甲基轉移酶PRMT3在大腸癌細胞惡化及侵襲移動能力中所扮演的角色

Role of protein arginine methyltransferase 3 in colorectal cancer cell invasion and progression

林苡勤(Yi-Chin Lin)

指導教授 ： 李明學

共同指導教授 ： 張富雄

國立臺灣大學/醫學院/生物化學暨分子生物學研究所/碩士(2019年)

https://doi.org/10.6342/NTU201903979

摘要

大腸直腸癌是現今世界各地常見的癌症，其癌症致死率高居第三名。在台灣，國人的大腸直腸癌發生率在十大癌症中排名第三名。雖然目前在大腸直腸癌的治療上已有許多突破，但在對於癌症發生轉移的病人身上，其死亡率仍是高居不下，五年存活率僅有一成。近年來的研究發現，甲基化修飾和大腸直腸癌疾病的進程有密切的關係。在本篇研究中，我探討精胺酸甲基轉移酶和大腸直腸癌惡化的關係。根據公開的資料庫，透過生物資訊的分析和統計，發現精胺酸甲基轉移酶2、精胺酸甲基轉移酶3、精胺酸甲基轉移酶5的基因表達量和大腸直腸癌病人的存活率有著高度的相關性。在這三個基因中，更進一步發現精胺酸甲基轉移酶3的基因表達量隨著癌症越惡化，其基因表現量也隨著下降。此外，在細胞實驗中也發現，當精胺酸甲基轉移酶3的表現量下降時，大腸直腸癌細胞的細胞移動能力增強，接著發現，絲胺酸蛋白酶抑制劑可以抑制精胺酸甲基轉移酶3基因低表現的癌細胞的侵襲能力。並進一步用人類蛋白質水解酵素晶片來分析，發現精胺酸甲基轉移酶3低表現的細胞中激肽釋放酶5的表現量顯著的上升。總結來說，精胺酸甲基轉移酶3在大腸直腸癌發展的過程中，透過調控激肽釋放酶5此酵素，扮演抑制癌症惡化的角色。

關鍵字

大腸直腸癌 ； 精胺酸甲基轉移酶3 ； 侵襲能力 ； 激肽釋放酶5 ； 甲基化修飾

並列摘要

Colorectal cancer is one of the most common cancers and the third leading cause of cancer-related mortality in Taiwan and worldwide. Although cancer therapies have been improved, the mortality of metastatic colorectal cancer patients still remains high. The epigenetic modification of methylation has been proposed to be involved in colorectal cancer development and progression and arginine methylation is a newly identified mechanism for post translation modification. In this study, I analyzed if there was an alteration of a protein arginine methyltransferase (PRMT) in human colorectal cancer. According to a public database, the bioinformatics analysis showed that the alterations of the PRMT2, PRMT3 and PRMT5 gene expression levels were correlated with the survival rates of colorectal cancer patients. Among these three genes, I further found that the expression levels of PRMT3 were decreased in the colorectal cancer cells isolated from Dukes’ D, compared to those cells from Dukes’ B and C. Moreover, PRMT3 silencing increased colorectal DLD-1 and HCT116 cancer cell invasion. The PRMT3 knockdown-induced colorectal cancer cell invasion was able to be inhibited by a broad serine protease inhibitor, suggesting a serine protease is involved in PRMT3 signaling of colorectal cancer cells. Moreover, I used a protease array analysis and found that the expression levels of kallikrein 5 were dramatically increased in PRMT3 silencing colorectal cancer cells. The results together indicate that PRMT3 plays a suppression role in colorectal cancer cell invasion and kallikerin 5 may be involved in PRMT3-mediated colorectal cancer progression.

並列關鍵字

Colorectal cancer ； PRMT3 ； Cell invasion ； KLK5 ； methylation

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