Loss of liver E-cadherin induces sclerosing cholangitis and promotes carcinogenesis

Nakagawa, Hayato; Hikiba, Yohko; Hirata, Yoshihiro; Font-Burgada, Joan; Sakamoto, Kei; Hayakawa, Yoku; Taniguchi, Koji; Umemura, Atsushi; Kinoshita, Hiroto; Sakitani, Kosuke; Nishikawa, Yuji; Hirano, Kenji; Ikenoue, Tsuneo; Ijichi, Hideaki; Dhar, Debanjan; Shibata, Wataru; Akanuma, Masao; Koike, Kazuhiko; Karin, Michael; Maeda, Shin

doi:10.1073/pnas.1322731111

Cited by 105 publications

(100 citation statements)

References 30 publications

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“…Loss of E-cadherin has been associated with induction of sclerosing cholangitis and promoting HCC. 18 Ecadherin was significantly reduced in DEN C HF-HC-HSD mice compared all other groups (Fig. 3B).…”

Section: Western Diet Accelerates Den-induced Hcc In Micementioning

confidence: 84%

Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10

et al. 2016

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Obesity-related inflammation promotes cancer development. Tissue resident macrophages affect tumor progression and the tumor micro-environment favors polarization into alternatively activated macrophages (M2) that facilitate tumor invasiveness. Here, we dissected the role of western diet-induced NASH in inducing macrophage polarization in a carcinogen initiated model of hepatocellular carcinoma (HCC). Adult C57BL/6 male mice received diethyl nitrosamine (DEN) followed by 24 weeks of high fat-high cholesterol-high sugar diet (HF-HC-HSD). We assessed liver MRI and histology, serum ALT, AFP, liver triglycerides, and cytokines. Macrophage polarization was determined by IL-12/TNFa (M1) and CD163/ CD206 (M2) expression using flow cytometry. Role of hif-1a-induced IL-10 was dissected in hepatocyte specific hif-1aKO and hif-1adPA (over-expression) mice. The western diet-induced features of NASH and accelerated HCC development after carcinogen exposure. Liver fibrosis and serum AFP were significantly increased in DEN C HF-HC-HSD mice compared to controls. Western diet resulted in macrophage (F4/ 80 C CD11b C ) infiltration to liver and DEN C HF-HC-HSD mice showed preferential increase in M2 macrophages. Isolated hepatocytes from western diet fed mice showed significant upregulation of the hypoxia-inducible transcription factor, hif-1a, and livers from hif-1a over-expressing mice had increased proportion of M2 macrophages. Primary hepatocytes from wild-type mice treated with DEN and palmitic acid in vitro showed activation of hif-1a and induction of IL-10, a M2 polarizing cytokine. IL-10 neutralization in hepatocyte-derived culture supernatant prevented M2 macrophage polarization and silencing hif-1a in macrophages blocked their M2 polarization. Therefore, our data demonstrate that NASH accelerates HCC progression via upregulation of hif-1a mediated IL-10 polarizing M2 macrophages.

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Section: Western Diet Accelerates Den-induced Hcc In Micementioning

confidence: 84%

Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10

et al. 2016

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“…The abnormal gene expression of E-cadherin is closely associated with the occurrence, development and metastasis of tumors, and is strongly associated with the degree of tumor differentiation, lymph node metastasis, distant metastasis and recurrence rate, suggesting that the evaluation of abnormal E-cadherin gene expression may be a vital indicator of tumor progression and prognosis (24,25). Studies on the expression of E-cadherin in a variety of tumors have observed the presence of E-cadherin gene mutations and subsequent functional changes, in the form of reductions or loss of E-cadherin expression accompanied by cancer invasion and increased metastasis (26)(27)(28). This indicates that the reduction or loss of E-cadherin may be a notable change associated with epithelial-mesenchymal transition.…”

