腫瘤微環境中麩醯胺酸耗竭對大腸直腸癌 癌症惡病質的影響;The effect of glutamine depletion in the tumor microenvironment on cancer cachexia in colorectal cancer

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题名:	腫瘤微環境中麩醯胺酸耗竭對大腸直腸癌癌症惡病質的影響;The effect of glutamine depletion in the tumor microenvironment on cancer cachexia in colorectal cancer
作者:	郭蕙瑄;Kuo, Hui-Hsuan
贡献者:	生命科學系
关键词:	癌症惡病質;麩醯胺酸;腫瘤微環境;cancer cachexia;glutamine;tumor microenvironment
日期:	2025-03-27
上传时间:	2025-04-09 16:09:46 (UTC+8)
出版者:	國立中央大學
摘要:	約有60%的大腸直腸癌(Colorectal cancer , CRC)患者受到癌症惡病質(Cancer Cachexia)的影響，且為約30%患者死亡的直接原因。研究指出，與正常組織相比，腫瘤微環境中麩醯胺酸的濃度相對低下，然而，關於腫瘤微環境麩醯胺酸缺乏與大腸直腸癌引發癌症惡病質的相關研究仍有限。因此，本研究旨在於探討在麩醯胺酸匱乏條件下的大腸直腸癌細胞分泌的因子對於C2C12肌肉細胞的影響和其分子機制。研究結果顯示，人類大腸直腸癌HCT116和SW620細胞分泌的因子均可誘導C2C12肌管萎縮，且促進麩醯胺酸合成酶與胺基酸轉運蛋白mRNA表達上調，推測進而調控肌肉細胞麩醯胺酸的代謝。進一步分析發現，在麩醯胺酸匱乏下，HCT116細胞分泌因子會加劇C2C12肌肉細胞萎縮，並顯著抑制C2C12肌肉細胞分化成肌管，同時更加上調C2C12肌肉細胞中麩醯胺酸合成酶mRNA表達，推測可促進麩醯胺酸的合成。IL-6白血球介素為一種可誘發惡病質的細胞分泌分子。本研究發現，在麩醯胺酸匱乏下的HCT116細胞中，IL-6 mRNA表現量上升，推測IL-6蛋白質分泌量亦會上調。綜合以上，我們推測，大腸直腸癌細胞於麩醯胺酸缺乏下，可能藉由釋放IL-6來促進肌肉中的蛋白水解與加強麩醯胺酸合成，導致釋放更多的麩醯胺酸以供應癌細胞使用。;Approximately 60% of colorectal cancer (CRC) patients experience cancer cachexia, which directly contributes to mortality in about 30% of cases. Studies have shown that glutamine levels in the tumor microenvironment are relatively low compared to normal tissues. However, research on the relationship between glutamine deficiency in the tumor microenvironment and CRC-induced cancer cachexia remains limited. Therefore, this study aims to investigate the effects of factors secreted by CRC cells under glutamine-deficient conditions on C2C12 muscle cells and the underlying molecular mechanisms. Our results demonstrate that factors secreted by human CRC cell lines HCT116 and SW620 induce atrophy in C2C12 myotubes and upregulate their mRNA expression of glutamine synthetase, suggesting a potential regulatory role in muscle cell glutamine metabolism. Further analysis revealed that under glutamine-deficient conditions, factors secreted by HCT116 cells exacerbate C2C12 muscle atrophy and significantly inhibit C2C12 myogenic differentiation, while further increasing the mRNA expression of glutamine synthetase in C2C12 muscle cells, potentially enhancing glutamine synthesis. Interleukin-6 (IL-6) is a cytokine known to induce cachexia. In this study, we found that IL-6 mRNA expression was upregulated in glutamine-deprived HCT116 cells, suggesting that IL-6 protein secretion may also be upregulated. In summary, our findings indicate that under glutamine-deficient conditions, CRC cells may promote protein degradation and enhance glutamine synthesis in muscle cells through IL-6 secretion, leading to increased glutamine release to support cancer cell metabolism.
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