NDRG2在胆管癌中的表达及其在铁鏊合剂抑制胆管癌生长和转移中的作用研究

Cholangiocarcinoma has an early propensity to metastasize to regional lymph nodes, the peritoneum, and the omentum. Since, it's characterized with notoriously fast progression and high chemoresistance, the effective systemic therapeutic strategy is still limited. Dp44mT is a new type of iron chelators; recent studies demonstrate that Dp44mT inhibits the proliferation of variety of malignant tumors such as the breast cancer. However, studies on the efficacy of Dp44mT in tumor metastasis are limited. Recent studies show NDRG2 plays an important role in cancer development and progression. NDRG2 protein is expressed at lower levels in the tissue of human malignant tumors such as the colon cancer, etc. Significant positive correlation has been proven between its expression and the prognosis. However, studies on the role of NDRG2 in cholangiocarcinoma are inadequate, especially in the metastasis of cholangiocarcinoma. In our preliminary experiment, the results show that the expression of NDRG2 is lower in the cholangiocarcinoma tissue compared to the normal bile duct tissue. When treated with Dp44mT, the expression of NDRG2 is upregulated in the cholangiocarcinoma cells whilst the proliferation and metastasis overall are inhibited by the treatment of Dp44mT. Therefore, we suppose that NDRG2 may play a pivotal role in predicting the prognosis of cholangiocarcinoma, especially when Dp44mT inhibits the prolifeartion and metastasis. The project will further elucidate the significance of NDRG2 in cholangiocarcinoma development as well as the therapeutic outcomes of iron chelators treatment and thus will provide new therapeutic targets and interventions for formulating the systemic therapeutic strategy of cholangiocarcinoma.

胆管癌具有早期转移的特性，其进展迅速并对化疗高度耐药,因此至今仍缺乏有效的系统治疗方案。Dp44mT是新型的铁鏊合剂,研究证明其可以有效的抑制乳腺癌等肿瘤的生长,可是其在肿瘤转移方面的功效研究甚少。新近的研究发现NDRG2在恶性肿瘤的发生发展中起着重要作用，NDRG2在结肠癌等多种恶性肿瘤中低表达，并与临床预后成显著正相关，可关于NDRG2在胆管癌方面的研究则十分有限，特别是NDRG2是否在胆管癌转移方面发挥作用尚属未知。本课题在前期研究中发现NDRG2在胆管癌组织中低表达，而在正常组织中高表达；胆管癌细胞经Dp44mT处理，NDRG2表达上调，细胞生长及转移均被抑制。因此，我们推测NDRG2在预测胆管癌的预后，尤其是在Dp44mT抑制胆管癌生长及转移中发挥着重要作用。本项目将进一步明确NDRG2在胆管癌发生发展以及在铁鏊合剂治疗中的作用，为胆管癌的系统治疗提供新的治疗靶点和干预手段。

胆管癌是一种高度恶性、致命的肿瘤。大多数患者就诊时已处于肿瘤晚期从而错失最佳手术时机。因此，迫切需要明确胆管癌进展的分子机制，以及通过何种机制使胆管癌获得侵袭及转移的能力。铁螯合剂是一类具有明显抗肿瘤活性的药物，其具有干扰铁代谢的功能，但其分子靶点和作用机制尚未完全阐明。目前为止，临床上应用最广泛的治疗铁超负荷的铁螯合剂是脱铁氨（DFO），并且临床实验证明其对神经母细胞瘤及白血病有抗增殖效应。但是，DFO细胞膜通透性差、半衰期短，其抗肿瘤增殖效果较弱。相比之下，新型缩氨基硫脲类螯合剂Dp44mT，与DFO相比表现出更强的抗肿瘤增殖活性及铁螯合能力。NDRG2最近被报道在一些人类肿瘤组织及细胞系中扮演抑癌基因的角色。在这些研究中，NDRG2在肿瘤组织中的表达明显下降，提示其可能在肿瘤的发生发展中起到调节作用。然而，虽然开展了大量的关于NDRG2的细胞学及动物学实验，其在细胞内的确切功能仍有待进一步明确。本项目研究成果表明：（1）NDRG2在人胆管癌和肝细胞癌组织中的表达明显低于正常组织；（2）体内和体外实验证明NDRG2可以抑制胆管癌细胞的增殖、化疗耐受及转移。体内和体外实验还证明NDRG2可以抑制肝细胞癌细胞的转移；（3）体内和体外实验证明铁螯合剂Dp44mT可以通过上调NDRG2的表达抑制肿瘤的转移；（4）NDRG2是miR-181c的靶基因，NDRG2在胆管癌中的低表达要归因于miR-181c在胆管癌中的高表达；（5）此外，miR-181c可以被LIF激活，而NDRG2可以通过破坏Smad复合物结合LIF启动子来抑制LIF的转录；（6）在胆管癌和肝细胞癌患者中，NDRG2低表达往往提示患者预后不良。本项目的主体研究成果现已发表于国际知名肿瘤学杂志Hepatology，影响因子11.711（Hepatology. 2016;64(5):1606-1622.）和Oncotarget，影响因子6.359（Oncotarget. 2014;5(18):8478-91.）。在该项目基金的支持下，本人以并列第一作者完成的论文相继发表于Molecular Cancer（Mol Cancer. 2013;12(1):114.影响因子：5.397）、BMC Cancer（BMC Cancer. 2014;14:783.影响因子：3.362）等杂志。