探討高濃度葡萄糖在大腸直腸癌中透過MicroRNA-9負調控IGF1R/Src/ERK訊息路徑

High Glucose Concentrations Negatively Regulate the IGF1R/Src/ERK Axis through the MicroRNA-9 in Colorectal Cancer

陳雅均(Ya-Chun Chen)

指導教授 ： 李宗賢 ； 曾淑玲

中山醫學大學/醫學院/醫學研究所/博士(2020年)

https://doi.org/10.6834/CSMU202000013

摘要

根據研究顯示患有高血糖症的人罹患大腸直腸癌（Colorectal cancer; CRC）風險較高。高血糖可能提供大腸直腸癌細胞能量，進而促進癌細胞的生長。然而，這種促進生長作用分子機制仍不清楚。此外有研究指出microRNA-9（miR-9）在大腸直腸癌中具有腫瘤抑制的功能。miR-9表現異常降低可能由高濃度葡萄糖所致，並參與惡性腫瘤的發展和病程進展。本研究中，我們利用高濃度葡萄糖使大腸直腸癌細胞中的miR-9活性下降。我們的研究結果顯示，miR-9會降低胰島素樣生長因子-1受體（IGF1R）/Src訊息路徑和下游蛋白細胞週期Cyclin B1和N-cadherin表現，但E-cadherin蛋白表現是增加的。高濃度葡萄糖不僅會促進細胞增生、增加細胞週期G1期，還會調節上皮-間質轉化過程（EMT）蛋白表達和細胞形態，而且也會促進SW480（低轉移潛能）和SW620（高轉移潛能）的細胞轉移和侵襲能力。除此之外，低濃度葡萄糖可以逆轉回復SW480和SW620細胞在高濃度葡萄糖刺激下的機制。綜上所述，我們的結果證明高濃度葡萄糖可以調節大腸直腸癌中的多種信號傳導途徑，而且促進癌細胞的生長與轉移能力。我們建議血糖的控制可以作為大腸直腸癌臨床管理的潛在策略。

關鍵字

高濃度葡萄糖 ； microRNA-9 ； 大腸直腸癌 ； 胰島素類生長因子-1受體 ； Src ； 細胞外調節蛋白激酶（ERK1/2） ； 增生 ； 轉移 ； 上皮-間質轉化過程

並列摘要

Studies have revealed that people with hyperglycemia have a high risk of colorectal cancer（CRC）. Hyperglycemia may be responsible for supplying energy to CRC cells. However, the potential molecular mechanism for this association remains unclear. Furthermore, microRNA-9（miR-9）has a tumor-suppressive function in CRC. Aberrant reduced expression of miR-9 is involved in the development and progression of malignancy caused by a high glucose（HG）concentration. In this study, we used an HG concentration to activate miR-9 downregulation in CRC cells. Our results indicated that miR-9 decreased the insulin-like growth factor-1 receptor（IGF1R）/Src signaling pathway and downstream cyclin B1 and N-cadherin but upregulated E-cadherin. The HG concentration not only promoted cell proliferation, increased the G1 population, and modulated epithelial-to-mesenchymal transition （EMT）protein expression and morphology but also promoted the cell migration and invasion ability of SW480（low metastatic potential）and SW620（high metastatic potential）cells. In addition, low glucose concentrations could reverse the effect of the HG concentration in SW480 and SW620 cells. In conclusion, our results provide new evidence for multiple signaling pathways being regulated through HG concentration in CRC. We propose that blood sugar control may serve as a potential strategy for the clinical management of CRC.

並列關鍵字

High concentration of glucose ； microRNA-9 ； colorectal cancer ； insulin-like growth factor-1 receptor ； Src ； extracellular signal- regulated kinase (ERK1/2) ； proliferation ； metastasis ； epithelial to mesenchymal transition

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