531314
52.   Yakicier MC, Irmak MB, Romano A, et al.Smad2 and Smad4 gene mutations in hepatocellular carcinoma. Oncogene 1999, 18: 4879-4883.
doi: 10.1038/sj.onc.1202866 pmid: 10490821
53.   Prunier C, Ferrand N, Frottier B, et al.Mechanism for mutational inactivation of the tumor suppressor Smad2. Mol Cell Bio 2001, 21: 3302-3313.
doi: 10.1128/MCB.21.10.3302-3313.2001
54.   Dumont E, Lallemand F, Prunier C, et al.Evidence for a role of Smad3 and Smad2 in stabilization of the tumor-derived mutant Smad2. Q407R. J Bio Chem 2003, 278: 24881-24887.
doi: 10.1074/jbc.M212496200 pmid: 12700238
55.   Zimonjic DB, Durkin ME, Keck-Waggoner CL, et al.SMAD5 Gene Expression, Rearrangements, Copy Number, Amplification at Fragile Site FRA5C in Human Hepatocellular Carcinoma. Neoplasia 2003, 5: 390-396.
doi: 10.1016/S1476-5586(03)80041-6 pmid: 14670176
56.   Kawate S, Ohwada S, Hamada K, et al.Mutational analysis of the Smad6 and Smad7 genes in hepatocellular carcinoma. Int J Mol Med 2001, 8: 49-52.
doi: 10.3892/ijmm.8.1.49 pmid: 11408948
57.   Houck KA, Michalopoulos GK, Strom SC.Introduction of a Ha-ras oncogene into rat liver epithelial cells and parenchymal hepatocytes confers resistance to the growth inhibitory effects of TGF-beta. Oncogene 1989, 4: 19-25.
doi: 10.1023/B:JOEY.0000010240.97364.41 pmid: 2783773
58.   Labbé E, Letamendia A, Attisano L.Association of Smads with lymphoid enhancer binding factor 1/T cell-specific factor mediates cooperative signaling by the transforming growth factor-β and wnt pathways. Proc Natl Acad Sci USA 2000, 97: 8358-8363.
doi: 10.1073/pnas.150152697 pmid: 10890911
59.   Tang Y, Katuri V, Dillner A, et al.Disruption of transforming growth factor-β signaling in ELF β-spectrin-deficient mice. Sci 2003, 299: 574-577.
doi: 10.1126/science.1075994
60.   Katuri V, Tang Y, Li C, et al.Critical interactions between TGF-β signaling/ELF, and E-cadherin/β-catenin mediated tumor suppression. Oncogene 2006, 25: 1871-1886.
doi: 10.1038/sj.onc.1209211 pmid: 16288220
61.   Tang Y, Katuri V, Srinivasan R, et al.Transforming growth factor-β suppresses nonmetastatic colon cancer through Smad4 and adaptor protein ELF at an early stage of tumorigenesis. Cancer Res 2005, 65: 4228-4237.
doi: 10.1158/0008-5472.CAN-04-4585 pmid: 15899814
62.   Wilkinson DS, Ogden SK, Stratton SA, et al.A direct intersection between p53 and transforming growth factor β pathways targets chromatin modification and transcription repression of the α-fetoprotein gene. Mol Cell Biol 2005, 25: 1200-1212.
doi: 10.1128/MCB.25.3.1200-1212.2005 pmid: 544019
63.   Zhu H, Wu K, Yan W, et al.Epigenetic silencing of DACH1 induces loss of transforming growth factor-β1 antiproliferative response in human hepatocellular carcinoma. Hepatology 2013, 58(6): 2012-2022.
doi: 10.1002/hep.26587 pmid: 23787902
64.   Zhang H, Ozaki I, Mizuta T, et al.Involvement of programmed cell death 4 in transforming growth factor-β1-induced apoptosis in human hepatocellular carcinoma. Oncogene 2006, 25: 6101-6112.
doi: 10.1038/sj.onc.1209634
65.   Jennings MT, Pietenpol JA.The role of transforming growth factor β in glioma progression. J Neuro Oncol 1998, 36: 123-140.
doi: 10.1023/A:1005863419880 pmid: 9525812
66.   Thiery JP, Acloque H, Huang RY, et al.Epithelial-mesenchymal transitions in development and disease. Cell 2009, 139: 871-890.
