P16 Methylation Leads to Paclitaxel Resistance of Advanced Non-Small Cell Lung Cancer
P16 Methylation Leads to Paclitaxel Resistance of Advanced Non-Small Cell Lung Cancer
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P16 甲基化导致晚期非小细胞肺癌紫杉醇耐药
DOI：
10.7150/jca.26482
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发表时间：
2019-01-01
影响因子：
3.9
通讯作者：
Deng, Dajun
中科院分区：
文献类型：
--
作者：
Liu, Zhaojun;Lin, Hongmei;Deng, Dajun
紫杉醇为主的化疗被广泛应用于非小细胞肺癌的一线治疗。然而，只有20%-40%的患者对紫杉醇敏感。本研究旨在探讨P16甲基化是否可用于预测非小细胞肺癌对紫杉醇的化疗敏感性。晚期非小细胞肺癌(N=45)来自参加基于紫杉醇的第三阶段随机临床试验的患者。基因组DNA样本是在化疗前从活检组织中提取的。用甲基光检测法检测p16基因甲基化。用P16特异性DNA去甲基酶(P16-Tet)和甲基转移酶(P16-Dnmt)体外检测细胞株中P16甲基化与紫杉醇敏感性的关系。低剂量紫杉醇为主的化疗加放疗在P16甲基化阳性的非小细胞肺癌中的总有效率显著低于P16甲基化阴性的非小细胞肺癌(2/15比16/30：调整OR=0.085；95%CI，0.012~0.579)。结果显示，P16去甲基化可显著降低肺癌H1299细胞对紫杉醇的耐药性(IC50值由2.15mU/ml降至1.13mU/ml，P<；0.001)。相反，P16-DNMT特异性甲基化显著增加了肺癌细胞和胃癌细胞对紫杉醇的耐药性(IC50值分别从18.224 ng/ml和0.18ug/ml增加到0.81ug/ml，P=0.049和0.001)。本研究结果提示P16基因甲基化可能导致紫杉醇耐药，并可作为预测非小细胞肺癌紫杉醇化疗敏感性的指标。
Paclitaxel-based chemotherapy is widely used as the first-line treatment for non-small cell lung cancer (NSCLC). However, only 20%-40% of patients have shown sensitivity to paclitaxel. This study aimed to investigate whether P16 methylation could be used to predict paclitaxel chemosensitivity of NSCLC. Advanced NSCLC (N=45) were obtained from patients who were enrolled in a phase-III randomized paclitaxel-based clinical trial. Genomic DNA samples were extracted from the biopsies prior to chemotherapy. P16 methylation was detected using MethyLight. The association between P16 methylation and the sensitivity of paclitaxel in cell lines was determined by in vitro assay using a P16-specific DNA demethylase (P16-TET) and methyltransferase (P16-Dnmt). The total response rate of the low-dose paclitaxel-based chemo-radiotherapy was significantly lower in P16 methylation-positive NSCLCs than that in the P16 methylation-negative NSCLCs (2/15 vs. 16/30: adjusted OR=0.085; 95% CI, 0.012-0.579). Results revealed that P16 demethylation significantly decreased paclitaxel resistance of lung cancer H1299 cells (IC50 values decreased from 2.15 to 1.13 mu g/ml, P< 0.001). In contrast, P16-specific methylation by P16-Dnmt significantly increased paclitaxel resistance of lung cancer HCC827 cells and gastric cancer BGC823 cells (IC50 values increased from 18.2 to 24.0 ng/ml and 0.18 to 0.81 mu g/ml, respectively; P=0.049 and < 0.001, respectively). The present results suggest that P16 methylation may lead to paclitaxel resistance and be a predictor of paclitaxel chemosensitivity of NSCLC.