Association between mismatch repair gene and irinotecan-based chemotherapy in metastatic colon cancer
Association between mismatch repair gene and irinotecan-based chemotherapy in metastatic colon cancer
复制标题
错配修复基因与转移性结肠癌伊立替康化疗的相关性
DOI：
10.1007/s13277-015-3723-5
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发表时间：
2015-12-01
期刊：
影响因子：
--
通讯作者：
Zeng, Shan
中科院分区：
文献类型：
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作者：
Ma, Junli;Zhang, Yan;Zeng, Shan
错配修复基因与结肠癌的发生密切相关。本研究旨在评估MMR状态与伊立替康化疗疗效之间的相关性。作为5-FU的靶点，伊立替康可能会影响胸苷酸合成酶（TS）的表达水平。了解TS的这种影响是否与MMR状态有关，有助于进一步探讨不同MMR状态转移性结肠癌对伊立替康敏感性的机制。纳入了184例接受伊立替康为基础的化疗作为一线治疗的转移性结肠癌患者。分析MMR与临床病理特征及预后的相关性。通过调节MMR状态建立了两对结肠癌细胞系（HCT-116-hMLH 1（Vector）（缺陷型MMR，dMMR）与HCT-116-hMLH 1（+）（有效型MMR，pMMR）; SW 480-shRNA-hMLH 1（dMMR）与SW 480-shRNA-Control（pMMR））。通过MTT法测定这些细胞系对伊立替康的敏感性。通过蛋白质印迹法和实时定量PCR试验评价伊立替康对TS的调节。dMMR占18.5%，与近端结肠癌（p = 0.005）、低分化肿瘤（p = 0.018）和良好疗效相关，具有较高的疾病控制率（DCR）、较长的无进展生存期（PFS）和较长的总生存期（OS）趋势。dMMR结肠癌细胞对伊立替康更敏感。伊立替康处理后dMMR细胞TS表达水平降低更明显（p < 0.05）。我们的研究支持伊立替康在dMMR状态的结肠癌中的敏感性增加。MMR状态可能是转移性结肠癌对基于伊立替康的化疗反应的预测性生物标志物。
Mismatch repair (MMR) gene is closely related to the pathogenesis of colon cancer. This study aimed to evaluate the association between MMR status and efficacy of irinotecan-based chemotherapy. As a target of 5-FU, thymidylate synthase (TS) expression level might be influenced by irinotecan. Understanding whether this influence of TS is related with MMR status is helpful to the further exploration of the mechanism of irinotecan sensitivity in metastatic colon cancer with different MMR status. One hundred eighty-four patients with metastatic colon cancer receiving irinotecan-based chemotherapy for the first-line treatment were included. Correlations between MMR and clinicopathological characteristics and prognosis were determined. Two pairs of colon cancer cell lines (HCT-116-hMLH1(Vector) (deficient MMR, dMMR) versus HCT-116-hMLH1(+) (proficient MMR, pMMR); SW480-shRNA-hMLH1 (dMMR) versus SW480-shRNA-Control (pMMR)) were established by regulating MMR status. Sensitivity of these cell lines to irinotecan was determined by MTT assay. Regulation of TS by irinotecan was evaluated by western blotting and quantitative real-time PCR assay. dMMR accounted for 18.5 % and was related with proximal colon cancer (p = 0.005), poorly differentiated tumors (p = 0.018) and favorable efficacy with a higher disease control rate (DCR), a longer progression-free survival (PFS) and a trend of longer overall survival (OS). dMMR colon cancer cells were more sensitive to irinotecan. TS expression level was reduced more in dMMR cells after irinotecan treatment (p < 0.05). Our study favors an increased sensitivity of irinotecan in colon cancer with dMMR status. MMR status may be a predictive biomarker of response to irinotecan-based chemotherapy in metastatic colon cancer.