2015-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/655470摘要：大腸直腸癌(colorectal cancer, CRC)為高致死率癌症之一，其五年存活率只有55 %，在臨床上， 大腸直腸癌預後差是因為容易侵襲鄰近組織，或轉移至其他器官。而且在我們之前「大腸直腸癌轉 移相關基因之功能並轉譯為基因署名以預測病人預後（98WFA0101435)」的研究中，發現 Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2)在早期和末期病人中有明顯表現 量的差異。HMGCS2為酮體生成路徑中速率決定步驟之酵素，此代謝途徑為葡萄糖缺乏時，利用 脂質代謝以產生能量；再加上先前的研究指出腫瘤與正常組織的代謝途徑有著明顯差異，因此推測 HMGCS2在腫瘤之進程中可能扮演重要角色。在本篇研究中，我們將探討HMGCS2是否參與腫瘤 進程及其分子訊息傳遞機制，首先，我們先利用real-time quantitative RT-PCR分析臨床CRC病人 的進程和HMGCS2之關聯性，接著，分析不同CRC細胞株的内生性HMGCS2表現量，以及是否 影響CRC的細胞移動力和生長速率。初步結果顯示HMGCS2的表現量與臨床上死亡率、淋巴轉 移或癌症分期高者呈現正相關，且HMGCS2與細胞移動力也呈現正相關，但仍需更進一步研究確 認是否此酮體生成的代謝路徑為一個潛在具有影響腫瘤進程的因素。<br> Abstract: Colorectal cancer (CRC) is one of the most common cancer and leading cancer-related death worldwide. The overall of 5-year survival rate is only about 55 %, the causing reasons of poor prognosis are known as the propensities of CRC invading to adjacent tissues or metastasizing to distant organs. In our previous study (Characterizing the Function of Metastasis-Associated Gene and Translating into Gene Signature for Survival Prediction in Colorectal Cancer, 98WFA0101435), we found the different expression levels of Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) between early and late stage CRC. HMGCS2 is the rate-limiting enzyme catalyzing the first reaction of ketogenesis, which provids lipid-derived energy (ketone bodies) for various organs during carbohydrate deprivation such as fasting. Besides, the previously studies have shown the fundamental differences in metabolic pathways between normal and malignant cells. Therefore, we speculate that HMGCS2 could play an important role in tumor progression. In this study, we are investigating whether HMGCS2 involve in tumor progression and evaluate the mechanisms of HMGCS2 in CRC progression. To examine the clinical relevance of HMGCS2 in CRC, its expression levels in patients’ specimens were analyzed by real-time quantitative RT-PCR. Moreover, we examined the correlection between HMGCS2 expression and cell motility or proliferation in CRC cells. Our preliminary data suggested that that elevated HMGCS2 levels were associated with advanced diseases and poor outcomes in CRC patients. The in vitro study also showed the expression levels of HMGCS2 were associated with cancer cells' abilities of invasion and migration. However, we still need to confirm whether and how ketogenesis involves in tumor progression in CRC.