大麻素通过AKT,TIMP-1抑制胃癌细胞侵袭转移的作用机制

Gastric cancer is one of the most common malignant tumors. Systemic chemotherapy usually results in resistance arising in gastric cancer cells, which is associated with poor prognosis.Therefore,ovel targets are necessary for the treatment of gastric cancers. Although cannabinoids are associated with antineoplastic activity in a number of cancer cell types, the effect in gastric cancer cells has not been clarified. We have reported previously that treatment of gastric cancer cells with cannabinoids significantly decreased cell proliferation and induced apoptosis, furthermore, cannabinoids treatment inhibited the cell proliferation and induced apoptosis of 5-fluorouracil(5-FU)-resistant human gastric cancer cell.In the present study, we investigate the effects of cannabinoids on gastric cancer invasion invitro and invivo,and improve the molecular mechanism.Here, we suppose that cannabinoids treatment inhibits the invasion of gastric cancer cells by upregulating E-cadherin and decreasing Snail,Slug,through AKT pathway, and upregulating TIMP-1.Our study will enrich and improve the molecular pathogenesis of cannabinoids effect in gastric cancer cells,and would supply new targets or ideas for preventing and treating this disease.

胃癌是最常见的恶性肿瘤之一，临床上应用多种化疗药物，但目前对进展期胃癌的治疗仍然没有达到理想的效果。因此，寻找一种新的抗癌药物成为目前胃癌研究的一个重要课题。越来越多的研究证实大麻素对多种恶性肿瘤细胞有抑制作用，但其对胃癌作用的研究甚少。我们前期研究已证实大麻素能抑制胃癌细胞增殖、诱导细胞凋亡，并且对5-氟尿嘧啶耐药的胃癌细胞增殖有显著抑制效果。本课题从细胞传导路径入手，通过细胞模型及动物模型，对大麻素抑制胃癌浸润转移的作用及分子机制进行深入研究，并首次探讨大麻素对胃癌浸润转移的作用及分子机制。我们提出大麻素通过上调E-cadherin表达及下调Snail、Slug表达，其作用通过AKT调控；并且通过上调TIMP-1表达达到抑制胃癌细胞侵袭转移能力的重要机制的假设。本课题将充实并完善大麻素治疗胃癌的作用及分子机制，为胃癌的临床治疗探索新的途径。

近年来，大麻素(大麻的活性成分)及其衍生物由于可以影响肿瘤的生长、迁移和转移而引起人们相当大的研究兴趣。先前的研究表明，大麻素激动剂WIN 55,212-2 (WIN) 与胃癌(GC)转移有关，但其机制尚不清楚。在本研究中，我们发现， WIN可以抑制GC细胞的迁移、侵袭和上皮间质转化(EMT)。在胃癌SGC7901细胞中，我们发现WIN处理引起了环氧合酶-2 (COX-2)表达下调，降低AKT的磷酸化，并且抑制EMT。WIN引起的COX-2和波形蛋白表达的降低以及上皮细胞钙粘蛋白表达的增加，可以通过过表达AKT可以恢复他们的表达，结果提示AKT至少在部分上介导了WIN抑制GC细胞EMT。综上所述，这些结果表明，WIN可以通过COX-2的下调抑制GC细胞的EMT。