Saudi Journal of Gastroenterology
Home About us Instructions Ahead of print Submission Subscribe Advertise Contact Login    Print this page  Email this page Small font sizeDefault font sizeIncrease font size 
Users Online: 79 

Table of Contents   
Year : 2018  |  Volume : 24  |  Issue : 1  |  Page : 5-11
Involvement of epithelial-mesenchymal transition in liver fibrosis

1 Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
2 Department of General Surgery, Qingdao Municipal Hospital, Qingdao, People's Republic of China

Click here for correspondence address and email

Date of Web Publication14-Feb-2018


Fibrosis of the liver is an inherent wound healing response to chronic liver injury. Regeneration of liver epithelium and restoration of normal liver structure were generally involved in this process. Although the liver has a striking capacity to adapt to damage through tissue repair, excessive accumulation of extracellular matrix during this process often leads to scar tissue formation and subsequent fibrosis. Epithelial to mesenchymal transition (EMT) enables a polarized epithelial cell to undergo multiple changes biochemically and to bear a mesenchymal cell phenotype. EMT plays a critical role in tissue and organ development and embryogenesis. In the liver, it is proposed that epithelial cells can acquire fibroblastic phonotype via EMT and contribute to fibrogenesis. This made EMT a potential target for antifibrotic strategies. Following an original passion, many investigators devote themselves to exploring this mechanism in liver fibrosis. However, as research continues, this hypothesis became highly controversial. The exact contribution of EMT to fibrogenesis was challenged due to the contradictory results from related studies. In this review, we summarized the recent advances regarding EMT in hepatic fibrosis and discussed the potentially involved liver cell types and pathways in order to reach rational and helpful conclusions.

Keywords: Cholangiocyte, epithelial-mesenchymal transition, hepatocyte, hepatic stellate cell, liver fibrosis

How to cite this article:
Yu K, Li Q, Shi G, Li N. Involvement of epithelial-mesenchymal transition in liver fibrosis. Saudi J Gastroenterol 2018;24:5-11

How to cite this URL:
Yu K, Li Q, Shi G, Li N. Involvement of epithelial-mesenchymal transition in liver fibrosis. Saudi J Gastroenterol [serial online] 2018 [cited 2018 Mar 17];24:5-11. Available from:

   Introduction Top

The epithelial-mesenchymal transition (EMT) is a process by which epithelial cells lose their cell polarity and cell-cell adhesion, and acquire migratory and invasive properties to become mesenchymal cells.[1],[2] EMT was first observed in embryogenesis and was critical for the development of tissues and organs.[3],[4] EMT is not irreversible; together with its reverse process mesenchymal-epithelial transition (MET), EMT plays crucial roles in cancer progression,[2],[5],[6] wound healing,[2],[7] and organ fibrosis.[1],[2],[8],[9]

Liver fibrosis is a protective response to chronic liver injury from diverse etiologies.[10],[11],[12] The feature of liver fibrosis is the excessive accumulation of extracellular matrix (ECM) produced by myofibroblasts.[13] Activated hepatic stellate cells (HSCs) are believed to be the primary source of myofibroblasts.[14] Advanced liver fibrosis results in cirrhosis, portal hypertension, even liver failure, and other life-threatening complications and only liver transplantation will rescue the patients.[10],[15] Recently, EMT was implicated in liver fibrosis.[16],[17],[18] As research continues, however, the notion becomes controversial.[19],[20]

   Classification of Emt Top

EMT was classified into three subtypes that carry different functional effects based on distinct settings they encountered.[21],[22] The EMTs that contributed to implantation, embryogenesis, and organ development through transformation of various cell types are termed as Type 1 EMT.[22] These transformed cells usually share common mesenchymal phenotypes and have the potential to undergo a reverse process, namely MET, to generate epithelial cells.[22] Type 2 EMT was implicated in wound healing, tissue regeneration, and organ fibrosis.[22] This kind of EMT usually occurs following tissue injuries such as inflammation, and forms fibroblasts to repair injured tissue. Once inflammation receded, the transition ceased.[22] However, in fibrotic organs, the EMT continuously responded to inflammation, and result in organ destruction ultimately.[22] The third proposed subtype of EMT is Type 3 EMT, which occurs in cancer cells that have previously undergone genetic and epigenetic alterations.[22] Through this transition, neoplastic cells may invade and metastasize via the circulation and finally lead to cancer progression and metastasis.[22]

