title: TMEM158 and FBLP1 as novel marker genes of cisplatin sensitivity in non-small cell lung cancer cells.
abstract: Even after development of molecular targeting therapies, platinum-based chemotherapy is still a standard care for treatment of locally advanced non-small cell lung cancer (NSCLC). So far, critical molecular markers capable to predict the therapeutic response in NSCLC patients remain undetermined. We here attempted to identify novel biomarker genes for cisplatin (CDDP) for a tailored therapy. Initial screening to explorer association of IC(50) values of CDDP obtained by MTT assay and gene expression levels measured with oligonucleotide microarray and real-time RT-PCR provided 6 candidate genes, namely, NUBPL, C9orf30, ZNF12, TMEM158, GSK3B, and FBLP1 using 9 lung cancer cells consisting of 3 small and 6 NSCLC cells. These 6 genes together with 5 reported biomarkers, i.e., GSTP1, ERCC1, BRCA1, FRAP1, and RRM1, were subjected to a linear regression analysis using 12 NSCLC cell lines including 6 additional NSCLC cells: only FBLP1 and TMEM158 genes showed positive associations with statistical significances (P = .016 and .026, respectively). The biological significance of these genes was explored by in vitro experiments: Knockdown experiments in PC-9/CDDP cells revealed that the reduced expression of TMEM158 significantly decreased the chemo-resistance against CDDP (P <.0001), while 2 transformants of PC-6 cells stably over-expressing FBLP1 resulted in an enhanced resistance to CDDP (P = .004 and P = .001). Furthermore, a stepwise multiple regression analysis demonstrated the best prediction formula could be fixed when we used expression data of TMEM158 and FBLP1 (R(2) = 0.755, P = .0018). TMEM158 and FBLP1 may be powerful predictive biomarkers for CDDP therapy in NSCLC.
authors.affiliation: Translational Research Center, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.
authors.forename: Ahmed El Sayed
authors.initials: Ael S
authors.lastname: Mohammed
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Eguchi
authors.forename: Satoru
authors.initials: S
authors.lastname: Wada
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Koyama
authors.forename: Michio
authors.initials: M
authors.lastname: Shimizu
authors.forename: Keiko
authors.initials: K
authors.lastname: Otani
authors.forename: Megu
authors.initials: M
authors.lastname: Ohtaki
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanimoto
authors.forename: Keiko
authors.initials: K
authors.lastname: Hiyama
authors.forename: Mohammed Soliman
authors.initials: MS
authors.lastname: Gaber
authors.forename: Masahiko
authors.initials: M
authors.lastname: Nishiyama
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D012044:Regression Analysis; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; C473794:FBLIM1 protein, human; D008565:Membrane Proteins; C449281:TMEM158 protein, human; D025521:Tumor Suppressor Proteins; D002945:Cisplatin