臺灣博碩士論文加值系統

在許多人類之癌症例如前列腺癌、胃癌及大腸癌，其癌前病灶中常見有α-甲基醯基輔酶A消旋酶(Alpha-methyacyl-CoA racemase, AMACR)出現提高的現象，尤其在人類前列腺癌，其過度表現更成為診斷用標記。在本研究中，我們以免疫組織化學染色法分析AMACR在89例膽囊癌檢體中表現情況，結果顯示AMACR的表現量，與許多不利預後的臨床病理參數有顯著相關，由單一變項分析顯示，病患的預後與病患年齡的增加、原發腫瘤的狀態、腫瘤分期、出現血管侵犯及AMACR的過度表現有顯著相關(p < 0.05)；而多變項分析更證實腫瘤分期、病患年齡的增加及AMACR的過度表現，為預後的獨立因素(p < 0.05)。以西方墨點法比較AMACR在三種不同膽囊上皮細胞株的表現，結果具轉移性的膽囊癌上皮細胞株RCB1129，其AMACR的表現較正常的膽管上皮細胞株MMNK-1及具局部侵犯性的膽囊癌上皮細胞株RCB1130有顯著的增加。利用XTT分析法來探討AMACR 抑制劑2-trifluoromethyltetradecanoic acid，對於人類的膽囊上皮細胞株之細胞毒性。結果發現AMACR 抑制劑對MMNK-1的細胞毒性較小，但對RCB1129與RCB1130之細胞毒性會隨劑量的增加而增加(p < 0.05)。本研究證實了AMACR在臨床上的重要性，它不止能作為預測膽囊癌病患的預後指標，加上目前已知AMACR基因缺乏，並無致命的臨床表徵，因此未來可能更可以利用針對AMACR蛋白來進行標的治療。

Alpha-methyacyl-CoA racemase (AMACR) is a critical peroxisomal and mitochondrial enzyme, encodes a key enzyme in the catabolism of long-chain fatty acid thus is indispensable in the β-oxidation of fatty acid to generate biological energy. AMACR stands in many organs with only very low expression level and its overexpression is exclusively in neoplastic conditions. Recently, AMACR overexpresison has been discerned to relevant to tumor progression of prostate, gastric, and colon cancers, and its overexpression has now been introduced in pathological differential diagnosis of prostate carcinoma from non-malignant mimickers. By using 89 gallbladder carcinoma (GBCA) samples for AMACR immunostaining we found AMACR overexpression is frequently discerned in GBCA. It not only significantly correlates with numerous adverse clinicopathologic factors but also manifests a significant independent predictor of worse outcome in GBCA patients. In multivariate comparison, higher tumor stage represented the strongest prognosticator (p = 0.0101), followed by old patient age (p = 0.0378). Moreover, AMACR overexpression also identified patients at around 2-fold higher risk of disease-specific death (p = 0.0452). By Western blot analyses, we found AMACR expression in the metastatic cells, RCB1129, was apparently more abundant than that in its primary lesion RCB1130. By XTT analyses, the viability of both RCB1129 and RCB1130 cells were significantly decreased by AMACR inhibitor. The RCB1129 cell line, with more abundant AMACR protein expression, was more resistant to AMACR inhibitor treatment than RCB1130 cell line at various drug concentrations. Our data suggest AMACR is a prognostic marker that can serve as a promising therapeutic target in gallbladder cancer.

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