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LIFR functions as a metastasis suppressor in hepatocellular carcinoma by negatively regulating phosphoinositide 3-kinase/AKT pathway.

Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes for cancer related mortality worldwide. Poor prognosis of HCC patients is mainly due to frequent metastasis and recurrence. Deregulation of metastasis suppressors in malignant cells plays critical roles during cancer metastasis. Thus, novel metastasis suppressors are urgently needed to be uncovered to shed new light on molecular mechanisms driving HCC metastasis. In the present study, decreased expression of leukemia inhibitory factor receptor (LIFR) was demonstrated in HCC, and its expression levels were even lower in HCC with metastasis. Downregulated LIFR expression predicted poor prognosis in HCC patients. LIFR was an independent and significant risk factor for their recurrence and survival. Silencing LIFR resulted in forced metastasis of HCC cells, whereas ectopic overexpression of LIFR attenuated migration and invasion of HCC cells in vitro and in vivo. Moreover, LIFR knockdown could activate phosphoinositide 3-kinase/V-akt Murine Thymoma Viral Oncogene Homolog (PI3K/AKT) signaling through enhancing phosphorylation of Janus kinase 1 (JAK1), which successively promoted matrix metalloproteinase 13 (MMP13) expression and HCC metastasis. Combination of LIFR and p-AKT or MMP13 was a more powerful predictor of poor prognosis for HCC patients. Together, these findings conclude that LIFR functions as a novel metastasis suppressor in HCC and may serve as a prognostic biomarker for HCC patients.
AuthorsQin Luo, Cun Wang, Guangzhi Jin, Dishui Gu, Ning Wang, Jin Song, Haojie Jin, Fangyuan Hu, Yurong Zhang, Tianxiang Ge, Xisong Huo, Wei Chu, Huiqun Shu, Jingyuan Fang, Ming Yao, Jianren Gu, Wenming Cong, Wenxin Qin
JournalCarcinogenesis (Carcinogenesis) Vol. 36 Issue 10 Pg. 1201-12 (Oct 2015) ISSN: 1460-2180 [Electronic] England
PMID26249360 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].
Chemical References
  • Biomarkers, Tumor
  • LIFR protein, human
  • Leukemia Inhibitory Factor Receptor alpha Subunit
  • Phosphatidylinositol 3-Kinases
  • JAK1 protein, human
  • Janus Kinase 1
  • Oncogene Protein v-akt
  • MMP13 protein, human
  • Matrix Metalloproteinase 13
Topics
  • Adult
  • Aged
  • Biomarkers, Tumor
  • Carcinoma, Hepatocellular (genetics, pathology)
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Janus Kinase 1 (metabolism)
  • Leukemia Inhibitory Factor Receptor alpha Subunit (biosynthesis, genetics)
  • Liver Neoplasms (genetics, pathology)
  • Male
  • Matrix Metalloproteinase 13 (biosynthesis)
  • Middle Aged
  • Neoplasm Metastasis
  • Oncogene Protein v-akt (genetics, metabolism)
  • Phosphatidylinositol 3-Kinases (genetics)
  • Phosphorylation
  • Prognosis
  • Signal Transduction

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