Premium
Notch1‐Snail1‐E‐cadherin pathway in metastatic hepatocellular carcinoma
Author(s) -
Wang Xiao Qi,
Zhang Wu,
Lui Eric L.H.,
Zhu Yongqiang,
Lu Ping,
Yu Xiaoming,
Sun Jisan,
Yang Sitian,
Poon Ronnie T.P.,
Fan Sheung Tat
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27336
Subject(s) - metastasis , cancer research , small hairpin rna , carcinogenesis , notch signaling pathway , hepatocellular carcinoma , cadherin , medicine , cancer , gene knockdown , pathology , biology , cell , cell culture , receptor , genetics
Notch signaling, a critical pathway for tissue development, also contributes to tumorigenesis in many cancers, but its pathological function in liver cancer is not well defined. In our study, Notch1 expression and its clinicopathological parameters were evaluated in 82 human hepatocellular carcinoma (HCC) patients. Plasmid‐based siNotch1 shRNA was transiently or stably transfected into metastatic HCC cells and subsequently evaluated for the effects on orthotopic liver tumor metastasis in a mouse model as well as the effects on downstream pathways. Aberrant high expression of Notch1 was significantly associated with metastatic disease parameters in HCC patients, such as tumor‐node‐metastasis Stages III–IV and tumor venous invasion. Knocking‐down Notch1 reduced cell motility in vitro and orthotopic tumor metastasis from the liver to the lung in vivo in a mouse model. In metastatic HCC cells, abnormal expression of Notch1 was associated with increased expression of Snail1 and repressed expression of E‐cadherin; the Notch1‐Snail1‐E‐cadherin association can also be found in HCC patient tumors. Inhibition of Notch1 by shRNA abolished Snail1 expression, which further resulted in the re‐establishment of repressed E‐cadherin in metastatic HCC cells. Thus, abnormal Notch1 expression was strongly associated with HCC metastatic disease, which might be mediated through the Notch1‐Snail1‐E‐cadherin pathway. Knock‐down of Notch1 reversed HCC tumor metastasis in a mouse model. Therefore, these data suggest that effective targeting of Notch signaling might also inhibit tumor metastasis.