   Main Liver Cell Types Involved in Emt Top

Hepatocyte and EMT

In fibrotic liver, the identified origin of collagen-producing cells includes activated HSCs, portal fibroblasts, and bone marrow-derived myofibroblasts.[10] However, evidence from research suggested that hepatocytes could also acquire a fibroblastic phenotype through EMT in liver fibrosis.[16],[17],[23],[24] Zeisberg et al.[23] found that upon stimulation with transforming growth factor β-1 (TGF-β1), adult mouse hepatocytes underwent changes phenotypically as well as functionally. In addition, using lineage-tracing technique, they observed that hepatocytes-derived cells demonstrated with fibroblast-like morphology and with expression of fibroblast-specific protein 1 (FSP-1), and this report provides the first in vivo evidence for hepatocyte EMT.[23] Similarly, other research also revealed that hepatocytes actively participate in fibrogenesis through TGF-β-dependent EMT.[17],[25],[26] Dooley et al.[17] confirmed a coexpression of collagen and transferrin in liver samples from patients with HBV infection, indicating the possible occurrence of EMT. They also found that specific inhibition of TGF-β signaling in hepatocyte-derived cells can attenuate fibrogenic response. Lee et al.[27] demonstrated that apamin can inhibit TGF-β1-induced E-cadherin loss and vimentin increase in vitro, and prevent CCL4-induced liver fibrosis in vivo. This suggests that through suppressed TGF-β1-induced hepatocyte EMT, apamin can inhibit hepatic fibrogenesis. Kong et al.[28] found that cobalt chloride (CoCl2) can upregulate mesenchymal markers, including vimentin, N-cadherin, and α-smooth muscle actin (α-SMA) and thus induce a mesenchymal cell phenotype in hepatocytes. They further confirmed that curcumin, a natural antifibrotic compound, can repress this process by decreasing TGF-β receptor expression and inhibiting Smad2/3 expression and phosphorylation. Other studies [29],[30] suggest that geniposide and celecoxib can inhibit hepatocytes EMT in liver fibrosis as well. These findings provided potential strategies to prevent liver fibrosis by targeting hepatocytes EMT. However, a recent study reported that mouse hepatocytes do not undergo EMT in liver fibrosis.[31] Using transgenic mice, Taura et al.[31] found that hepatocytes do assume a TGF-β-induced fibroblast-like morphology, but failed to express mesenchymal markers including FSP-1, α-SMA, and vimentin.[31] They also confirmed that hepatocytes are not the origin of type I collagen-producing cells in liver fibrosis.[31] These results were quite different from the previous work performed by Zeisberg and his colleagues. Taura et al.[31] hold that β-Gal staining in Zeisberg study may yield false-positive results due to technical limitations. Although Taura and colleagues' work effectively challenges the existence of hepatocyte EMT, lineage tracing technique has its own pitfalls,[32] and it is still too early to exclude EMT in liver fibrosis completely.

Cholangiocyte and EMT

Cholangiocyte, another cell type which has been proposed, contributes to liver fibrosis through EMT.[24] Omenetti et al.[33] provided direct evidence of the contribution of cholangiocyte EMT to liver fibrosis. In their study, the investigators found that cholangiocytes isolated from rats with biliary fibrosis induced by bile duct ligation (BDL) expressed high level of FSP-1 and low level of aquaporin-1 and cytokeratin 7/9 (Krt7/9). In addition, they demonstrated that an immature cholangiocyte line cocultured with myofibroblastic HSCs (MF-HSC), or treated with activated HSC conditioned medium, was induced to undergo complete EMT by silencing epithelial gene expression, inducing mesenchymal gene expression and acquiring a migratory phenotype. Moreover, they confirmed that inhibiting Hedgehog (Hh) signaling pathway can block EMT in the cholangiocytes under MF-HSC conditioned medium treatment.[33],[34] Several other studies found cholangiocytes from rats with biliary fibrosis or human tissues coexpressed epithelial and mesenchymal markers.[35],[36],[37] In biliary atresia, evidence also support that biliary epithelial cells may directly contribute to fibrogenesis via EMT.[38],[39] Diaz et al.[40] provided histological evidence, suggesting that EMT occurs in biliary atresia. In consistence with this, Xiao et al.[39] showed that Krt7 and α-SMA colocalized to the intrahepatic biliary epithelial cells in patients with biliary atresia. Besides, they demonstrated that EMT in primary human intrahepatic biliary epithelial cells was induced by TGF-β and confirmed that the process can be inhibited significantly by miR-200b.[39] Seemingly, there is solid evidence that cholangiocytes can contribute to fibrosis via EMT. However, the authenticity of cholangiocyte EMT was seriously challenged recently. Using cell fate tracing technique, Scholten et al.[41] revealed that no EMT of cholangiocytes was identified by genetic labeling that contributes to liver fibrosis in mice. Actually, the investigators detected no coexpression of myofibroblast marker and cholangiocyte marker in both biliary and panlobular fibrosis.[41] In addition, they also showed that no epithelial or liver progenitor marker was coexpressed by genetically labeled HSCs in response to liver injury.[41] Consistent with this, Chu et al.[42] also found no cholangiocytes undergone EMT in murine models of hepatic fibrosis. Although they observed that cultured primary cholangiocytes can undergo EMT (i.e., loss of cell-cell contacts and acquisition of fibroblast-like morphology) after TGF-β1 treatment, but in the mouse BDL and CCL4 models, the investigators found that cholangiocytes do not undergo EMT in vivo.[42] Moreover, they further demonstrated that EMT does not occur in cholangiocyte precursors (oval cells). However, further studies are still needed to confirm whether cholangiocyte EMT contributes to liver fibrosis.