doi: 10.1016/j.cell.2009.11.007 pmid: 19945376
67.   Derynck R, Akhurst RJ.Differentiation plasticity regulated by TGF-β family proteins in development and disease. Nature cell biol 2007, 9: 1000-1004.
doi: 10.1038/ncb434 pmid: 17762890
68.   Thiery JP.Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003, 15: 740-746.
doi: 10.1016/ pmid: 14644200
69.   Oft M, Heider KH, Beug H.TGFβ signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol 1998, 8: 1243-1252.
doi: 10.1016/S0960-9822(07)00533-7 pmid: 9822576
70.   Valcourt U, Kowanetz M, Niimi H, et al.TGF-β and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol Bio Cell 2005, 16: 1987-2002.
doi: 10.1091/mbc.E04-08-0658
71.   LaGamba D, Nawshad A, Hay ED. Microarray analysis of gene expression during epithelial-mesenchymal transformation. Dev Dynam 2005, 234: 132-142.
doi: 10.1002/dvdy.20489 pmid: 16010672
72.   Mani SA, Guo W, Liao MJ, et al.The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008, 133: 704-715.
doi: 10.1016/j.cell.2008.03.027 pmid: 18485877
73.   Tian F, Byfield SDC, Parks WT, et al.Smad-binding defective mutant of transforming growth factor β type I receptor enhances tumorigenesis but suppresses metastasis of breast cancer cell lines. Cancer Res 2004, 64: 4523-4530.
doi: 10.1158/0008-5472.CAN-04-0030 pmid: 15231662
74.   Tian F, Byfield S DC, Parks WT, et al.Reduction in Smad2/3 signaling enhances tumorigenesis but suppresses metastasis of breast cancer cell lines. Cancer Res 2003, 63: 8284-8292.
75.   Shim JH, Xiao C, Paschal AE, et al.TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Gene Dev 2005, 19: 2668-2681.
doi: 10.1101/gad.1360605
76.   Bhowmick NA, Zent R, Ghiassi M, et al.Integrin β1 signaling is necessary for transforming growth factor-β activation of p38MAPK and epithelial plasticity. J Bio Chem 2001, 276: 46707-46713.
doi: 10.1074/jbc.M106176200 pmid: 11590169
77.   Gressner OA, Gressner AM.Connective tissue growth factor: a fibrogenic master switch in fibrotic liver diseases. Liver Int 2008, 28: 1065-1079.
doi: 10.1111/j.1478-3231.2008.01826.x pmid: 18783549
78.   Ihn H.Pathogenesis of fibrosis: role of TGF-β and CTGF. Curr Opin Rheumatol 2002, 14: 681-685.
doi: 10.1097/00002281-200211000-00009 pmid: 12410091
79.   Lehmann K, Janda E, Pierreux CE, et al.Raf induces TGFβ production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells. Gene Deve 2000, 14: 2610-2622.
doi: 10.1016/0005-2760(70)90057-3
80.   Janda E, Lehmann K, Killisch I, et al.Ras and TGFβ cooperatively regulate epithelial cell plasticity and metastasis dissection of Ras signaling pathways. J Cell bio 2002, 156: 299-314.
doi: 10.1083/jcb.200109037
81.   Gotzmann J, Huber H, Thallinger C, et al.Hepatocytes convert to a fibroblastoid phenotype through the cooperation of TGF-β1 and Ha-Ras: steps towards invasiveness. J Cell Sci 2002, 115: 1189-1202.
doi: 10.3410/f.1004801.55605 pmid: 11884518
82.   Dooley S, Delvoux B, Lahme B, et al.Modulation of transforming growth factor β response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts. Hepatology 2000, 31: 1094-1106.
doi: 10.1053/he.2000.6126 pmid: 10796885
83.   Yu W, Huang C, Wang Q, et al.MEF2 transcription factors promotes EMT and invasiveness of hepatocellular carcinoma through TGF-β1 autoregulation circuitry. Tumor Biol 2014, 35: 10943-10951.
