Identification of galanin and its receptor GalR1 as novel determinants of resistance to chemotherapy and potential biomarkers in colorectal cancer.
Identification of galanin and its receptor GalR1 as novel determinants of resistance to chemotherapy and potential biomarkers in colorectal cancer.
复制标题
DOI：
10.1158/1078-0432.ccr-12-1780
复制
发表时间：
2012-10-01
期刊：
影响因子：
--
通讯作者：
Johnston PG
中科院分区：
文献类型：
--
作者：
Stevenson L;Allen WL;Turkington R;Jithesh PV;Proutski I;Stewart G;Lenz HJ;Van Schaeybroeck S;Longley DB;Johnston PG
限制结直肠癌临床有效治疗的主要因素是化疗耐药。因此，鉴定新的、治疗上可靶向的耐药介质至关重要。我们使用以结直肠癌疾病为中心的微阵列平台转录分析化疗应答和无应答的治疗前转移性结直肠癌肝活检和体外样本，对临床相关化疗药物（5-FU和奥沙利铂）敏感和耐药。途径和基因集富集分析（GSEA）确定了介导耐药的关键途径中的候选基因。功能性RNAi筛选鉴定了耐药调节因子。MAPK信号、局灶黏附、细胞周期、胰岛素信号和细胞凋亡是介导耐药的关键途径。g蛋白偶联受体甘丙氨酸受体1 （GalR1）被认为是一种新的耐药调节剂。值得注意的是，沉默GalR1或其配体galanin均可诱导药敏和耐药细胞系凋亡，并协同增强化疗效果。在机制上，GalR1/galanin沉默导致内源性caspase 8抑制剂FLIPL的下调，从而诱导caspase 8依赖性细胞凋亡。研究发现，甘丙肽mRNA在结直肠癌中过表达，重要的是，甘丙肽高表达与早期结直肠癌患者较差的无病生存率相关。这项研究证明了系统生物学方法的力量，以确定在功能上参与介导化疗耐药性的关键途径和基因。此外，我们已经确定了GalR1/ gal丙氨酸受体配体轴在化疗耐药中的新作用，为其作为结直肠癌潜在治疗靶点和生物标志物的进一步评估提供了证据。
A major factor limiting the effective clinical management of colorectal cancer (CRC) is resistance to chemotherapy. Therefore, the identification of novel, therapeutically targetable mediators of resistance is vital. We used a CRC disease-focused microarray platform to transcriptionally profile chemotherapy-responsive and non-responsive pre-treatment metastatic CRC liver biopsies and in vitro samples, both sensitive and resistant to clinically relevant chemotherapeutic drugs (5-FU and oxaliplatin). Pathway and gene set enrichment analyses (GSEA) identified candidate genes within key pathways mediating drug resistance. Functional RNAi screening identified regulators of drug resistance. MAPK signalling, focal adhesion, cell cycle, insulin signalling and apoptosis were identified as key pathways involved in mediating drug resistance. The G-protein coupled receptor galanin receptor 1 (GalR1) was identified as a novel regulator of drug resistance. Notably, silencing either GalR1 or its ligand galanin, induced apoptosis in drug-sensitive and resistant cell lines and synergistically enhanced the effects of chemotherapy. Mechanistically, GalR1/galanin silencing resulted in down-regulation of the endogenous caspase 8 inhibitor FLIPL, resulting in induction of caspase 8-dependent apoptosis. Galanin mRNA was found to be overexpressed in colorectal tumours, and importantly, high galanin expression correlated with poor disease-free survival of early stage CRC patients. This study demonstrates the power of systems biology approaches to identify key pathways and genes that are functionally involved in mediating chemotherapy resistance. Moreover, we have identified a novel role for the GalR1/galanin receptor-ligand axis in chemo-resistance, providing evidence to support its further evaluation as a potential therapeutic target and biomarker in CRC.