Section: Discussionmentioning

confidence: 99%

Expression of E-cadherin in oral lichen planus

2015

Experimental and Therapeutic Medicine

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Abstract. Oral lichen planus (OLP) is a common lesion of the oral mucosa that can progress to cancer. E-cadherin is involved in intercellular adherence and the pathogenesis, development and metastasis of tumors, and is considered to be an important indicator of tumor progression and prognosis. The aim of this study was to investigate the expression of E-cadherin in OLP in order to elucidate its role in the pathogenesis and malignant transformation of OLP and provide evidence to support the early diagnosis and treatment of OLP with malignant potential. OLP specimens (n=52) and samples of normal oral mucosa (n=41) as the control were collected. Immunohistochemical staining was conducted to reveal the expression of E-cadherin in the OLP samples and normal oral mucosa. It was observed that 25 of the 52 OLP specimens exhibited normal positive expression of E-cadherin and 27 exhibited abnormal positive expression, corresponding to an abnormal positive rate of 51.92%. In the normal oral mucosa group, 39 of the 41 cases exhibited normal positive expression and 2 exhibited abnormal positive expression. The abnormal positive rate in the normal oral mucosa was 4.88%, which was significantly lower than that in the OLP group. The significantly elevated rate of abnormal positive expression of E-cadherin in the OLP group indicates the involvement of E-cadherin in the malignant transformation of OLP and supports the malignant potential of OLP.

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“…In mature hepatocytes, loss of E-cadherin leads to EMT induction, upregulation of stem cell markers, and ERK activation, which eventually results in enhanced carcinogenesis and an invasive phenotype [ 15 ]. Thus, E-cadherin plays critical roles in maintaining homeostasis and suppressing carcinogenesis in the liver.…”

Section: Discussionmentioning

confidence: 99%

Roles of E-cadherin in Hepatocarcinogenesis

Maeda

Nakagawa

2015

Innovative Medicine

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Loss of E-cadherin function has been reported to be associated with progression and poor prognosis of liver cancer. However, the precise role of E-cadherin in liver cancer development has not been elucidated. Thus, we generated liver-specifi c E-cadherin ( Cdh1 ) knockout mice ( Cdh1 ∆ Liv ) by crossing Cdh1 fl ox/fl ox mice with albumin-Cre transgenic mice. Interestingly, Cdh1 ∆ Liv mice developed spontaneous infl ammation in the portal areas, and then developed periductal onion skin-like fi brosis, which resembled primary sclerosing cholangitis. Microarray analysis showed that expression of stem cell markers such as CD44 and Sox9, and infl ammatory cytokines such as IL-6 and TNF-α, are increased in Cdh1 ∆ Liv liver compared with Cdh1 fl ox/fl ox liver. To investigate the role of E-cadherin in the liver tumorigenesis, we crossed Cdh1 ∆ Liv mice with lox-stop-lox Kras G12D mice ( Kras + Cdh1 ∆ Liv ). Kras + Cdh1 ∆ Liv mice developed liver tumors at age 28 weeks (8/8, 100 %), whereas Kras + Cdh1 fl ox/+ mice did not develop any tumors. Histologically, these tumors were hepatocellular carcinomas with a small proportion of ductal lesions and strongly positive for progenitor cell markers such as CD44 and Sox9. Interestingly, epithelial to mesenchymal transition (EMT) was found in the tumors of Kras + Cdh1 ∆ Liv mice. We also found that diethylnitrosamine-induced tumorigenesis was signifi cantly accelerated in Cdh1 ∆ Liv mice. In summary, loss of E-cadherin in the liver leads to sclerosing cholangitis and promotes tumorigenesis. Its tumor-promoting function seemed to be caused by gain of stem cell properties as well as induction of EMT.

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Loss of liver E-cadherin induces sclerosing cholangitis and promotes carcinogenesis

Cited by 105 publications

References 30 publications

Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10

Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10

Expression of E-cadherin in oral lichen planus

Roles of E-cadherin in Hepatocarcinogenesis

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