doi: 10.1007/s13277-014-2403-1 pmid: 25087096
84.   Minkyung K, Suyong C, Soo-Jin J, et al.Cross-talk between TGFbeta1 and EGFR signaling pathways induces TM4SF5 expression and epithelial-mesenchymal transition. Biochem J 2012, 443: 691-700.
doi: 10.1042/BJ20111584
85.   Dhanasekaran R, Nakamura I, Hu C, et al.Activation of the transforming growth factor-β/ SMAD transcriptional pathway underlies a novel tumor-promoting role of sulfatase 1 in hepatocellular carcinoma. Hepatology 2015 , 61: 1269-1283
doi: 10.1002/hep.27658 pmid: 25503294
86.   Mima K1, Okabe H, Ishimoto Tet al. CD44s regulates the TGF-β-mediated mesenchymal phenotype and is associated with poor prognosis in patients with hepatocellular carcinoma. Cancer Res 2012, 72: 3414-3423.
doi: 10.1158/0008-5472.CAN-12-0299 pmid: 22552294
87.   Y. Maehara, Y. Kakeji, A. Kabashima, et al.Role of transforming growth factor-β in invasion and metastasis in gastric carcinoma. J Clin Oncol 1999, 17: 607-614.
doi: 10.1200/JCO.1999.17.2.607
88.   Prunier C, Mazars A, No? V, et al.Evidence that Smad2 is a tumor suppressor implicated in the control of cellular invasion. J Bio Chem 1999, 274: 22919-22922.
doi: 10.1074/jbc.274.33.22919
89.   Giannelli G, Fransvea E, Marinosci F, et al.Transforming growth factor-β1 triggers hepatocellular carcinoma invasiveness via α3β1 integrin. Am J Pathol 2002, 161: 183-193.
doi: 10.1016/S0002-9440(10)64170-3 pmid: 12107103
90.   De Wever O, Mareel M.Role of tissue stroma in cancer cell invasion. J Pathol 2003, 200: 429-447.
doi: 10.1002/path.1398 pmid: 12845611
91.   Allinen M, Beroukhim R, Cai L, et al.Molecular characterization of the tumor microenvironment in breast cancer. Cancer cell 2004, 6: 17-32.
doi: 10.1016/j.ccr.2004.06.010 pmid: 2729518
92.   Lewis MP, Lygoe KA, Nystrom ML, et al.Tumour-derived TGF-β1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells. Brit J Cancer 2004, 90: 822-832.
doi: 10.1038/sj.bjc.6601611 pmid: 2410183
93.   Bhowmick NA, Chytil A, Plieth D, et al.TGF-? signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Sci 2004, 303: 848-851.
doi: 10.1126/science.1090922
94.   Ito N, Kawata S, Tamura S, et al.Positive correlation of plasma transforming growth factor-β1 levels with tumor vascularity in hepatocellular carcinoma. Cancer lett 1995, 89: 45-48.
doi: 10.1016/0304-3835(95)90156-6 pmid: 7882301
95.   Hasegawa Y, Takanashi S, Kanehira Y, et al.Transforming growth factor-β1 level correlates with angiogenesis, tumor progression, and prognosis in patients with nonsmall cell lung carcinoma. Cancer 2001, 91: 964-971.
doi: 10.1002/1097-0142(20010301)91:5<964::AID-CNCR1086>3.0.CO;2-O pmid: 11251948
96.   Ivanovic V, Melman A, Davis-Joseph B, et al.Elevated plasma levels of TGF-β1 in patients with invasive prostate cancer. Nature Med 1995, 1: 282-284.
doi: 10.1038/nm0495-282 pmid: 7585049
97.   Wikstr?m P, Stattin P, Franck-Lissbrant I, et al.Transforming growth factor β1 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer. Prostate 1998, 37: 19-29.
doi: 10.1002/(SICI)1097-0045(19980915)37:1<19::AID-PROS4>3.0.CO;2-3 pmid: 9721065
98.   Pepper MS.Transforming growth factor-beta: vasculogenesis, angiogenesis, and vessel wall integrity. Cytokine Growth F R 1997, 8: 21-43.
doi: 10.1016/S1359-6101(96)00048-2
99.   Tsunawaki S, Sporn M, Ding A, et al. Deactivation of macrophages by transforming growth factor-β 1988, 334: 260-262.