Hepatic stellate cell and MET

HSC is the best studied fibrogenic mesenchymal cell in the liver. Now HSCs, as the main source of ECM, have been corroborated to be the dominant contributors to liver fibrosis independent of its etiology.[10],[43],[44] The concept that HSCs are able to undergo MET is intriguing. Sicklick et al.[45] analyzed the expression profile of primary HSC, HSC cell lines, and hepatic epithelial progenitors and found that epithelial progenitors express HSC markers. Furthermore, epithelial progenitor microRNAs were also expressed by HSC cell lines.[45] In addition, HSCs that express progenitor cell markers were confirmed with the potential to differentiate into hepatocytes when cultured under certain condition.[46] Yovchev et al.[47] revealed that oval cells coexpressed epithelial and mesenchymal markers, and transplantation of these hepatic progenitor cells could repopulate injured livers. Choi et al.[48] even found that transition of quiescent HSCs between epithelial and mesenchymal fates were regulated by Hh signaling pathway. Loss of E-cadherin is a characteristic behavior of EMT.[49] Cho et al.[50] reported that E-cadherin is capable of inhibiting TGF-β1 gene induction in HSCs by suppressing RHoA-dependent Smad3 phosphorylation and preventing liver fibrosis. But Scholten et al.,[41] using cell fate tracing technique, found no epithelial markers coexpressed by HSCs in response to fibrogenic liver injury in mice. However, Conigliaro et al.[51] lately reported that hepatocytes and HSCs may arise from common progenitor isolated from embryonic livers. Their study also showed that these progenitor cells were able to transdifferentiate into both hepatocytes and HSCs in vitro and in vivo.[51] Interestingly, Yang et al.[52] found that HSCs can secrete type I collagen to trigger EMT of hepatoma cells. Zhao et al.[53] found that microRNA-21 (miR-21) can simultaneously promote HSC activation and hepatocyte EMT in liver fibrosis. They also confirmed that miR-155 can modulate similar process.[54] Collectively, there seems to be plenty of evidence indicating that HSCs can undergo MET during hepatic fibrogenesis. But more recently, Lua et al.[55] demonstrated that HSCs are not capable of differentiating into either hepatocytes or cholangiocytes in mouse. Using cell lineage tracing technique, they found that mesodermal mesenchymal cells, including HSCs and portal fibroblasts, comprise a major source of MFs and do not undergo MET during fibrogenesis.[55] In addition, they even found that no HSCs contributed to oval cells via MET.[55] This was supported by research from Troeger et al.[56] Troeger et al. employed single-cell polymerase chain reaction and genetic cell fate tracking to investigate whether HSC deactivation represents an alternative mechanism for liver fibrosis resolution. They found that HSC activation gradually decreased during fibrosis reversal and no HSC contributed to hepatocytes and cholangiocytes via MET.[56] Together, these data provided fairly good evidence that refutes the notion that HSCs undergo MET to yield either hepatocytes or cholangiocytes. The contradictory conclusion from Yang and colleagues' report may result from the inappropriate engagement of HSC marker.

   Main Signaling Pathways Implicated in Emt Top

Hedgehog Signaling Pathway and EMT

Signaling pathways involved in EMT have been explored substantially, and one of the well-documented pathways is Hh signaling. The Hh pathway plays crucial role in organogenesis and tissue remodeling.[57],[58] Recent studies suggest that activation of Hh pathway appears to be implicated in fibrogenesis through regulation of EMT.[33],[34],[35],[48],[59],[60],[61] Omenetti et al.[35] showed that in rodent model induced by BDL, Hh signaling was activated to guide remodeling of the biliary epithelia and stroma after cholestatic injury. They further revealed that enhanced EMT responses to BDL were related to excessive activation of Hh pathway, which promotes biliary fibrosis progression.[33] Syn et al.[59] found that in nonalcoholic fatty liver disease (NAFLD), sonic Hh suppressed expression of epithelial genes and EMT inhibitors but induced mesenchymal genes in cultured progenitors of ductular cell. In mouse models of NAFLD, they also found that activation of Hh pathway was followed by EMT, expansion of myofibroblastic populations, and liver fibrosis.[59] In addition, researchers found that Hh pathway functions critically in transition of quiescent HSCs into myofibroblastic HSCs, and enables quiescent HSC to transit between epithelial and mesenchymal fates.[48] Omenetti et al.[34] demonstrated that Hh signaling was excessively activated in biliary atresia and resulted in biliary EMT, which may lead to biliary dysmorphogenesis and finally fibrosis. Interestingly, Yu et al.[62] recently reported that patched1, a negative regulator of Hh pathway, was downregulated during liver fibrosis. They further confirmed that decreased expression of patched1 was associated with its DNA hypermethylation. Slvianolic acid B can induce miR-152 to target DNA methyltransferase 1 and demethylate patched1; thus prevent liver fibrosis by inhibiting Hh signaling-induced EMT.[62] Although these data provide evidence that Hh signaling pathway can regulate EMT, given the questioned existence of EMT of hepatocytes or cholangiocytes, its contribution to liver fibrosis remains a subject of some debate. However, it is indisputable that Hh signaling can coordinate epithelial-mesenchymal interactions to regulate repair and regeneration and maintain tissue homeostasis.[63]

