以KMO作為診斷犬乳腺腫瘤及評估預後的生物性標誌

Abstract

腫瘤生物標誌為評估腫瘤狀態及臨床預後情況的指標分子。由於大部分的生物標誌與腫瘤生長有密切的關係，因此可用來監測腫瘤的發展或開發有效的治療方法。第二型類表皮生長因子的受體(human epidermal growth factor receptor 2) ，動情素受體(estrogen receptor)及黃體素受體(progesterone receptor)是目前常用於診斷人類乳癌的生物標誌。相較於此，犬乳腺腫瘤則缺乏有效的生物標誌協助腫瘤診斷及治療。在我們先前的研究發現，參與在色胺酸(Trytophan)代謝途徑中的酵素，尿胺酸-3-單氧脢(kynurenine 3-monooxygenase, kmo)，其基因的表現量可用來評估腫瘤惡性及病畜的預後情形。為了進一步確認KMO在臨床腫瘤診斷上的應用性，我們自國立臺灣大學生農學院附設動物醫院收集54例犬乳腺腫瘤，其中包含29例良性及25例惡性病例。並以免疫化學組織染色研究KMO蛋白質的表現量是否和該腫瘤的各項臨床特性相關。分析結果顯示，有73.3%的惡性犬乳腺腫瘤具有KMO蛋白質高度表現的情況。相較於無KMO或KMO蛋白質低度表現的犬乳腺腫瘤，具有KMO蛋白質高度表現的腫瘤，其病畜術後的存活時間顯著較短(P<0.001)。除了KMO外，HER-2蛋白質的過量表現也和腫瘤大小及臨床上的惡性分級相關(P<0.05)。此外， KMO和Ki-67的蛋白質表現量有正相關性，顯示KMO可能藉由促進細胞的增生使腫瘤更加惡性。此篇研究顯示KMO可作為診斷腫瘤惡性及評估病畜預後狀況的生物標誌，並且提供了開發犬乳腺腫瘤療法的新標的。

Tumor biomarkers are developed to indicate tumor status, clinical outcome or prognosis. Due to the involvement in tumor progression, most biomarkers are often used to monitor tumor development or exploit treatments for patients. Human epidermal growth factor receptor 2 (HER-2), estrogen receptor (ER) and progesterone receptor (PR) are known authentic biomarkers applied for routine examinations for human breast cancer; however, compared to their human counterparts, there are no effective biomarkers for diagnosing canine mammary gland tumor (cMGT). Our previous study has shown screening the gene expression of kynurenine 3-monooxygenase (kmo), an enzyme involved in tryptophan metabolism, could predict tumor malignancy and survival time of cMGT-suffering dogs. Here we intend to confirm if KMO could be a real cancer biomarker by investigating its protein expression in a serious of 54 cMGT cases, 29 of them were benign and 25 malignant collected at the Veterinary Hospital of National Taiwan University (NTU) with immunohistochemistry. The results indicated about 73.3% of malignant cMGT showed strong expression of KMO, and patients with strong KMO expression had markedly lower overall survival rate than those with negative or weak ones. Comparing to KMO investigations, increasing HER-2 manifestation was also shown to correlate with tumor size and cMGT stages. A positive correlation between KMO and Ki-67 expression was found in our cMGT cases and it suggests KMO may contribute to tumor development by promoting cell proliferation. This study demonstrated KMO as a potential biomarker in tumor diagnosis and might open new perspectives for clinical applications of cMGT.