遠端轉移是大腸直腸癌致死的首要原因。微核糖核酸是參與調控癌細胞增生、腫瘤侵犯及轉移的重要因子。從大腸直腸癌轉移組織中的篩選顯示，有大量miR-338-5p微核糖核酸的表現，而且phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) 可能是miR-338-5p調控細胞自噬作用的標靶基因之一。我們使用定量聚合酶連鎖反應，分析良性大腸直腸息肉及惡性直腸癌組織的miR-338-5p及其標靶基因的表現。使用小鼠脾臟注射動物模式，驗證miR-338-5p對於癌細胞轉移的重要性。本研究確認PIK3C3是miR-338-5p其中的一個標靶基因。在臨床檢體中的miR-338-5p表現，和腫瘤分期、遠端轉移、及病人存活率呈現正相關。組織中有較高miR-338-5p/PIK3C 3比值的病人，其術後的存活率也較差。以miR-338-5p穩定過度表現的細胞株進行動物實驗，證明過度表現miR-338-5p，會促進大腸直腸癌細胞轉移到小鼠的肝臟及肺臟，而且在轉移腫瘤中的PIK3C3表現的確也被抑制。我們也發現PIK3C3可以抑制轉移腫瘤的生長。透過試管中的實驗，發現miR-338-5p 透過抑制PIK3C3的表現，可以誘發細胞爬行及侵襲。經由正向及反向的方法，證明細胞自噬也參與miR-338-5p誘發大腸直腸癌細胞侵犯及轉移的過程。我們發現miR-338-5p也會抑制Sprouty 2 (SPRY2)的表現，因此推測 miR-338-5p還會透過細胞自噬機轉以外的其他訊息傳導路徑，來調控大腸直腸癌的腫瘤形成。我們的研究證明，miR-338-5p可以促進大腸直腸癌的細胞爬行、侵犯及轉移；而且PIK3C3相關的細胞自噬訊息傳導路徑是其中重要的機轉。PIK3C3是miR-338-5p調控大腸直腸癌轉移的重要標靶基因。miR-338-5p/PIK3C3的比值，可以成為評估大腸直腸癌病人預後的生物標記。

Tumor metastasis is the leading cause of cancer-related mortality in colorectal cancer (CRC). MicroRNAs (miRNAs) are epigenetic factors that regulate cell proliferation, invasion, and tumor metastasis. Our pilot study found that expression of miR-338-5p is significantly higher in primary CRCs with metastasis and phosphatidylinositol 3-kinase, catalytic subunit type 3 (PIK3C3) might be targeted by miR-338-5p. Here, we provide direct evidence that expression of miR-338-5p is positively related to tumor staging, distant metastasis and poor patient survival. PIK3C3 is one of the target genes of miR-338-5p. Patients with higher ratios of miR-338-5p/PIK3C3 in primary CRCs had an increased risk of poor overall survival. Over-expression of miR-338-5p promoted CRC metastasis to the liver and lung in a mouse spleen xenograft experiment, in which PIK3C3 was down-regulated in the metastatic tumors. In contrast, overexpression of PIK3C3 in miR-338-5p stable cells inhibited the growth of metastatic tumors. Both migration and invasion of CRC in vitro induced by miR-338-5p are mediated by suppression of PIK3C3. Using forward and reverse approaches, autophagy was proved to involve in CRC migration and invasion induced by miR-338-5p. Additionally, SPRY2 was suppressed by overexpression of miR-338-5p in CRC cells. In addition, autophagy-independent pathway (e.g. SPRY2-related signaling) might also play a role in the miR-338-5p-related CRC tumorigenesis. Taken together, miR-338-5p induces migration, invasion and metastasis of CRC, in part through PIK3C3-related autophagy pathway. The miR-338-5p/PIK3C3 ratio may become a prognostic biomarker for CRC patients.

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