TGF-β Signaling Pathway and EMT

TGF-β has been commonly recognized as a critical factor stimulating collagen and ECM production in HSCs during hepatic fibrogenesis.[64] Kaimori et al.[25] reported that TGF-β1 is capable of mediating EMT in hepatocytes in vitro. They found that administration of TGF-β1 significantly increased α1 collagen mRNA expression and type I collagen deposition, which were defined as the characteristic of EMT state.[25] They also showed that in the EMT state, TGF-β1 induced snail-1 and activated Smad2/3 pathway in hepatocytes, while silencing Smad4 inhibited EMT.[25] Similarly, Kojima et al.[26] reported that in mature hepatocytes, EMTs were induced by TGF-β-mediated downregulation of claudin-1. Furthermore, studies revealed that hepatocytes actively participated in fibrogenesis after EMT induced by TGF-β, whereas specific ablation of TGF-β signaling by Smad7 in hepatocytes effectively slacked the fibrogenic response.[17] Rygiel et al.[36] also showed that EMT in response to TGF-β contributes to portal tract fibrogenesis. Recently, Kong et al.[28] confirmed that curcumin can inhibit EMT in hepatocytes by interfering with TGF-β/Smad signaling. Schizandrin and propolis have also been shown to inhibit fibrosis and EMT induced by TGF-β.[65],[66] Transmembrane 4 L6 family member 5 (TM4SF5) is a transmembrane glycoprotein which can induce EMT and is highly expressed in hepatocellular carcinoma.[67] Investigators found that expression of TM4SF5 in hepatocytes can be induced by TGF-β1 and epidermal growth factor receptor (EGFR) signaling pathways.[67] Increased TM4SF5 expression was found in CCl4-mediated liver fibrosis mouse model and correlated with α-SMA expression, collagen I deposition, and TGF-β1 and EGFR signaling activation.[68] Interestingly, as a kinase inhibitor drug approved for the treatment of cancer, sorafenib was confirmed to be capable of inhibiting TGF-β-mediated EMT in hepatocytes and fibrosis.[67],[69] Collectively, TGF-β and its related proteins are major inducers of EMT. However, contrary to the popular notion that TGF-β is a main contributor to liver fibrosis,[70] Mu et al.[71] showed that epithelial TGF-β signaling does not promote liver fibrosis, but inhibits cholangiocytes proliferation to prevent cholangiocarcinoma development.[71] Therefore, further studies are needed to clarify whether TGF-β-induced EMT plays a role in liver fibrosis.

Extracellular Signal-Regulated Kinase Signaling Pathway and EMT

Extracellular signal-regulated kinases (ERKs), namely the classical mitogen-activated protein (MAP) kinases, are serine/threonine kinases that play crucial roles in the modulation of cell growth and differentiation.[72] Evidence suggests that ERK signaling contributes to repression of EMT.[73],[74] Arnoux et al.[7] reported that Erk5 controls the expression of slug, which involves the basal keratinocyte activation, spreading, and migration and contributes to re-epithelialization during cutaneous wound healing. Thum et al.[75] showed that increased ERK-MAP kinase activity promotes interstitial fibrosis and cardiac function and this process can be inhibited by miR-21. In liver fibrosis, Zhong et al.[76] found that reduced ERK1 expression suppressed HSCs proliferation and their expression of fibrosis-related genes in vitro; specific inhibition of ERK1 significantly weakens ECM deposition in fibrotic liver. They also found that myofibroblasts derived from hepatocytes and cholangiocytes were reduced markedly by selective inhibition of ERK1.[76] Dai et al.[53] reported that miRNA-21 was significantly higher in cirrhotic patients and rats, and sprouty 2 (SPRY2) and hepatocyte nuclear factor 4α (HNF4α) were identified as effective targets of miR-21. By targeting SPRY2 and HNF4α, miR-21 simultaneously stimulates ERK1 signaling in HSCs and induces hepatocytes EMT.[53] In another report, they found that miR-155, on the contrary, simultaneously suppresses EMT process and ERK1 signaling, attenuates HSC activation, and prevents hepatic fibrosis.[54] These studies showed that inhibition of ERK signaling contributes to prevention of liver fibrosis, and EMT may be involved in this process.

