结直肠癌是严重危害人类健康的常见的恶性肿瘤，其发病率、死亡率呈逐年上升趋势。如何逆转化疗抵抗是结直肠癌治疗亟待解决的重要科学问题之一。传统结直肠癌研究注重肿瘤细胞基因突变等经典遗传学改变，大量证据表明异常甲基化等表观遗传修饰的改变在肿瘤发生、发展及药物抵抗过程中具有关键作用。甲基化可作为肿瘤癌变及鉴别诊断的生物学标志。最新国内外临床试验显示，低剂量DNA去甲基化药物（如地西他滨）联合化疗能够显著增强肿瘤细胞的药物敏感性，获得较好的临床疗效。以此线索，我们首先通过大规模测序寻找去甲基化药物治疗前后差异表达基因，通过与结直肠癌化疗敏感/抵抗患者的表达谱数据进行整合分析，并从细胞、动物模型层面进行研究，以挖掘表观治疗后重激活的化疗增敏关键基因。

Colorectal cancer (CRC) is one of the most common serious malignant tumors to human health, with increased incidence and mortality year by year. How to reverse the resistance to chemotherapy is one of the major scientific issues in CRC treatment. The traditional tumor research mainly concerns on the genetic alterations of genes. Large evidences have revealed that the epigenetic regulation such as methylation played a crucial role in tumor development, metastasis, and drug resistance. DNA methylation has been viewed as novel biomarkers for carcinogenesis and diagnosis. The latest clinical trials demonstrated that low dose DNA demethylating drugs (such as decitabine) and combined chemotherapy significantly increased the sensitivity of CRC cells to the chemotherapeutic agents and showed improved clinical response. Based on this observation, we first investigated the differential genes after decitabine treatment by deep sequencing, and performed the bioinformatics analysis together with data from the chemotherapy sensitive/resistant CRC patients; to search for the chemotherapy sensitivity related reactivated genes.

结直肠癌是严重危害人类健康的常见的恶性肿瘤，传统结直肠癌研究注重肿瘤细胞基因突变等经典遗传学改变，大量证据表明异常甲基化等表观遗传修饰的改变在肿瘤发生、发展及药物抵抗过程中具有关键作用。肿瘤细胞中，抑癌基因、肿瘤抗原、MHC分子、共刺激分子等基因启动子往往高甲基化而表达沉默，导致肿瘤细胞免疫原性降低、凋亡抵抗，从而逃避免疫监控。低剂量DNA去甲基化药物（如地西他滨）能够诱导一系列基因重新表达，从而增强肿瘤细胞的药物敏感性。我们前期研究证明低剂量地西他滨能够通过上调肿瘤中miRNA-497的表达而提高化疗药物对结肠癌肿瘤干细胞的敏感性。本项目，我们从分子、细胞、动物及临床样本多层面检测分析地西他滨对机体T细胞抗肿瘤免疫活性的调控作用。我们证明低剂量地西他滨能够直接促进T细胞增殖、激活、Th1细胞分化及T细胞杀伤活力，而且地西他滨治疗后，肿瘤患者外周IFN-γ阳性T细胞比例和杀伤活性的增加能够预测地西他滨治疗临床反应性。