Chen Qi, Xia Hong-Wei, Ge Xiao-Jun, Zhang Yu-Chen, Tang Qiu-Lin, Bi Feng
Department of Medical Oncology, West China Hospital, University of Sichuan, Chengdu, China E-mail :
Asian Pac J Cancer Prev. 2013;14(12):7421-6. doi: 10.7314/apjcp.2013.14.12.7421.
Colorectal cancer is the fourth most common cancer worldwide and the second leading cause of cancer-related death. FOLFOX is the most common regimen used in the first-line chemotherapy in advanced colorectal cancer, but only half of the patients respond to this regimen and we have almost no clue in predicting resistance in such first-line application.
To explore the potential molecular biomarkers predicting the resistance of FOLFOX regimen as the first-line treatment in advanced colorectal cancer, we screened microRNAs in serum samples from drug-responsive and drug-resistant patients by microarrays. Then differential microRNA expression was further validated in an independent population by reverse transcription and quantitative real- time PCR.
62 microRNAs expressing differentially with fold-change >2 were screened out by microarray analysis. Among them, 5 (miR-221, miR-222, miR-122, miR-19a, miR-144) were chosen for further validation in an independent population (N=72). Our results indicated serum miR-19a to be significantly up-regulated in resistance-phase serum (p=0.009). The ROC curve analysis showed that the sensitivity of serum miR-19a to discriminate the resistant patients from the response ones was 66.7%, and the specificity was 63.9% when the AUC was 0.679. We additionally observed serum miR-19a had a complementary value for cancer embryonic antigen (CEA). Stratified analysis further revealed that serum miR-19a predicted both intrinsic and acquired drug resistance.
Our findings confirmed aberrant expression of serum miR-19a in FOLFOX chemotherapy resistance patients, suggesting serum miR-19a could be a potential molecular biomarker for predicting and monitoring resistance to first-line FOLFOX chemotherapy regimens in advanced colorectal cancer patients.
结直肠癌是全球第四大常见癌症，也是癌症相关死亡的第二大主要原因。FOLFOX是晚期结直肠癌一线化疗中最常用的方案，但只有一半的患者对该方案有反应，而且我们几乎无法预测在这种一线应用中的耐药性。
为了探索预测FOLFOX方案作为晚期结直肠癌一线治疗耐药性的潜在分子生物标志物，我们通过微阵列筛选了药物反应性和耐药性患者血清样本中的微小RNA。然后通过逆转录和定量实时PCR在独立人群中进一步验证差异微小RNA表达。
通过微阵列分析筛选出62个差异表达倍数变化>2的微小RNA。其中，选择了5个（miR-221、miR-222、miR-122、miR-19a、miR-144）在独立人群（N=72）中进行进一步验证。我们的结果表明，血清miR-19a在耐药期血清中显著上调（p=0.009）。ROC曲线分析显示，血清miR-19a区分耐药患者和反应患者的敏感性为66.7%，当AUC为0.679时，特异性为63.9%。我们还观察到血清miR-19a对癌胚抗原（CEA）具有补充价值。分层分析进一步表明，血清miR-19a可预测内在和获得性耐药。
我们的研究结果证实了血清miR-19a在FOLFOX化疗耐药患者中的异常表达，表明血清miR-19a可能是预测和监测晚期结直肠癌患者对一线FOLFOX化疗方案耐药性的潜在分子生物标志物。
