Roles of E-cadherin in Hepatocarcinogenesis

Excerpt

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-specific E-cadherin (Cdh1) knockout mice (Cdh1 ^∆Liv ) by crossing Cdh1 ^flox/flox mice with albumin-Cre transgenic mice. Interestingly, Cdh1 ^∆Liv mice developed spontaneous inflammation in the portal areas, and then developed periductal onion skin–like fibrosis, which resembled primary sclerosing cholangitis. Microarray analysis showed that expression of stem cell markers such as CD44 and Sox9, and inflammatory cytokines such as IL-6 and TNF-α, are increased in Cdh1 ^∆Liv liver compared with Cdh1 ^flox/flox 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 ^flox/+ 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 significantly 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.