Future perspectives

As a solid organ, the liver has a striking ability to adapt to damage through tissue repair, but excessive accumulation of ECM proteins during this wound healing response will lead to liver fibrosis; this highlights the significance of the balance of this process. Nevertheless, the complicated mechanisms underlying hepatic fibrogenesis have not been fully elucidated. The past decades have witnessed enormous progress in our understanding of hepatic fibrosis, and the discovery of EMT/MET provides us with new insights into its pathogenesis. However, in the light of conflicting evidence that refutes the role of EMT/MET in liver fibrosis, perhaps our enthusiasm should be curbed. Yet despite this, the role of EMT in hepatocellular carcinoma (HCC) has been identified recently. Although EMT has been proved not indispensable for breast cancer and pancreatic cancer metastasis,[77],[78] its contribution to HCC metastasis and invasion has been confirmed and thus may serve as a prognosis predictor.[79],[80],[81],[82] In addition, studies have revealed that EMT could induce chemoresistance in some types of cancer.[77],[78] Therefore, a comprehensive understanding of EMT is urgently needed and will enable the development of novel diagnostic and effective therapeutic strategies to prevent HCC progression and improve patients' prognosis.


This work was funded by the Natural Science Foundation of China (Nos 81101240 and 81371821).

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 2003;112:1776-84.  Back to cited text no. 1
Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell 2009;139:871-90.  Back to cited text no. 2
Hay ED. Organization and fine structure of epithelium and mesenchyme in the developing chick embryo. Epithelial Mesenchymal Interactions 1968;2:31-5.  Back to cited text no. 3
Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 2006;7:131-42.  Back to cited text no. 4
Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002;2:442-54.  Back to cited text no. 5
Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science 2011;331:1559-64.  Back to cited text no. 6
Arnoux V, Nassour M, L'Helgoualc'h A, Hipskind RA, Savagner P. Erk5 controls slug expression and keratinocyte activation during wound healing. Mol Biol Cell 2008;19:4738-49.  Back to cited text no. 7
Carew RM, Wang B, Kantharidis P. The role of EMT in renal fibrosis. Cell Tissue Res 2012;347:103-16.  Back to cited text no. 8
Kriz W, Kaissling B, Le Hir M. Epithelial-mesenchymal transition (EMT) in kidney fibrosis: Fact or fantasy? J Clin Invest 2011;121:468-74.  Back to cited text no. 9
Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005;115:209-18.  Back to cited text no. 10
Lotersztajn S, Julien B, Teixeira-Clerc F, Grenard P, Mallat A. Hepatic fibrosis: Molecular mechanisms and drug targets. Annu Rev Pharmacol Toxicol 2005;45:605-28.  Back to cited text no. 11
Rockey DC, Bell PD, Hill JA. Fibrosis - A common pathway to organ injury and failure. N Engl J Med 2015;372:1138-49.  Back to cited text no. 12
Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver fibrosis and repair: Immune regulation of wound healing in a solid organ. Nat Rev Immunol 2014;14:181-94.  Back to cited text no. 13
Yin C, Evason KJ, Asahina K, Stainier DY. Hepatic stellate cells in liver development, regeneration, and cancer. J Clin Invest 2013;123:1902-10.  Back to cited text no. 14
Wang FS, Zhang Z. Liver: How can acute-on-chronic liver failure be accurately identified? Nat Rev Gastroenterol Hepatol 2013;10:390-1.  Back to cited text no. 15
Nitta T, Kim JS, Mohuczy D, Behrns KE. Murine cirrhosis induces hepatocyte epithelial mesenchymal transition and alterations in survival signaling pathways. Hepatology 2008;48:909-19.  Back to cited text no. 16
Dooley S, Hamzavi J, Ciuclan L, Godoy P, Ilkavets I, Ehnert S, et al. Hepatocyte-specific Smad7 expression attenuates TGF-beta-mediated fibrogenesis and protects against liver damage. Gastroenterology 2008;135:642-59.  Back to cited text no. 17
Matsuzaki K, Murata M, Yoshida K, Sekimoto G, Uemura Y, Sakaida N, et al. Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor beta signaling, promoting cirrhosis and hepatocellular carcinoma. Hepatology 2007;46:48-57.  Back to cited text no. 18
Wells RG. The epithelial-to-mesenchymal transition in liver fibrosis: Here today, gone tomorrow? Hepatology 2010;51:737-40.  Back to cited text no. 19
