miR-486對鼻咽癌的發生所扮演之功能角色

Abstract

相較於其他癌症，鼻咽癌具有相當高的「地區性」，盛行於中國大陸東南沿海、香港、新加坡、台灣等地，其致病機轉相當複雜。雖然診斷及治療方法不斷進步，但因其發病部位較為隱密，待病患查覺異狀至確診，往往已是晚期，使得預後不良。近期有研究指出Epstein-Barr virus (EBV)與鼻咽癌的惡化有關。在本次研究中發現鼻咽癌細胞株經異體移植(xenografts)得到的同源亞細胞株(sub-cell line)，其腫瘤生長力(tumorgenesis)遠大於原細胞株。分析兩細胞株的表現和細胞行為，可得知鼻咽癌亞細胞株在細胞增殖(proliferation)及細胞侵犯(invasion)上具有較強勢的作用。已知microRNA可調控細胞的基因表現，比較兩種細胞株發現在亞細胞株中之hsa-miR-486表現量明顯較高。經由RNA微陣列分析(RNA microarray analysis)發現Reversion-inducing-cysteine-rich protein with kazal motifs (RECK)腫瘤抑制基因會受到miR-486的調節。我們找到RECK基因上miR-486的結合位，將建構好具有miR-486結合位的RECK基因mRNA片斷載體轉染入此二細胞株中，以觀察其對腫瘤發生的能力，並同時進行老鼠活體試驗，從而證實miR-486可抑制RECK基因造成鼻咽癌細胞的腫瘤發生。RECK基因可調控鼻咽癌之生長在之前的SXO-5基因表達之研究中已發現，但與miR-486之關係在鼻咽癌的進展中未曾被發現過，在未來研發中可預期其可能作為分子標靶之治療。

To compare with other cancer disease, nasopharyngeal carcinoma (NPC) often occurs in local region, such as in the southeast coast of the mainland China , Hong Kong, Singapore , and Taiwan. Its pathogenesis is quite complex. Despite advances in diagnosis and treatment , and because of the incidence of the more intimate parts , the abnormal symptoms in patients with perceptible to the diagnosis often is late, resulting in a poor prognosis . Recent researches have pointed out that Epstein-Barr virus (EBV) is one of the reasons that cause nasopharyngeal carcinoma progression. In our laboratory study, we have established a NPC sub-line from one NPC line which was produced from the NPC xenografts. This sub-line showed a higher capacity to induce tumor progression. Analysis of the behavior and phenotype of the original and sub-line showed that NPC sub-line had more higher potential to proliferation, and invasion. Since microRNA can regulate gene expression, we found that the expression of miR-486 has significantly higher in the sub-line. Via RNA microarray analysis of over expressed miR-486, we found that reversion-inducing-cysteine-rich protein with kazal motifs (RECK) gene (a metastasis suppressor) was down regulated by miR-486. Since we have identified that miR-486 binding site presented in RECK gene, therefor we constructed the specific vector expression to transfect in those two cell line. Results showed that miR-486 can regulate RECK gene in two transfected cell lines. At the same time, we have also confirmed the identical results in the in vivo experiment. This is a new finding that RECK gene can regulate NPC progression through miR-486 transfection. In the future for development of NPC treatment, miR-486 may be used as a molecular targeted therapy.