STAT3調控EZH2表現進而影響口腔癌的轉移

STAT3-mediated EZH2 expression modulates migration and invasion of oral cancer

林孟瑾

口腔癌 ； 轉移 ； EZH2 ； oral cancer ； STAT3 ； ADAMTS1 ； MMP3 ； metastasis

清華大學分子醫學研究所學位論文

2016年

碩士

陳令儀

英文

口腔癌是頭頸癌的一種，百分之九十以上的口腔癌屬於口腔鱗狀上皮細胞癌。在過去十年間，口腔癌在台灣的死亡率已經上升到第五名，因此口腔癌的研究便顯得非常重要。口腔癌的轉移通常發生在病程的中後期，同時也是它致死的原因。現今，治療口腔癌的方法主要是透過手術切除大部分的癌症，再利用化療以及放射線治療等方式，移除手術後所遺留下來的癌細胞。但是，許多惡性轉移的口腔癌患者在接受治療後，常常會有復發的情形發生。因此，避免口腔癌的轉移便可以作為一種減少患者復發的方法。我們致力於研究口腔癌細胞可能的轉移機制，希望可以降低口腔癌病患復發的風險。在這篇論文中，我們使用了由原位癌分離培養的口腔癌細胞株 (OC3 cells) 以及經篩選後轉移能力較強的細胞株 (IV2 cells)，來探討惡性口腔癌細胞轉移的機制。研究結果顯示，EZH2這個組蛋白甲基轉移酶，在轉移能力較強的IV2 細胞中是下降的。而EZH2的下降會透過甲基化H3K27而增加ADAMTS1、MMP3、ROS1、CXCL1以及GLI1基因的表現，進而增強IV2細胞的轉移能力。同時，我也證實了轉錄因子STAT3為EZH2的上游，它會藉由調控上述的機制而提升IV2細胞的轉移能力。此外，在IV2細胞中IL8訊號以及STAT3間具有反饋迴路 (feedback loop)，互相調控彼此。總結此篇論文研究結果，EZH2在口腔癌中可以藉由調控轉移相關的基因，而扮演一個抑制腫瘤生長的角色。

The cancer mortality rate of oral cancer has risen from the sixth to the fifth place in the past decade in Taiwan. More than 90% of oral cancers are oral squamous cell carcinomas (OSCC). Currently, patients with malignant oral cancer are treated with surgery to remove a large proportion of tumor, followed by radiation therapy or chemotherapy to destroy any remaining cancer cells. However, many patients developed recurrence after treatment, especially for those who suffered from lymphatic metastasis and distant metastasis. Thus, preventing metastasis is a way to reduce recurrence. In this thesis, we investigated the possible mechanism that promotes metastasis of OSCC. To this end, we used an OSCC cell line, OC3, which was derived from a betel nut-chewing oral cancer patient, and a more invasive line, IV2, to study the mechanism of OSCC invasion. We found that the expression of EZH2, a histone methyltransferase responsible for tri-methylation of histone H3 at lysine 27 (H3K27me3), was lower in the more invasive IV2 cells compared to that in OC3 cells. Consistent with this finding, knocking down EZH2 in OC3 cells enhanced migration and invasion. Several target genes of EZH2 have been identified, including ADAMTS1, MMP3, ROS1, CXCL1 and GLI1. To determine what leads to reduced EZH2 in IV2 cells, chromatin immunoprecipitation (ChIP) analysis suggests the involvement of STAT3 in the transcriptional expression of EZH2. In fact, STAT3 level was reduced in IV2 cells compared to OC3 cells. Knocking down STAT3 or inhibiting STAT3 decreased EZH2 expression and increased EZH2 target genes, ADAMTS1, ROS1, CXCL1 and GLI1, to regulate cell migration, invasion and proliferation. We also determined the feedback regulation between STAT3 and IL8 signaling, an upstream of STAT3. Taken together, these findings implicate that EZH2 may serve as a tumor suppressor by inhibiting metastasis-related genes in OSCC cells.

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