Popov Y, Schuppan D. Epithelial-to-mesenchymal transition in liver fibrosis: Dead or alive? Gastroenterology 2010;139:722-5.  Back to cited text no. 20
Kalluri R. EMT: When epithelial cells decide to become mesenchymal-like cells. J Clin Invest 2009;119:1417-9.  Back to cited text no. 21
Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009;119:1420-8.  Back to cited text no. 22
Zeisberg M, Yang C, Martino M, Duncan MB, Rieder F, Tanjore H, et al. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem 2007;282:23337-47.  Back to cited text no. 23
Choi SS, Diehl AM. Epithelial-to-mesenchymal transitions in the liver. Hepatology 2009;50:2007-13.  Back to cited text no. 24
Kaimori A, Potter J, Kaimori JY, Wang C, Mezey E, Koteish A. Transforming growth factor-beta1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro. J Biol Chem 2007;282:22089-101.  Back to cited text no. 25
Kojima T, Takano K, Yamamoto T, Murata M, Son S, Imamura M, et al. Transforming growth factor-beta induces epithelial to mesenchymal transition by down-regulation of claudin-1 expression and the fence function in adult rat hepatocytes. Liver Int 2008;28:534-45.  Back to cited text no. 26
Lee WR, Kim KH, An HJ, Kim JY, Lee SJ, Han SM, et al. Apamin inhibits hepatic fibrosis through suppression of transforming growth factor beta1-induced hepatocyte epithelial-mesenchymal transition. Biochem Biophys Res Commun 2014;450:195-201.  Back to cited text no. 27
Kong D, Zhang F, Shao J, Wu L, Zhang X, Chen L, et al. Curcumin inhibits cobalt chloride-induced epithelial-to-mesenchymal transition associated with interference with TGF-beta/Smad signaling in hepatocytes. Lab Invest 2015;95:1234-45.  Back to cited text no. 28
Park JH, Yoon J, Lee KY, Park B. Effects of geniposide on hepatocytes undergoing epithelial-mesenchymal transition in hepatic fibrosis by targeting TGFbeta/Smad and ERK-MAPK signaling pathways. Biochimie 2015;113:26-34.  Back to cited text no. 29
Wen SL, Gao JH, Yang WJ, Lu YY, Tong H, Huang ZY, et al. Celecoxib attenuates hepatic cirrhosis through inhibition of epithelial-to-mesenchymal transition of hepatocytes. J Gastroenterol Hepatol 2014;29:1932-42.  Back to cited text no. 30
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;51:1027-36.  Back to cited text no. 31
Lemaigre FP. Determining the fate of hepatic cells by lineage tracing: Facts and pitfalls. Hepatology 2015;61:2100-3.  Back to cited text no. 32
Omenetti A, Porrello A, Jung Y, Yang L, Popov Y, Choi SS, et al. Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. J Clin Invest 2008;118:3331-42.  Back to cited text no. 33
Omenetti A, Bass LM, Anders RA, Clemente MG, Francis H, Guy CD, et al. Hedgehog activity, epithelial-mesenchymal transitions, and biliary dysmorphogenesis in biliary atresia. Hepatology 2011;53:1246-58.  Back to cited text no. 34
Omenetti A, Yang L, Li YX, Mccall SJ, Jung Y, Sicklick JK, et al. Hedgehog-mediated mesenchymal-epithelial interactions modulate hepatic response to bile duct ligation. Lab Invest 2007;87:499-514.  Back to cited text no. 35
Rygiel KA, Robertson H, Marshall HL, Pekalski M, Zhao L, Booth TA, et al. Epithelial-mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease. Lab Invest 2008;88:112-23.  Back to cited text no. 36
Schulze F, Schardt K, Wedemeyer I, Konze E, Wendland K, Dirsch O, et al. Epithelial-mesenchymal transition of biliary epithelial cells in advanced liver fibrosis. Verh Dtsch Ges Pathol 2007;91:250-6.  Back to cited text no. 37
Deng YH, Pu CL, Li YC, Zhu J, Xiang C, Zhang MM, et al. Analysis of biliary epithelial-mesenchymal transition in portal tract fibrogenesis in biliary atresia. Dig Dis Sci 2011;56:731-40.  Back to cited text no. 38
Xiao Y, Zhou Y, Chen Y, Zhou K, Wen J, Wang Y,et al. The expression of epithelial-mesenchymal transition-related proteins in biliary epithelial cells is associated with liver fibrosis in biliary atresia. Pediatr Res 2015;77:310-5.  Back to cited text no. 39
Diaz R, Kim JW, Hui JJ, Li Z, Swain GP, Fong KS, et al. Evidence for the epithelial to mesenchymal transition in biliary atresia fibrosis. Hum Pathol 2008;39:102-15.  Back to cited text no. 40
Scholten D, Osterreicher CH, Scholten A, Iwaisako K, Gu G, Brenner DA, et al. Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in mice. Gastroenterology 2010;139:987-98.  Back to cited text no. 41
