title: MTBP inhibits migration and metastasis of hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with increasing incidence. Despite curative surgical resection and advanced chemotherapy, its survival rate remains low. The presence of microvascular invasion and occult metastasis is one of the major causes for this poor outcome. MDM2 Binding Protein (MTBP) has been implicated in the suppression of cell migration and cancer metastasis. However, clinical significance of MTBP, particularly in human cancer, is poorly understood. Specifically, clinical relevance of MTBP in human HCC has never been investigated. Here we demonstrated that expression of MTBP was significantly reduced in human HCC tissues compared to adjacent non-tumor tissues. MTBP expression was negatively correlated with capsular/vascular invasion and lymph node metastasis. Overexpression of MTBP resulted in the suppression of the migratory and metastatic potential of HCC cells, while its downregulation increased the migration. Consistent with the previous report, MTBP endogenously bound to alpha-actinin 4 (ACTN4) and suppressed ACTN4-mediated cell migration in multiple HCC cell lines. However, MTBP also inhibited migratory potential of PLC/PRF/5 HCC cells whose migration was not altered by manipulation of ACTN4 expression. These results suggest that mechanisms behind MTBP-mediated migration suppression may not be limited to the pathway involving ACTN4 in certain cellular contexts. Additionally, as a potential mechanism for reduced MTBP expression in tumors, we found that MTBP expression was increased following the treatment with histone deacetylase inhibitors (HDIs). Our study, for the first time, provides clinical relevance of MTBP in the suppression of HCC metastasis.
authors.affiliation: Diagnosis and Treatment Center for Liver Cirrhosis, 302 Military Hospital of China, Beijing, 10039, People's Republic of China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Bi
authors.forename: Atul
authors.initials: A
authors.lastname: Ranjan
authors.forename: Rui
authors.initials: R
authors.lastname: Fan
authors.forename: Neeraj
authors.initials: N
authors.lastname: Agarwal
authors.forename: Danny R
authors.initials: DR
authors.lastname: Welch
authors.forename: Steven A
authors.initials: SA
authors.lastname: Weinman
authors.forename: Jie
authors.initials: J
authors.lastname: Ding
authors.forename: Tomoo
authors.initials: T
authors.lastname: Iwakuma
mesh_terms: D000185:Actinin / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002648:Child; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics; D009368:Neoplasm Transplantation; D016707:Tissue Fixation; D014183:Transplantation, Heterologous; D055815:Young Adult
chemical_list: C111453:ACTN4 protein, human; D002352:Carrier Proteins; D056572:Histone Deacetylase Inhibitors; C485931:MTBP protein, human; D000185:Actinin