Notch1-Snail1-E-cadherin pathway in metastatic hepatocellular carcinoma

Int J Cancer. 2012 Aug 1;131(3):E163-72. doi: 10.1002/ijc.27336. Epub 2011 Dec 14.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Cadherins / metabolism
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / secondary*
  • Cell Line, Tumor
  • Cell Movement
  • Epithelial-Mesenchymal Transition
  • Female
  • Humans
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Mice, Nude
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • RNA Interference
  • RNA, Small Interfering
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism*
  • Signal Transduction
  • Snail Family Transcription Factors
  • Transcription Factors / metabolism*

Substances

  • Cadherins
  • NOTCH1 protein, human
  • RNA, Small Interfering
  • Receptor, Notch1
  • SNAI1 protein, human
  • Snai1 protein, mouse
  • Snail Family Transcription Factors
  • Transcription Factors