MicroRNA是近年來重要的發現，調控許多基因，異常表現可能導致癌症。在各類型癌症中，包括大腸直腸癌，已知microRNA-137 (miR-137) 都是扮演腫瘤抑制因子的角色;但是，miR-137在大腸直腸癌中所參與的功能，或為早期癌症病人治療和預後的生物指標仍未被探究。在本研究中，我們證實了人類大腸直腸癌組織和大腸瘜肉中miR-137都不表現，是由於其啟動子區被甲基化所致。我們發現大腸直腸癌的癌化過程中，Aurora-A， PTGS2， CDK6 和 CDC42這些致癌基因參與其中，皆為miR-137的目標基因。大量表現 miR-137，使得Aurora-A， PTGS2， CDK6 和 CDC42的mRNA，protein以及luciferase activity表現量皆下降。分析人類大腸直腸癌和瘜肉檢體，發現Aurora-A或 PTGS2的表現，與miR-137的表現，呈現負相關。重要的是，miR-137在不同類型的大腸瘜肉中表現量下降的不同，與造成後續癌症的產生具有潛在意義。藉由receiver operating characteristic (ROC)曲線分析，大腸瘜肉檢體miR-137的表現量下降與Aurora-A或 PTGS2的過量表現，可作為預測是否罹患大腸直腸癌的生物指標。在大腸直腸癌細胞株中大量表現miR-137，會抑制細胞生長，箝制在G2/M期，最後造成細胞凋亡；這些現象皆可再以外送大量表現Aurora-A而中止。異體移植動物模式中，也證實了miR-137大量表現時會抑制腫瘤生長，使癌細胞走向凋亡。在Azoxymethane/ dextran sodium sulfate (AOM/DSS)小鼠大腸直腸癌模式中，我們也發現以甲基轉移酶抑制劑Decitabine治療，可抑制腫瘤產生和浸潤。由我們的研究得知，大腸瘜肉中miR-137表現量下降的情況可作為早期預測是否罹患大腸直腸癌的生物指標。miR-137抑制Aurora-A的調控機制可作為大腸直腸癌的早期預測或未來癌症治療的新亮點。

MicroRNAs constitute a new class of gene expression regulators that express aberrantly in cancer. MiR-137 acts as a tumor suppressor in many kinds of cancers, including colorectal cancer (CRC). However, the functional roles of miR-137 and its possibility to serve as a biomarker for clinical outcome in CRC remain largely unclear. Our study indicated that miR-137 silences in human CRC tissues and colon polyps owing to the methylation of the miR-137 promoter region. Several oncogenes involved in the carcinogenesis of CRC, including Aurora-A, PTGS2, CDK6 and CDC42, are the targets of miR-137. The expression pattern of miR-137 and Aurora-A or PTGS2 is negatively correlated in human CRC tissues and colon polyps. Importantly, the decreased expression level of miR-137 is significantly different in various types of polyps that maintain different potentials to lead to the development of CRC. In a receiver operating characteristic (ROC) curve analysis, loss of miR-137 expression as well as overexpressed Aurora-A or PTGS2 in colon polyps can serve as a biomarker to predict a predisposition for colorectal carcinogenesis. Enforcing expression of miR-137 in CRC cells and in a xenograft animal model can result in the reduction of cell proliferation and tumor formation, G2/M arrest, and finally lead to apoptosis. Additionally, Azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC can be restored by Decitabine treatment. Taken together, our study suggests that epigenetic silencing of miR-137 in colon polyps can serve as a biomarker to predict a tendency towards CRC formation through the impaired inhibitory effect of Aurora-A. The investigation of the regulatory mechanism of miR-137-mediated Aurora-A inhibition may shed new light on early prognosis or cancer therapy for CRC in the future.

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