TMEM158 and FBLP1 as novel marker genes of cisplatin sensitivity in non-small cell lung cancer cells
TMEM158 and FBLP1 as novel marker genes of cisplatin sensitivity in non-small cell lung cancer cells
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DOI：
10.3109/01902148.2012.731625
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发表时间：
2012-11-01
影响因子：
1.7
通讯作者：
Nishiyama, Masahiko
中科院分区：
文献类型：
--
作者：
Mohammed, Ahmed El Sayed;Eguchi, Hidetaka;Nishiyama, Masahiko
即使在分子靶向治疗发展之后，铂类化疗仍然是局部晚期非小细胞肺癌（NSCLC）的标准治疗方案。到目前为止，能够预测非小细胞肺癌患者治疗反应的关键分子标志物仍未确定。我们在此试图为顺铂（CDDP）的定制治疗鉴定新的生物标记基因。初步筛选MTT法获得的CDDP IC50值与寡核苷酸芯片和实时RT-PCR测定的基因表达水平之间的相关性，获得了6个候选基因，分别是NUBPL、C9orf30、ZNF12、TMEM158、GSK3B和FBLP1，这些候选基因由3个小细胞和6个NSCLC细胞组成。将这6个基因与已报道的5个生物标志物GSTP1、ERCC1、BRCA1、FRAP1、RRM1进行线性回归分析，使用12个NSCLC细胞系，其中包括另外6个NSCLC细胞：只有FBLP1和TMEM158基因呈显著正相关，差异有统计学意义（P = 0.016和P = 0.016）。026年,分别)。通过体外实验探索这些基因的生物学意义：在PC-9/CDDP细胞中进行敲低实验发现，TMEM158的表达降低显著降低了对CDDP的化学抗性（P < 0.0001），而PC-6细胞的2个转化子稳定过表达FBLP1导致对CDDP的抗性增强（P = 0.004和P = 0.001）。逐步多元回归分析表明，使用TMEM158和FBLP1的表达数据可以确定最佳预测公式（R-2 = 0.755, P = 0.0018）。TMEM158和FBLP1可能是CDDP治疗非小细胞肺癌的强有力的预测性生物标志物。
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 IC50 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.