title: Overexpression of Numb suppresses tumor cell growth and enhances sensitivity to cisplatin in epithelioid malignant pleural mesothelioma.
abstract: Malignant pleural mesothelioma (MPM) is a highly aggressive and conventional treatment-resistant tumor with a dismal prognosis. Among the three histological subtypes of MPM, the epithelioid is the most common type. Numb is considered as a tumor suppressor playing a critical role in controlling asymmetric cell division, maintenance of stem cell compartments, ubiquitination of specific substrates and regulating Notch-, Hedgehog- and TP53-activated pathways. The present study was designed to analyze the role of Numb in epithelioid MPM. We investigated the expression of Numb in 39 epithelioid MPM and 22 normal pleural tissues by immunohistochemistry. Furthermore, we overexpressed Numb in NCI-H2452, an epithelioid human MPM cell line, and investigated the effect of Numb overexpression on the proliferation, apoptosis and sensitivity to cisplatin in cells. The expression of Numb was significantly lower in MPM compared to the control group and Numb had an inverse correlation with the ki-67 labeling index. Loss of Numb expression was associated with poor prognosis in epithelioid MPM. Overexpression of Numb in NCI-H2452 cells significantly inhibited proliferation, promoted apoptosis and enhanced sensitivity to cisplatin. Moreover, Numb overexpression activated caspase-9 and caspase-3 through release of cytochrome c as well as downregulation of XIAP and survivin. We speculate that cytochrome c/caspase signaling is a possible mechanism through which Numb enhances the apoptosis of NCI-H2452 cells. These results suggest that Numb may be involved in epithelioid MPM development, and its upregulation may confer sensitivity to cisplatin, suggesting potential therapeutic options for MPM.
authors.affiliation: Department of Respiratory Medicine, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, P.R. China.
authors.forename: Yanmeng
authors.initials: Y
authors.lastname: Kang
authors.forename: Mingjie
authors.initials: M
authors.lastname: Ding
authors.forename: Guangyan
authors.initials: G
authors.lastname: Tian
authors.forename: Haisheng
authors.initials: H
authors.lastname: Guo
authors.forename: Yunyan
authors.initials: Y
authors.lastname: Wan
authors.forename: Zhouhong
authors.initials: Z
authors.lastname: Yao
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Dianjie
authors.initials: D
authors.lastname: Lin
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002945:Cisplatin / Q000627:therapeutic use*; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D019394:Ki-67 Antigen; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000378:metabolism*; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000378:metabolism*; D011379:Prognosis; D015398:Signal Transduction; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D019394:Ki-67 Antigen; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9; D002945:Cisplatin