doi: 10.1038/334260a0 pmid: 30412833041283
100.   Perz JF, Armstrong GL, Farrington LA, et al.The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006, 45: 529-538.
doi: 10.1016/j.jhep.2006.05.013
101.   Jemal A, Siegel R, Ward E, et al.Cancer statistics, 2008. CA: a cancer journal for clinicians, 2008, 58: 71-96.
doi: 10.3322/CA.2007.0010
102.   Evans AA, London WT, Gish RG, et al.Chronic HBV infection outside treatment guidelines: is treatment needed. Antivir Ther 2013, 18: 229-235.
doi: 10.3851/IMP2325 pmid: 22914436
103.   Jonuleit H, Schmitt E.The regulatory T cell family: distinct subsets and their interrelations. J Immunol 2003, 171: 6323-6327.
doi: 10.4049/jimmunol.171.12.6323 pmid: 14662827
104.   Wan YY, Flavell RA.TGF-β and regulatory T cell in immunity and autoimmunity. J Clin immunol 2008, 28: 647-659.
doi: 10.1007/s10875-008-9251-y pmid: 18792765
105.   Funahashi H, Imai T, Tanaka Y, et al.Wakame seaweedsuppresses the proliferation of 7,12-dimethylbenz(a)-anthraceneinduced mammary tumors in rats. Cancer Res 1999, 90: 922-927.
doi: 10.1111/j.1349-7006.1999.tb00836.x pmid: 10551319
106.   Lu R. Serrero G.Resveratrol, a natural product derived from grape, exhibits antiestrogenic activity and inhibits the growth of human breast cancer cells. J Cell Physiol 1999, 179: 297-304.
doi: 10.1002/(SICI)1097-4652(199906)179:33.0.CO;2-P pmid: 10228948
107.   Yamamoto M, Ogawa K, Morita M, et al.The herbal medicine Inchin-ko-to inhibits liver cell apoptosis induced by transforming growth factor beta 1. Hepatology 1996, 23: 552-559.
doi: 10.1053/jhep.1996.v23.pm0008617437 pmid: 8617437
108.   Chou CC, Pan SL, Teng CM, et al.Pharmacological evaluation of several major ingredients of Chinese herbal medicines in human hepatoma Hep3B cells. Eur J Pharm Sci 2003, 19: 403-412.
doi: 10.1016/S0928-0987(03)00144-1 pmid: 12907291
109.   McCarty MF. Isoflavones made simple-genistein's agonist activity for the beta-type estrogen receptor mediates their health benefits. Med Hypotheses 2006, 66: 1093-114.
doi: 10.1016/j.mehy.2004.11.046 pmid: 16513288
110.   Roomi MW, Roomi N, Ivanov V, et al. Inhibitory effect of a mixture containing ascorbic acid, lysine, proline and green tea extract on critical parameters in angiogenesis. Oncol Rep 2005, 14: 807-815.
doi: 10.3892/or.14.4.807 pmid: 16142336
111.   Mandal D, Bhattacharyya S, Lahiry L, et al.Black tea-induced decrease in IL-10 and TGF-beta of tumor cells promotes Th1/Tc1 response in tumor bearer. Nutr Cancer 2007, 58: 213-221.
doi: 10.1080/01635580701328503 pmid: 17640168
112.   Han G, Zhou YF, Zhang MS, et al.Angelica sinensis down-regulates hydroxyproline and Tgfb1 and provides protection in mice with radiation-induced pulmonary fibrosis. Radiat. Res 2006, 165: 546-552.
doi: 10.1667/RR3543.1 pmid: 16669709
113.   Park EY, Shin SM, Ma CJ, et al.Mesodihydroguaia- retic acid from Machilus thunbergii down-regulates TGF-beta1 gene expression in activated hepatic stellate cells via inhibition of AP-1 activity. Planta Med 2005, 71: 393-398.
doi: 10.1055/s-2005-864131
114.   Shin JW, Son JY, Oh SM, et al.An herbal formula, CGX, exerts hepatotherapeutic effects on dimethylnitrosamine-induced chronic liver injury model in rats. World J Gastroenterol 2006, 12: 6142-6148.
doi: 10.3748/wjg.v12.i38.6142
115.   Xiao Z, Su Y, Yang S, et al.Protective effect of esculentoside A on radiation-induced dermatitis and fibrosis. Int J Radiat Oncol Biol Phys 2006, 65: 882-889.
doi: 10.1016/j.ijrobp.2006.01.031 pmid: 16751070
116.   Yu HM, Liu YF, Cheng YF, et al.Effects of rhubarb extract on radiation induced lung toxicity via decreasing transforming growth factor-beta-1 and interleukin-6 in lung cancer patients treated with radiotherapy. Lung Cancer 2008, 59: 219-226.
doi: 10.1016/j.lungcan.2007.08.007 pmid: 17870203
117.   Liu X, Yang Y, Zhang X, et al.Compound Astragalus and Salvia miltiorrhiza extract inhibits cell invasion by modulating transforming growth factor-beta/Smad in HepG2 cell. J Gastroenterol Hepatol 2010, 25: 420-426.
doi: 10.1111/j.1440-1746.2009.05981.x pmid: 19793165
118.   Pitchakarn P, Ogawa K, Suzuki S, et al.Momordica charantia leaf extract suppresses rat prostate cancer progression in vitro and in vivo. Cancer Sci 2010, 101: 2234-2240.
doi: 10.1111/j.1349-7006.2010.01669.x pmid: 20731662
119.   Philips N, Dulaj L, Upadhya T, et al.Cancer cell growth and extracellular matrix remodeling mechanism of ascorbate; beneficial modulation by P. leucotomos. Anticancer Res 2009, 29: 3233-3238.
pmid: 19661340
120.   Philips N, Conte J, Chen YJ, et al.Beneficial regulation of matrixmetalloproteinases and their inhibitors, fibrillar collagens and transforming growth factor-beta by Polypodium leucotomos, directly or in dermal fibroblasts, ultraviolet radiated fibroblasts, and melanoma cells. Arch Dermatol Res 2009, 301: 487-495
doi: 10.1007/s00403-009-0950-x
121.   Whyte L, Huang YY, Torres K, et al.Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res 2007, 67: 12007-12017.
doi: 10.1158/0008-5472.CAN-07-2464 pmid: 18089832
122.   Jia L, Jin H, Zhou J, et al.A potential anti-tumor herbal medicine, Corilagin, inhibits ovarian cancer cell growth through blocking the TGF-β signaling pathways. BMC Complement Altern Med 2013, 13: 33.
doi: 10.1186/1472-6882-13-33 pmid: 3598193
123.   Ji G, Yang Q, Hao J, et al.Anti-inflammatory effect of genistein on non-alcoholic steatohepatitis rats induced by high fat diet and its potential mechanisms. Int Immunopharmacol 2011, 11: 762-768.
doi: 10.1016/j.intimp.2011.01.036 pmid: 21320636
[1] Yue Ji, Xue-Rou Yan, Hong-Tao Yang, Kang Yang, Qing-Yun Zhao, Shou-Ci Hu, Qi-Hang Su. Influence of astragalus polysaccharide on kidney status and fibrosis indices of a rat model of streptozotocin-induced diabetic nephropathy[J]. Traditional Medicine Research, 2018, 3(4): 173-180.
[2] Rui Tang, Qia-Qia Li, Di Wang, Jing Chen, Jin-Hua Huang, Qing-Hai Zeng. The protective effect of Dendrobium officinale polysaccharides on photoaging fibroblasts by scavenging reactive oxygen species and promoting the expression of TGF-β1[J]. Traditional Medicine Research, 2018, 3(3): 131-139.
[3] Nie Hai-Yang, Chen Rui, Zhang Hong-Na, Pan Zhi. Effects of saponin from the seed of Litchi chinensis Sonn on TGF-β1, FN and SOCS-1 in renal tubular epithelial cells under high glucose[J]. Traditional Medicine Research, 2017, 2(3): 144-148.
[4] Cui-HongZhu, Hao Jian, Yang Xue, Wang Xiao-Dong, Xiong-ZhiWu. Complete response of hepatocellular carcinoma treated with traditional Chinese medicine treatment: A case report[J]. Traditional Medicine Research, 2016, 1(1): 52-57.