MALAT-1调控EMT促进甲状腺乳头状癌转移的分子机制

Distant metastasis is the major failure reason in therapy of papillary thyroid carcinoma (PTC). Recent studies have indicated that LncRNA-MALAT1 can cause metastasis of multiple tumors. But the mechanism of LncRNA functioned in thyroid carcinoma remained unclear. Our preliminary experiments found that:①The overexpression of MALAT1 in PTC tissues with metastasis is negatively correlated with the expression of E-cadherin.②Knockdown of MALAT1 significantly inhibited expression of ZEB1、ZEB2、Snail、vimentin and enhanced E-cadherin expression. Furthermore, the migration and invasion of PTC cells was enhanced, but the clone formation was not influenced. Therefore, we suppose that MALAT-1 promotes metastasis of papillary thyroid carcinoma by regulating epithelial-to-mesenchymal transition. Next we will perform gene microarray, RNAi technique to screen and verify the main signaling pathways though which MALAT-1 regulating epithelial-to-mesenchymal transition. Furthermore, to clarify weather MALAT-1 can be a therapeutic target, we will inject mice with MALAT-1 antisense oligonucleotide. This study can contribute to illuminate molecular mechanism of MALAT-1 taking part in the process of PTC and may provide clues of new therapeutic targets.

远处转移是甲状腺乳头状癌（PTC）患者治疗失败的主要原因，近年发现长非编码RNA（LncRNA）MALAT1可以促进多种肿瘤的转移。但LncRNA在甲状腺癌中的作用尚不明确。我们的前期研究发现：①合并转移的PTC组织中MALAT1的表达显著升高，并与E-cadherin的表达呈负相关；②沉默MALAT1后，上皮间质转化（EMT）相关分子ZEB1、ZEB2、Snail、vimentin表达减少，E-cadherin表达上调，PTC细胞的侵袭、迁移能力降低，而克隆形成能力无明显变化。以上结果提示MALAT1可能通过调控EMT促进PTC的转移。本研究拟进一步通过基因芯片和RNA干扰技术筛选、验证MALAT1调控EMT的关键信号通路，并采用MALAT1反义寡核苷酸体内治疗技术探讨MALAT1是否可以作为PTC的治疗靶点，从而为阐明MALAT1在PTC中作用的分子机制及发现PTC治疗新靶点奠定基础。

甲状腺乳头状癌（PTC）的发病率逐年升高，而远处转移是PTC患者治疗失败的主要原因。近年发现长非编码RNA（LncRNA）MALAT1可以促进多种肿瘤的转移，且上皮间质转化（EMT）在肿瘤转移过程中发挥重要作用。但MALAT1及EMT在甲状腺乳头状癌中的作用尚不明确。我们的研究发现：①PTC组织高表达MALAT1，而合并转移的PTC组织中MALAT1的表达显著升高，并与E-cadherin的表达呈负相关；②沉默MALAT1后，上皮间质转化（EMT）相关分子ZEB1、ZEB2、Snail、vimentin、MMP-2、MMP-9表达减少，E-cadherin表达上调，PTC细胞的侵袭、迁移、克隆形成能力均显著降低，而细胞凋亡增加。③沉默MALAT-1表达后，PTC 细胞的皮下成瘤能力减弱，肿瘤体积较对照组明显缩小，肿瘤组织MALAT-1表达水平较对照组明显降低。④本研究进一步通过基因芯片和RNA干扰技术筛选、验证了MALAT1调控EMT的关键信号通路为PI3K/AKT信号通路。以上结果提示MALAT1通过作用于PI3K/AKT信号通路调控EMT从而促进PTC的转移。该研究结果为阐明MALAT1在PTC中作用的分子机制及发现PTC治疗的新靶点奠定了基础。