SphK1对甲状腺癌细胞自噬的重要调控作用及分子机制研究

Accumulating evidence has demonstrated that autophagy play an imoportant role in chemoresistant of various cancers. It has been showed that inhibition of autophagy decrease the chemotherapy sensitivity of human thyroid cancer. However, the underlying precise mechanism is largely unkonwn. In our recent published paper, we found that SphK1 is overexpressed and promotes proliferation in human thyroid cancer. Moreover, our preliminary studies observed that: 1) SphK1 inhibited the autophagy of thyroid cancer cells, and thereby decrease the chemotherapy sensitivity of human thyroid cancer; 2）SphK1-induced inhibition of autophagy was Akt independent and maybe associated with Erk1/2 activation; 3）miR-101 was significantly down-regulated by ecotopic expression of SphK1and miR-101 could suppress the expression of mTOR, Rap1b, Rac1, and Pak2. Therefore, our aim in current project is to systematically explore the mechanism underlying SphK1-induced chemoresistance and inhibition of autophagy via activation of Erk1/2-TSC1/2-Rheb-mTOR signaling in thyroid cancer, which would provide new insights into the therapeutic strategies for thyroid cancer.

自噬在肿瘤细胞的化疗抵抗性中起重要作用。研究表明在甲状腺癌中抑制自噬活性导致细胞对化疗的敏感性降低，但调控机制尚不明确。前期我们证明鞘氨醇激酶1（SphK1）在甲状腺癌中高表达并促进细胞增殖。预实验显示，SphK1抑制甲状腺癌细胞自噬并增强甲状腺癌细胞的对化疗药物的抵抗性；同时发现SphK1抑制甲状腺癌细胞自噬不依赖于Akt活性而可能与Erk1/2活性相关；芯片提示miR-101是SphK1最为显著下调的microRNA，而miR-101下调mTOR及Erk1/2信号通路的正性调控因子Rap1b、Rac1及Pak2。基于以上基础，本项目将系统性研究SphK1具有抑制甲状腺癌细胞自噬的能力,从而增强甲状腺癌细胞的化疗抵抗性。在此过程中，SphK1下调miR-101的表达以促进mTOR、Rap1b、Rac1及Pak2的表达，因而激活Erk1/2-TSC1/2-Rheb-mTOR通路。

近年来，甲状腺癌的发病率在世界范围内有逐渐升高的趋势，进一步研究其恶性表型背后的分子机制，有利了解疾病发生发展的过程，并提供可能的治疗靶点。本项目研究发现：（1）甲状腺乳头状癌（PTC）细胞中SphK1异常表达调控miR-144-3p的表达下调，miR-144-3p通过调控靶基因FN1，从而调控PTC的侵袭能力（J Cancer Res Clin Oncol. 2017; 143: 601-611）；（2）TMPRSS4在甲状腺癌中表达升高，调控CREB磷酸化从而促进cyclin D1的表达，进而促进细胞增殖（Thyroid 2015; 25: 85-94）；（3）miR-144在甲状腺癌组织中表达降低并通过靶基因ZEB-1及ZEB-2调控甲状腺癌细胞侵袭 （Endocrine 2015; 48: 566-74）；（4）SOSTDC1在甲状腺癌中低表达通过下调cyclin A2及cyclin E2的表达抑制甲状腺癌细胞的增殖（Oncotarget. 2015 Oct 13; 6: 31780-91）；（5）Trop2表达量在人甲状腺癌组织中明显升高并通过通过活化ERK及JNK通路促进MMP2表达从而促进甲状腺肿瘤细胞侵袭性（BMC Cancer. 2017 Jul 14; 17: 486）；（6）PSAT1调控cyclin D1蛋白降解从而促进非小细胞肺癌细胞增殖（Int J Cancer 2015; 136: E39-50）。以上研究表明SphK1、TMPRSS4、 miR-144、 SOSTDC1及Trop2等在甲状腺癌中异常表达并参与甲状腺癌的发生发展。