Chu AS, Diaz R, Hui JJ, Yanger K, Zong Y, Alpini G, et al. Lineage tracing demonstrates no evidence of cholangiocyte epithelial-to-mesenchymal transition in murine models of hepatic fibrosis. Hepatology 2011;53:1685-95.  Back to cited text no. 42
Henderson NC, Arnold TD, Katamura Y, Giacomini MM, Rodriguez JD, McCarty JH, et al. Targeting of alphav integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med 2013;19:1617-24.  Back to cited text no. 43
Mederacke I, Hsu CC, Troeger JS, Huebener P, Mu X, Dapito DH, et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun 2013;4:2823.  Back to cited text no. 44
Sicklick JK, Choi SS, Bustamante M, McCall SJ, Perez EH, Huang J, et al. Evidence for epithelial-mesenchymal transitions in adult liver cells. Am J Physiol Gastrointest Liver Physiol 2006;291:G575-83.  Back to cited text no. 45
Kordes C, Sawitza I, Muller-Marbach A, Ale-Agha N, Keitel V, Klonowski-Stumpe H, et al. CD133+ hepatic stellate cells are progenitor cells. Biochem Biophys Res Commun 2007;352:410-7.  Back to cited text no. 46
Yovchev MI, Grozdanov PN, Zhou H, Racherla H, Guha C, Dabeva MD. Identification of adult hepatic progenitor cells capable of repopulating injured rat liver. Hepatology 2008;47:636-47.  Back to cited text no. 47
Choi SS, Omenetti A, Witek RP, Moylan CA, Syn WK, Jung Y, et al. Hedgehog pathway activation and epithelial-to-mesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis. Am J Physiol Gastrointest Liver Physiol 2009;297:G1093-106.  Back to cited text no. 48
Wong AS, Gumbiner BM. Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin. J Cell Biol 2003;161:1191-203.  Back to cited text no. 49
Cho IJ, Kim YW, Han CY, Kim EH, Anderson RA, Lee YS, et al. E-cadherin antagonizes transforming growth factor beta1 gene induction in hepatic stellate cells by inhibiting RhoA-dependent Smad3 phosphorylation. Hepatology 2010;52:2053-64.  Back to cited text no. 50
Conigliaro A, Amicone L, Costa V, De Santis Puzzonia M, Mancone C, Sacchetti B, et al. Evidence for a common progenitor of epithelial and mesenchymal components of the liver. Cell Death Differ 2013;20:1116-23.  Back to cited text no. 51
Yang MC, Wang CJ, Liao PC, Yen CJ, Shan YS. Hepatic stellate cells secretes type I collagen to trigger epithelial mesenchymal transition of hepatoma cells. Am J Cancer Res 2014;4:751-63.  Back to cited text no. 52
Zhao J, Tang N, Wu K, Dai W, Ye C, Shi J, et al. MiR-21 simultaneously regulates ERK1 signaling in HSC activation and hepatocyte EMT in hepatic fibrosis. PLoS One 2014;9:e108005.  Back to cited text no. 53
Dai W, Zhao J, Tang N, Zeng X, Wu K, Ye C, et al. MicroRNA-155 attenuates activation of hepatic stellate cell by simultaneously preventing EMT process and ERK1 signalling pathway. Liver Int 2015;35:1234-43.  Back to cited text no. 54
Lua I, James D, Wang J, Wang KS, Asahina K. Mesodermal mesenchymal cells give rise to myofibroblasts, but not epithelial cells, in mouse liver injury. Hepatology 2014;60:311-22.  Back to cited text no. 55
Troeger JS, Mederacke I, Gwak GY, Dapito DH, Mu X, Hsu CC, et al. Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology 2012;143:1073-83.e22.  Back to cited text no. 56
Ingham PW, Mcmahon AP. Hedgehog signaling in animal development: Paradigms and principles. Genes Dev 2001;15:3059-87.  Back to cited text no. 57
Ingham PW, Placzek M. Orchestrating ontogenesis: Variations on a theme by sonic hedgehog. Nat Rev Genet 2006;7:841-50.  Back to cited text no. 58
Syn WK, Jung Y, Omenetti A, Abdelmalek M, Guy CD, Yang L, et al. Hedgehog-mediated epithelial-to-mesenchymal transition and fibrogenic repair in nonalcoholic fatty liver disease. Gastroenterology 2009;137:1478-88.e8.  Back to cited text no. 59
Omenetti A, Popov Y, Jung Y, Choi SS, Witek RP, Yang L, et al. The hedgehog pathway regulates remodelling responses to biliary obstruction in rats. Gut 2008;57:1275-82.  Back to cited text no. 60
Swiderska-Syn M, Syn WK, Xie G, Kruger L, Machado MV, Karaca G, et al. Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy. Gut 2014;63:1333-44.  Back to cited text no. 61
Yu F, Lu Z, Chen B, Wu X, Dong P, Zheng J. Salvianolic acid B-induced microRNA-152 inhibits liver fibrosis by attenuating DNMT1-mediated patched1 methylation. J Cell Mol Med 2015;19:2617-32.  Back to cited text no. 62
Peng T, Frank DB, Kadzik RS, Morley MP, Rathi KS, Wang T, et al. Hedgehog actively maintains adult lung quiescence and regulates repair and regeneration. Nature 2015;526:578-82.  Back to cited text no. 63
