口腔鱗狀細胞癌 (oral squamous cell carcinoma, OSCC) 是全球常見的癌症之一。癌轉移是造成癌症病患死亡最主要的原因，但現今對於轉移的機制仍未清楚。MicroRNAs (miRNAs) 是一小片段不進行轉錄的ribonucleic acid (RNA)，會負調控其目標基因並參與大部分的生物功能，但至今尚未清楚miRNAs在口腔癌轉移中扮演的角色。而我們初步的結果發現在OSCC中microRNA-320 (miR-320) 的表現量明顯下降，且與檳榔嚼食呈現負相關。miR-320的預測轉錄起始點座落於容易甲基化的CpG島，顯示miR-320的轉錄可能受到表觀修飾機制之調控。我們發現檳榔子萃取液會抑制人類口腔癌細胞human squamous cell carcinoma 3 (HSC3) 的miR-320，然而表觀修飾藥物 (epigenetic modifier drug)，5-aza-2'-deoxycytidine，無法促進miR-320表現，這表示deoxyribonucleic acid (DNA) 甲基化可能不調控miR-320的轉錄。此外，實驗室先前發現內皮細胞處於低氧及營養缺乏環境會影響miR-320表現，而本篇論文發現HSC3細胞處於低氧環境下也會抑制miR-320。由於過量表現miR-320會抑制口腔癌細胞的移行，因此我們利用complementary DNA (cDNA) 微陣列 (microarray) 技術找出兩個表現量下降並可能受miR-320調控的移行相關基因，分別是serum response factor (SRF) 與caveolin-1 (CAV1) 基因。實驗結果顯示miR-320會直接結合到SRF與CAV1的3端非轉譯區 (3’ untranslated region, 3’UTR) 並抑制基因的轉譯，並發現以RNA干擾技術降低SRF表現會明顯抑制OSCC細胞的移行，然而抑制CAV1表現對OSCC細胞移行的影響不一致。以上結果顯示miR-320藉由負調控SRF進而抑制口腔癌細胞的移行。我們的研究探討miRNAs影響口腔癌轉移的機制並提供標靶治療的新目標。

Oral squamous cell carcinoma (OSCC) is a common neoplasm worldwide. Metastasis is the most important contributing factor to oral cancer mortality; however, the mechanism of metastasis remained unclear. MicroRNAs (miRNAs) are small non-coding ribonucleic acids (RNAs) of ~22 nucleotides and negatively regulate their targets to play important role in a wide range of biological functions. The role of miRNAs in mediating oral cancer metastasis still remained largely unexplored. Our preliminary results indicated that the expression of microRNA-320 (miR-320) is significantly downregulated in OSCC and negatively correlated with betel nut chewing. A predicted miR-320 transcription start site is found to be located in a CpG island which has a high probability of deoxyribonucleic acid (DNA) methylation implied that the transcription of miR-320 might regulate by an epigenetic mechanism. In this study, we found that miR-320 does be down-regulated by an areca nut extract in human squamous cell carcinoma 3 (HSC3) OSCC cells. However, the epigenetic modifier drug, 5-aza-2'-deoxycytidine, did not reactivate miR-320 expression showing that DNA methylation might not involved in its transcriptional control. Besides, in our previous finding that hypoxia and nutrients deprivation contributed to the expression of miR-320 in endothelial cells. In this study, we found that miR-320 is also down-regulated in HSC3 cell in response to hypoxia. Furthermore, overexpression of miR-320 in oral cancer cells inhibited cell migration. Hence, we analyzed the migration-related genes regulated by miR-320 using complementary DNA (cDNA) microarray analyses, and found two particular genes, serum response factor (SRF) and caveolin-1 (CAV1), were down-regulated and might be miR-320 target genes. Our results showed that miR-320 directly targeted the 3’ untranslated region (3’UTR) of SRF and CAV1 and decreased their translational levels. By RNA interference approaches, we found that knockdown of SRF obviously reduced OSCC cell migration, but the effect of CAV1 silenced in cell migration is controversial. The results suggested that miR-320 inhibited oral cancer cell migration might via targeting and negatively regulating SRF. Our study explores how miRNAs influences oral cancer metastasis and provides new candidates for therapeutic targets.

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