低氧微环境通过调控ENO1对甲状腺癌细胞代谢和恶性表型的影响及机制研究

The global incidence of thyroid carcinoma is rising rapidly, in many areas of China, it has entered the top five common female malignant tumors. And patients with locally advanced tumors have poor overall treatment results. Hypoxic tumor microenvironment is the fuel of tumor, which leads to malignant progression of disease by inhibiting apoptosis, resisting treatment, causing tumor metabolic reprogramming and enhancing metastasis. Enolase 1(ENO1), as a key enzyme in glycolysis, is a potential effective therapeutic target in the treatment of tumors. Previously, we found that ENO1 was significantly increased in thyroid cancer tissues, and the expression of ENO1 in cancer cells was increased under hypoxic condition. Knockdown of ENO1 inhibited the growth of tumor cells and cancer stem cell phenotype. Moreover, the genes involved in oxidative phosphorylation and metabolism were significantly changed. These indicated that ENO1 was closely related to the growth and progression of thyroid cancer. We aim to found the molecular mechanism of ENO1 to regulate thyroid cancer cell proliferation, metabolism and drug sensitivity under hypoxic tumor microenvironment. Thus confirmed that targeted ENO1 joint change hypoxic tumor microenvironment in the treatment of thyroid cancer. Proven ENO1 as a potential clinical predictor of thyroid carcinoma, providing clues for the diagnosis and treatment as well as prognosis of thyroid carcinoma.

甲状腺癌全球发病率迅速攀升，目前我国许多地区已进入女性常见恶性肿瘤前五位，部分局部晚期患者总体治疗效果欠佳。低氧肿瘤微环境是驱动肿瘤的能源力量，通过抑制细胞凋亡、抵抗治疗致肿瘤代谢重编程和增强转移能力导致疾病的恶性进展。烯醇化酶1（ENO1）是糖酵解中的关键酶，是潜在的有效治疗靶点。前期我们发现ENO1在病人甲状腺癌组织中显著升高，低氧条件下细胞中ENO1的表达升高。敲低ENO1抑制肿瘤细胞的生长和肿瘤干细胞特性，且参与氧化磷酸化和代谢的基因发生显著变化，表明在ENO1与甲状腺癌肿瘤生长和恶性进展密切相关。我们旨在解决ENO1在低氧肿瘤微环境下是如何调控甲状腺癌细胞增殖、代谢和药物敏感性及其具体的分子机制这一科学问题，明确是否可通过靶向ENO1联合改变低氧肿瘤微环境治疗甲状腺癌，证明ENO1可作为一个潜在的临床预测甲状腺癌发生和恶性进展的关键指标，为甲状腺癌的诊疗预后预测提供新的线索。

近些年来，甲状腺癌全球发病率明显增加，北京市2016年数据显示，甲状腺癌已经成为女性发病率第三位的肿瘤。虽然多数甲状腺癌患者预后较好，但是局部晚期患者并不少见，数据显示约有13%的分化型甲状腺癌出现外侵，导致预后较差。即便目前甲状腺癌的首选治疗是根治性手术，但晚期甲状腺癌患者的手术治疗常常面临重要器官的切除（如喉、气管、食管），严重影响生活质量，迫切需要新的治疗方式。烯醇化酶1（ENO1）是糖酵解中的关键酶，是潜在的有效治疗靶点。本研究主要发现ENO1在病人甲状腺癌组织中显著升高。敲低ENO1可以抑制肿瘤细胞的生长和转移能力，抑制细胞周期进展，并诱导细胞凋亡；而过表达ENO1可以促进肿瘤细胞的生长和转移能力，促进细胞周期进展，并抑制细胞凋亡。并且干扰ENO1可以抑制甲状腺癌细胞的体内增殖能力。分子机制研究显示干扰ENO1可以下调CST家族基因的表达，包括CST1，CST4和CTSS等。后续研究发现干扰CST1和CTSS均可以抑制甲状腺癌细胞的增殖能力，并且通过功能回复实验显示ENO1通过CST1发挥作用。本研究表明ENO1及其下游基因CST1和CTSS与甲状腺癌肿瘤生长和恶性进展密切相关，证明ENO1可作为一个潜在的临床预测甲状腺癌发生和恶性进展的关键指标，为甲状腺癌的诊疗预后预测提供新的线索。针对这部分结果，我们也进行了相关临床研究，用于早期预测甲状腺微小乳头状癌是否可能出现侧颈部淋巴结转移，以及局部晚期甲状腺癌相关指标的表达是否与预后相关，以期将基础研究转化到临床应用中，对甲状腺微小乳头状癌以及局部晚期甲状腺癌的治疗提供新的依据。