Tacke F, Luedde T, Trautwein C. Inflammatory pathways in liver homeostasis and liver injury. Clin Rev Allergy Immunol 2009;36:4-12.  Back to cited text no. 64
Park JH, Yoon J. Schizandrin inhibits fibrosis and epithelial-mesenchymal transition in transforming growth factor-beta1-stimulated AML12 cells. Int Immunopharmacol 2015;25:276-84.  Back to cited text no. 65
Kao HF, Chang-Chien PW, Chang WT, Yeh TM, Wang JY. Propolis inhibits TGF-beta1-induced epithelial-mesenchymal transition in human alveolar epithelial cells via PPARgamma activation. Int Immunopharmacol 2013;15:565-74.  Back to cited text no. 66
Chen YL, Lv J, Ye XL, Sun MY, Xu Q, Liu CH, et al. Sorafenib inhibits transforming growth factor beta1-mediated epithelial-mesenchymal transition and apoptosis in mouse hepatocytes. Hepatology 2011;53:1708-18.  Back to cited text no. 67
Kang M, Jeong SJ, Park SY, Lee HJ, Kim HJ, Park KH, et al. Antagonistic regulation of transmembrane 4 L6 family member 5 attenuates fibrotic phenotypes in CCl(4)-treated mice. FEBS J 2012;279:625-35.  Back to cited text no. 68
Deng YR, Ma HD, Tsuneyama K, Yang W, Wang YH, Lu FT, et al. STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib. J Autoimmun 2013;46:25-34.  Back to cited text no. 69
Yang L, Inokuchi S, Roh YS, Song J, Loomba R, Park EJ, et al. Transforming growth factor-beta signaling in hepatocytes promotes hepatic fibrosis and carcinogenesis in mice with hepatocyte-specific deletion of TAK1. Gastroenterology 2013;144:1042-54.e4.  Back to cited text no. 70
Mu X, Pradere JP, Affo S, Dapito DH, Friedman R, Lefkovitch JH, et al. Epithelial transforming growth factor-beta signaling does not contribute to liver fibrosis but protects mice from cholangiocarcinoma. Gastroenterology 2016;150:720-33.  Back to cited text no. 71
Rao VN, Reddy ES. Elk-1 proteins interact with MAP kinases. Oncogene 1994;9:1855-60.  Back to cited text no. 72
Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 2014;15:178-96.  Back to cited text no. 73
Ichikawa K, Kubota Y, Nakamura T, Weng JS, Tomida T, Saito H, et al. MCRIP1, an ERK substrate, mediates ERK-induced gene silencing during epithelial-mesenchymal transition by regulating the co-repressor CtBP. Mol Cell 2015;58:35-46.  Back to cited text no. 74
Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M,et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 2008;456:980-4.  Back to cited text no. 75
Zhong W, Shen WF, Ning BF, Hu PF, Lin Y, Yue HY, et al. Inhibition of extracellular signal-regulated kinase 1 by adenovirus mediated small interfering RNA attenuates hepatic fibrosis in rats. Hepatology 2009;50:1524-36.  Back to cited text no. 76
Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 2015;527:525-30.  Back to cited text no. 77
Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST, et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 2015;527:472-6.  Back to cited text no. 78
Wang YP, Yu GR, Lee MJ, Lee SY, Chu IS, Leem SH, et al. Lipocalin-2 negatively modulates the epithelial-to-mesenchymal transition in hepatocellular carcinoma through the epidermal growth factor (TGF-beta1)/Lcn2/Twist1 pathway. Hepatology 2013;58:1349-61.  Back to cited text no. 79
Ye LY, Chen W, Bai XL, Xu XY, Zhang Q, Xia XF, et al. Hypoxia-induced epithelial-to-mesenchymal transition in hepatocellular carcinoma induces an immunosuppressive tumor microenvironment to promote metastasis. Cancer Res 2016;76:818-30.  Back to cited text no. 80
Meng FD, Wei JC, Qu K, Wang ZX, Wu QF, Tai MH, et al. FoxM1 overexpression promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma. World J Gastroenterol 2015;21:196-213.  Back to cited text no. 81
Hou KZ, Fu ZQ, Gong H. Chemokine ligand 20 enhances progression of hepatocellular carcinoma via epithelial-mesenchymal transition. World J Gastroenterol 2015;21:475-83.  Back to cited text no. 82

Correspondence Address:
Dr. Ning Li
Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai – 200040
People's Republic of China
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/sjg.SJG_297_17

Rights and Permissions


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Email Alert *
    Add to My List *
* Registration required (free)  

    Classification o...
    Main Liver Cell ...
    Main Signaling P...

 Article Access Statistics
    PDF Downloaded97    
    Comments [Add]    

Recommend this journal