title: Early mitotic inhibitor-1, an anaphase-promoting complex/cyclosome inhibitor, can control tumor cell proliferation in hepatocellular carcinoma: correlation with Skp2 stability and degradation of p27(Kip1).
abstract: Early mitotic inhibitor-1 (Emi1) is a key cell-cycle regulator that promotes S-phase and M-phase entry by inhibiting anaphase-promoting complex/cyclosome (APC/C) activity. Immunohistochemical analysis was performed in 114 human hepatocellular carcinoma (HCC) samples, and the data were correlated with clinicopathologic features. Univariate and multivariate survival analyses were performed to determine the prognostic significance of the proteins. Expression of Emi1 correlated directly with the stage of HCC. More importantly, high expression of Emi1 was associated with a poor outcome. Western blot analysis showed that Emi1 was highly expressed in HCC compared with the adjacent noncancerous tissue. In vitro, after the release of HCC cell lines from serum starvation, the expression of Emi1 APC/C substrates (cyclins A, B) and Skp2 was up-regulated, whereas p27(Kip1) was down-regulated. In addition, we used small interfering RNA to knock out Emi1 expression and observed its effects on HCC growth in vitro to determine whether loss of Emi1 could inhibit cell proliferation by blocking S-phase and mitotic entry. Western blot analyses indicated that deletion of Emi1 was positively correlated with APC/C substrates (cyclins A, B) and Skp2 but was negatively correlated with p27(Kip1). Emi1 inhibits APC/C activity, whereas Skp2 degradation is mediated by APC/C, and degradation of Skp2 can stabilize p27(kip1). These results suggested that Emi1 participates in HCC cell proliferation and that progression is controlled by APC/C inhibition, which stabilized Skp2 and enabled p27(kip1) degradation. These findings provide a potential therapeutic strategy for HCC.
authors.affiliation: Department of Pathology, Nantong University Cancer Hospital, Medical College of Nantong University, Nantong, Jiangsu 226001, PR China.
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Qiyun
authors.initials: Q
authors.lastname: Tang
authors.forename: Runzhou
authors.initials: R
authors.lastname: Ni
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Huang
authors.forename: Yuchan
authors.initials: Y
authors.lastname: Wang
authors.forename: Cuihua
authors.initials: C
authors.lastname: Lu
authors.forename: Aiguo
authors.initials: A
authors.lastname: Shen
authors.forename: Yingying
authors.initials: Y
authors.lastname: Wang
authors.forename: Chunmiao
authors.initials: C
authors.lastname: Li
authors.forename: Qin
authors.initials: Q
authors.lastname: Yuan
authors.forename: Hongwei
authors.initials: H
authors.lastname: Chen
authors.forename: Chun
authors.initials: C
authors.lastname: Cheng
authors.forename: Song
authors.initials: S
authors.lastname: He
mesh_terms: D000328:Adult; D064173:Anaphase-Promoting Complex-Cyclosome; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D008938:Mitosis; D055550:Protein Stability; D059748:Proteolysis; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes / Q000037:antagonists & inhibitors
chemical_list: C436291:CDKN1B protein, human; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; C498960:FBXO5 protein, human; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome