桑辛素透過ERK途徑調控人類鼻咽癌基質金屬蛋白水解酶-2的表現及細胞移行與侵犯

Regulation of MMP-2 expression and cell migration and invasion by morusin through ERK signaling in human nasopharyngeal carcinoma

黃承楨(Cheng-Chen Huang)

指導教授 ： 王博輝

中山醫學大學/醫學院/醫學研究所/博士(2022年)

https://doi.org/10.6834/csmu202200209

摘要

鼻咽癌為一地區性常見的癌症，好發在中國南方或是東南亞地區。放射線治療對於鼻咽癌是非常有效的。然而，淋巴轉移或遠端轉移依然臨床治療失敗的主因。桑辛素(Morusin)是一種天然化合物，被證明對乳癌、前列腺癌、和大腸直腸癌具有抗癌作用。然而，目前並無相關文獻探討桑辛素是否具有對抗鼻咽癌作用以及其涉及之機制。本研究利用細胞毒性試驗、傷口癒合試驗、細胞移行及侵犯試驗，觀察桑辛素對於三株鼻咽癌細胞株其細胞毒性及細胞移行及侵犯的能力。並利用明膠蛋白酵素電泳法測定基質金屬蛋白水解酶-2 (Matrix Metalloproteinase-2; MMP-2)活性及利用西方墨點法測定相關的訊息傳遞蛋白路徑。結果顯示，桑辛素在不同的試驗中有效抑制鼻咽癌的移行及侵犯。此外，桑辛素有效抑制MMP-2活性及蛋白表現。桑辛素具有抑制鼻咽癌細胞extracellular signal-regulated kinase 1/2 (ERK1/2) 磷酸化的能力。然而，對於其他AKT, p38, c-Jun N-treminal kinase 1/2 (JNK1/2) 磷酸化能力並無影響。另外，合併處理桑辛素及ERK抑制劑(U0126)可以增加抑制MMP-2活性及鼻咽癌細胞移行能力。綜上所述，本研究顯示在人類鼻咽癌細胞中觀察到桑辛素能有效抑制鼻咽癌的移行及侵犯，其中機制為透過ERK1/2途徑抑制MMP-2表現。桑辛素對於鼻咽癌患者可能是一個有潛力之抗癌物質。

關鍵字

桑辛素 ； 鼻咽癌 ； 轉移 ； 基質金屬蛋白水解酶-2

並列摘要

Nasopharyngeal carcinoma (NPC) is endemic in Southern China and Southeast Asia. Radiation therapy revealed excellent results. However, lymph node metastasis or distant metastasis remains the main clinical treatment failure. Morusin is a natural chemotherapeutic agent in many human cancers such as breast cancer, prostate cancer and colorectal cancer. However, the effect and underlying mechanism of morusin in NPC are still unclear. In this study, cell cytotoxicity assay, wound healing assay, cell migration and invasion assays were performed. Gelatin zymography was used to determine the activities of Matrix Metalloproteinase-2 (MMP-2). MAPK pathway were investigated by Western blotting assay. The result showed that morusin can inhibit the migration and invasion in the different assays. Morusin could reduce the MMP-2 activity and expression in NPC cell lines. Morusin significantly inhibited the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the NPC cell line, while no effect on the phosphorylation of AKT, p38, and c-Jun N-treminal kinase 1/2 (JNK1/2) was measured. Furthermore, the combination treatment of morusin and U0126 resulted in the intense inhibition of the MMP-2 activity and cell migratory ability. In conclusion, our study demonstrated that morusin inhibits the migration and invasion activity of human NPC cells by suppressing the expression and activity of MMP-2 by downregulating the ERK1/ 2 signaling pathway. Morusin can exert inhibitory effects on NPC metastasis and may be a potential chemotherapeutic agent for patients with NPC.

並列關鍵字

morusin ； nasopharyngeal carcinoma ； metastasis ； matrix Metalloproteinase-2

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