title: Intermedin is overexpressed in hepatocellular carcinoma and regulates cell proliferation and survival.
abstract: Angiogenesis is one of the hallmarks of tumor growth and metastasis. Identification of tumor angiogenic factors has been a critical component in understanding cancer biology and treatment. Intermedin (IMD) has been reported to promote angiogenesis in a rat ischemic model and human umbilical vascular endothelial cells. Our study sought to determine the role of IMD in human hepatocellular carcinoma tumor progression. High IMD mRNA expression levels were observed in human hepatocellular carcinoma tumors, even in early stage disease, by real-time RT-PCR. Immunohistochemical analysis of hepatocellular carcinoma clinical samples demonstrated that the tumor regions were significantly more immunoreactive for IMD than adjacent benign liver. Inhibition of IMD expression using RNA interference reduced cell proliferation in SK-Hep-1 and SNU-398 cells. Blockage of IMD signaling using either an antagonist peptide or a neutralizing antibody inhibited growth in a dose-dependent manner with concomitant induction of apoptosis, causing cleavage of caspase-8 and downregulation of Gli1 and Bcl2. Conversely, addition of IMD active peptide increased the phosphorylation level of extracellular signal-regulated kinase. Thus, IMD might play an important role in cell proliferation and survival of hepatocellular carcinoma. Our data suggests that IMD is a potential biomarker and therapeutic target for hepatocellular carcinoma.
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Guo
authors.forename: John C
authors.initials: JC
authors.lastname: Schmitz
authors.forename: Barton C
authors.initials: BC
authors.lastname: Kenney
authors.forename: Edward M
authors.initials: EM
authors.lastname: Uchio
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kulkarni
authors.forename: Charles H
authors.initials: CH
authors.lastname: Cha
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015870:Gene Expression; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D036361:Peptide Hormones / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D016019:Survival Analysis; D055815:Young Adult
chemical_list: C484330:ADM2 protein, human; D036361:Peptide Hormones