細胞自噬現象藉由降解老化或損壞的胞器，將能量重新釋出以維持細胞的恆定。不規律的細胞自噬可能造成癌症產生。MicroRNAs (miRNAs)是一種非編碼的核醣核酸，可以影響基因的表現。MiRNA 在癌症的過程中扮演重要角色，並調控細胞增生，細胞週期，分化，轉移等等進而影響腫瘤生成。過去的研究著重關於miRNA如何調控細胞自噬反應，但在腫瘤生成過程之中較少研究細胞自噬反應如何調控miRNA。實驗室先前研究發現在誘發細胞自噬反應情況下，miR-449a 表現量最高；此外，在大腸直腸癌檢體中也發現，miR-449a與復發和轉移呈現負相關。利用Amiodarone(原抗心律不整藥物)為誘導劑誘發細胞自噬反應並伴隨miR-449a大量表現及抑制大腸癌細胞SW480之爬行，增生及腫瘤形成。上述結果顯示低落的細胞自噬反應及miRNA表現與大腸直腸癌之形成有關。本研究進一步了解細胞自噬正向調控miR-449a表現之機制。在72對大腸直腸癌病人檢體中，細胞自噬反應活性及miR-449a表現量均較低落，miR-449a 標的基因LEF-1的表現則相對較高。為了瞭解細胞自噬，miR-449a之間關係以及他們對於腫瘤生成之影響，我們以amiodarone誘導劑誘發大腸直腸癌細胞SW480細胞自噬反應及miR-449a表現。本研究發現細胞自噬藉轉錄因子FOXO1結合在啟動子上正向調控miR-449a之表現。Fukamizu et al.報導當FOXO1被p300蛋白乙醯化時，其與DNA結合的能力和轉錄活性會減少，並且p300的大量表現與大腸直腸癌預後不佳有關係。本研究發現誘發細胞自噬反應時p300的表現下降，因此我們推論在大腸直腸癌當中miR-449的表現低落是由於p300的大量表現並且乙醯化FOXO1，使得FOXO1轉錄因子無法進入細胞核中正向調控miR-449a表現。總結，本篇研究揭示大腸直腸癌中細胞自噬經由降解p300蛋白質促使轉錄因子FOXO1正向調控miR-449a之表達，因此影響標的基因LEF-1之表現，最後抑制癌症之進程。

Autophagy maintains cellular homeostasis through recruitment and degradation of accumulated and dysfunctional materials in the cell. Aberrant autophagy can cause diseases including tumorigenesis. MicroRNAs (miRNAs) are small non-coding RNAs that can regulate gene expression. MiRNAs play a key role in cancer progression and control cell proliferation, cell cycle, differentiation, metastasis et al to affect tumor growth. Recent studies focus on miRNA in regulation of autophagy processes. However, few studies focus on autophagy regulation of miRNAs, especially in tumorigenesis. We previously showed that miR-449a is the most up-regulated miRNA under autophagy induced conditions and the expression of miR-449a was inversely correlated with recurrence and metastasis of the colorectal cancers (CRC). Furthermore, amiodarone (an antiarrhythmic drug) induced autophagy up-regulates miR-449a to suppress the cell migration, invasion, proliferation, colony formation and tumor formation of CRC cells SW480. Above data indicate that reduced autophagy and miRNA contribute to the tumorigenesis of CRC. This study intends to the underlying mechanism of autophagy regulation of miR-449a. In 72 paired CRC patient specimens, the autophagy activity and miR-449a were lower in the tumor part. In addition, the target gene of miR-449a, LEF-1 was up-regulated in CRC. To clarify the relationship between autophagy and miR-449a and their effects on tumorigenesis, amiodarone, an antianginal and antiarrhythmic drug, was used to induce autophagy, and miR-449a expression was induced in colon cancer SW480 cells. Furthermore, we reveal that autophagy up-regulates miR-449a through FOXO1 at the transcription level and further down-regulates its target gene. Fukamizu et al. reported that p300-mediated acetylation of FOXO1 reduces its DNA-binding affinity and transcription activity, and overexpression p300 correlates with poor prognosis of colorectal cancer. Here, we demonstrated that autophagy may down-regulate the expression of p300 through a degradation pathway, indicating that miR-449a down expression in CRC may be regulated by overexpression of p300 which further acetylates FOXO1. In summary, our findings indicate that autophagy regulates miRNA expression through promoting its transcription and further affects its target gene in CRC.

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