自噬在miR-98/MTDH轴介导的头颈鳞癌上皮-间质转化及转移中的作用研究

Epithelial-mesenchymal transition (EMT) is a popular star in cancer metastasis research. Our previous results demonstrated that both miR-98 and MTDH modulated the EMT changes and metastasis in squamous cell carcinoma of the head and neck (SCCHN) in vitro, and miR-98 directly targeted the expression of MTDH, which indicated that miR-98/MTDH axis was important for the metastasis of SCCHN. Autophagy is a hot spot in basic research. However, there are few publications about the function of autophagy in cancer metastasis. Therefore, we further found that MTDH overexpression promoted the occurrence of autophagy phenomenon, which accompanied by EMT changes in SCCHN in vitro. Based on the above data, we aim to carry out the functional investigations of autophagy in the miR-98/MTDH axis mediated EMT and metastasis in SCCHN. In order to test the hypothesis, lentivirus-mediated miR-98 and MTDH overexpression and silencing vector will be utilized to change their expression levels in diverse SCCHN cell lines. Autophagy, EMT changes and metastasis associated malignant phenotypes in SCCHN will be observed to analyse the effect of miR-98/MTDH axis in vitro. Morever, autophagy process is impeded or enhanced to observe whether the above alterations caused by miR-98/MTDH axis will be reversed. Finally, in vitro results will be confirmed in lymph node metastatic mouse model. Taken together, the accomplishment of this study will clarify the important roles of miR-98/MTDH axis and autophagy in the metastasis of SCCHN, which will provide novel theory and experimental data in the field of cancer metastasis.

上皮-间质转化（EMT）在肿瘤转移研究中备受关注。我们发现miR-98和MTDH均能影响EMT及头颈鳞癌转移，且miR-98对MTDH具有直接靶向调控作用，提示miR-98/MTDH轴在头颈鳞癌转移中的重要作用。自噬为目前研究热点，其在肿瘤转移中的研究较少。我们发现上调MTDH能促使头颈鳞癌发生自噬，且在体外诱导自噬头颈鳞癌细胞随之发生EMT改变。本项目拟在前期研究基础上探索自噬在miR-98/MTDH轴介导的EMT及头颈鳞癌转移中的作用。为此我们拟构建miR-98和MTDH的慢病毒过表达及沉默载体，细胞水平阐明改变miR-98/MTDH轴对头颈鳞癌自噬、EMT及转移相关恶性表型的影响；再通过诱导或阻断自噬，观察该轴所介导的上述变化能否逆转；并最终在体内实验中予以证实。该项目的顺利实施将阐明自噬与miR-98/MTDH轴在头颈鳞癌转移中的作用，为肿瘤转移机理研究奠定新的理论依据。

上皮-间质转化（EMT）在肿瘤转移研究中备受关注。自噬为目前研究热点，其在肿瘤转移中的研究较少。本项目拟在前期研究基础上探索自噬在miR-98/MTDH轴介导的EMT及头颈鳞癌转移中的作用。.本项目的研究计划是通过拟构建miR-98和MTDH的慢病毒过表达及沉默载体，在细胞水平阐明改变miR-98/MTDH轴对头颈鳞癌自噬、EMT及转移相关恶性表型的影响；再通过诱导或阻断自噬，观察该轴所介导的上述变化能否逆转；并最终在体内实验中予以证实。.在课题组的共同努力下，我们已证实：1）与癌旁组织相比，miR-98在头颈鳞癌组织中显著低表达；2）miR-98的表达与头颈鳞癌患者的生存预后、淋巴结转移、肿瘤T分期等显著相关；3）miR-98可通过直接靶向MTDH 3UTR调控MTDH mRNA及蛋白表达；4）恢复MTDH的表达，可逆转miR-98对头颈鳞癌EMT及侵袭转移的影响；5）抑制自噬可逆转头颈鳞癌细胞的EMT发生及侵袭转移；6）MTDH通过调控自噬诱导头颈鳞癌细胞的EMT、侵袭转移（具体内容及体内实验的部分结果正在投稿阶段）。.在该项目的资助下，共培养在读博士研究生6名，毕业博士3名，在读硕士研究生6名，毕业硕士2名。已发表SCI论文9篇（总IF为33.28） 中文期刊 4篇。