title: 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.
authors.forename: Qin
authors.initials: Q
authors.lastname: Luo
authors.forename: Cun
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Jin
authors.forename: Dishui
authors.initials: D
authors.lastname: Gu
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Jin
authors.initials: J
authors.lastname: Song
authors.forename: Haojie
authors.initials: H
authors.lastname: Jin
authors.forename: Fangyuan
authors.initials: F
authors.lastname: Hu
authors.forename: Yurong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Tianxiang
authors.initials: T
authors.lastname: Ge
authors.forename: Xisong
authors.initials: X
authors.lastname: Huo
authors.forename: Wei
authors.initials: W
authors.lastname: Chu
authors.forename: Huiqun
authors.initials: H
authors.lastname: Shu
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Fang
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.forename: Jianren
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Wenming
authors.initials: W
authors.lastname: Cong
authors.forename: Wenxin
authors.initials: W
authors.lastname: Qin
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053613:Janus Kinase 1 / Q000378:metabolism; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D051058:Oncogene Protein v-akt / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010766:Phosphorylation; D011379:Prognosis; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; C507840:LIFR protein, human; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D019869:Phosphatidylinositol 3-Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D051058:Oncogene Protein v-akt; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13