Snail/miR-375/Jak2通路在胃癌细胞侵袭和转移中的作用及其分子机制研究

Metastasis is the most terrible aspects of cancer. And metastasis is responsible for the gastric cancer-related mortality. In gastric cancer, cells invasion into the surrounding tissue is a crucial early step. However, the mechanisms of gastric cancer cells migration, invasion and metastasis have not been fully understood. In our previous study, the expression level of Jak2 was significantly upregulated in gastric cancer tissues and was associated with lymph node metastasis. Interestingly, we further found that the expression level of Jak2 protein was negatively regulated by miR-375, the expression of which was downregulated in gastric cancer. Thus, we proposed that Jak2 might have a causal role in gastric cancer metastasis. Our studies further uncovered that overexpression of Jak2 promoted the migration and invasion of gastric cancer cells. Inversely, reduced of Jak2 could significantly inhibit the migration and invasion of gastric cancer cells. We further prompted to find out how miR-375 expression was regulated in gastric cancer. Results indicated that miR-375 was a target of the metastasis associated transcription factor Snail and its expression was inversely correlated with Snail in gastric cancer. Thus, we proposed a hypothesis that there was an undescribed regulatory pathway, Snail/miR-375/Jak2, in which a transcription factor Snail regulates the expression of miR-375, which suppresses its direct target Jak2, leading to inhibit the migration, invasion and metastasis of gastric cancer cells. Our data indicates that restoration of miR-375 or inhibition of Snail or Jak2 may be useful therapeutic strategies for gastric cancer treatment. Our study focus on the association between Snail and Jak2 with specific dysregulated miR-375 and specific metastasis step of gastric cancer, which will provide insights into the potential mechanisms of gastric cancer cells migration, invasion and metastasis, and search the potential targets for the early diagnosis, the prognosis prediction and provide new ideas for the effective treatment of gastric cancer.

早期就发生局部侵袭和转移是胃癌的一个特点。前期研究提示Jak2在胃癌中表达增高，并与淋巴结转移相关。进一步研究提示Snail可能是Jak2调控因子miR-375的上游调控因子。我们设想：在胃癌中，转录因子Snail表达异常增高，抑制miR-375的转录，致其表达降低，对其下游靶蛋白Jak2的负向调控减弱，导致Jak2表达增高，从而促进胃癌细胞的侵袭和转移。前期研究提示Snail/miR-375/Jak2通路可能在胃癌的侵袭和转移过程中起重要作用，靶向三者的小分子抑制剂均可能会有效干预胃癌进程。本项目拟在胃癌中检测Snail和Jak2的蛋白表达，分析其与miR-375的表达水平及与胃癌病程进展的相关性；研究三者的相互调控关系及Snail/miR-375/Jak2通路对胃癌细胞侵袭和转移的影响；深入了解胃癌侵袭和转移分子机制的同时寻找胃癌早期诊断、预测预后的靶点，并为有效治疗胃癌提供新思路。

早期就发生局部侵袭和转移是胃癌的一个特点。前期研究提示Jak2在胃癌中表达增高，并与淋巴结转移相关。进一步研究提示Snail可能是Jak2调控因子miR-375的上游调控因子。我们的研究发现在胃癌中转录因子Snail表达异常增高，抑制miR-375的转录，致其表达降低，对其下游靶蛋白Jak2的负向调控减弱，导致Jak2表达增高，从而促进胃癌细胞的侵袭和转移。研究提示Snail/miR-375/Jak2通路可能在胃癌的侵袭和转移过程中起重要作用，靶向三者的小分子抑制剂均可能会有效干预胃癌进程。本项目在胃癌中检测Snail和Jak2的表达，发现其与miR-375的表达水平及与胃癌病程进展的相关；三者存在相互调控关系，Snail/miR-375/Jak2通路对胃癌细胞侵袭和转移的存在显著的影响；本研究的开展不仅深入了解胃癌侵袭和转移分子机制，同时为寻找胃癌早期诊断、预测预后的靶点提供了新思路。