研究積雪草酸抑制人類腎臟癌細胞轉移之分子機轉

Research on molecular mechanism of Asiatic acid inhibiting metastasis in human renal cancer cells

楊仁德(Jen-Te Yang)

指導教授 ： 謝逸憲博士

中山醫學大學/醫學院/醫學研究所 (原生化微生物免疫研究所)/碩士(2021年)

https://doi.org/10.6834/csmu202100122

摘要

腎細胞癌（Renal cell carcinoma, RCC）是衍生自近端小管的上皮細胞的惡性腫瘤，也是成年人中最常見的腎臟癌，約占70~80％。通常發現症狀時表示腫瘤細胞已經侵犯到鄰近的器官或已有遠端轉移。積雪草酸（AA）是從Centella Asiatica中分離出的且是一種存在於自然界植物中五環三萜類天然化合物，積雪草酸已經被證明具有抗腫瘤功能。然而，積雪草酸對於腎臟癌細胞仍然不清楚其抗癌效果和機制。因此，我們探討積雪草酸抗腎臟癌細胞抗腫瘤活性和分子機制。我們的研究結果說明積雪草酸並不會抑制腎臟癌細胞的生長、增生和細胞週期分佈。利用細胞移動和侵襲實驗說明積雪草酸抑制腎臟癌細胞的遷移和侵襲能力，同時也會抑制MMP-15的蛋白質和mRNA表現，但不影響MMP-2、MMP-7、MMP-9的表現。此外我們發現積雪草酸會抑制ERK1/2和 p38MAPK活化路徑，利用siRNA-ERK或siRNA-p38MAPK合併積雪草酸會更顯著協同減少786-O細胞內MMP15蛋白表現及抑制移動和侵襲作用。綜合以上研究說明，積雪草酸減少ERK/p38MAPK活化路徑，進而抑制MMP15表現來達到抑制腎臟癌細胞的移動和侵襲作用。未來需要進一步研究積雪草酸當作腎臟癌細胞具潛力的抗轉移試劑。

關鍵字

腎臟 ； 積雪草酸 ； 癌 ； 抑制人類腎臟癌細胞轉移 ； 分子機轉

並列摘要

Renal cell carcinoma (RCC) is a malignant tumor derived from epithelial cells of the proximal tubule and the most common type of kidney cancer in adults, responsible for approximately 70~80 % of the patients. As symptoms occur, RCC tumor cells have invaded neighboring organs or distant metastases. Asiatic acid (AA) is a natural pentacyclic triterpene isolated from Centella Asiatica that has demonstrated possesses potential health benefits and significant antitumor activities. However, the precise anticancer effects and mechanisms by which AA impact RCC cells remain unclear. Therefore, we explored the anti-tumor activity and molecular mechanism of AA in RCC cells. Our findings indicated cell viability and cell cycle distribution of RCC cells were not significantly influenced by AA treatment. AA inhibited migration and invasion of RCC cells and significantly down-regulated mRNA and protein expression of MMP-15 in a dose-dependent manner, but not affected the expression of MMP-2, MMP-7 and MMP-9. Extracellular signal-regulated protein kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38MAPK) activation were inhibited with AA, whereas combined AA with siRNA-ERK or siRNA-p38MAPK synergically reduced the migratory and invasive ability of 786‐O and A‐498 cells and decreased MMP-15 expression. In conclusion, AA inhibits the metastatic properties of RCC cells via inhibition of the p-ERK/p-p38MAPK axis and the subsequent down-regulation of MMP-15. Further study of AA as a potential anti-metastatic agent for RCC is warranted.

並列關鍵字

renal ； Asiatic acid ； cancer ； inhibiting metastasis in human renal cancer cells ； molecular mechanism

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