使用生物資訊分析方法探討犬尿氨酸-3-單氧化酶在人類乳癌發生的作用

Abstract

Kynurenine 3-monooxygenase（KMO）是位於粒線體外膜上的單體蛋白，在犬尿氨酸途徑中扮演重要的角色。已有研究指出，在犬隻乳腺腫瘤、人類肝細胞癌和乳癌中KMO轉錄上調，並發現過表達的KMO調節兩種人類癌細胞的增殖，遷移和侵襲。我們使用了多種生物資訊分析工具來調查臨床人類乳癌患者的KMO基因改變，mRNA表現量和臨床結果，在基因層面，我們發現KMO在人類乳癌中的突變率很低，這與KMO在所有癌症統計中相似。在mRNA層面，與正常組織相比，KMO在八種類型的癌症中過表達，其中，在浸潤性乳管癌發現最高的KMO mRNA表達變化，並且在許多惡性狀況（例如TNBC，淋巴結轉移陽性和高級別的NPI患者）中KMO mRNA表達較高。在臨床結果中，我們發現KMO表達較高的乳癌患者，其無復發存活期（RFS）和總體生存期（OS）明顯較短。使用KMO相關的基因來建構蛋白質交互作用（PPI）網絡，並在PPI網絡中進一步鑑定了10個中樞基因，在這10個中樞基因中包含了趨化因子以及促炎蛋白。許多研究表明，趨化因子以及促炎細胞因子參與了各種人類癌症的進展。總合上述結果，此研究通過各種生物資訊分析工具研究了臨床乳癌患者中KMO的分子特徵，結果表明KMO可能在癌症中具有關鍵的作用。

Kynurenine 3-monooxygenase (KMO) is a monomeric protein located on the outer membrane of mitochondrial and plays a significant role in the kynurenine pathway. KMO transcripts were found upregulated in canine mammary gland tumors, human hepatocellular carcinoma, and breast cancers. Overexpressed KMO positively regulated proliferation, migration, and invasion in human liver and breast cancer cells. We used various bioinformatic analysis tools to investigate the KMO genetic alternation, mRNA expression, and clinical outcome of human breast cancer patients. At the gene level, we found that KMO has a lower mutation rate in human breast cancer, which is similar in all cancer. At the mRNA level, it was found that KMO was overexpressed in eight types of cancers compared with normal tissues. The highest KMO mRNA expression fold change was found in invasive ductal breast carcinoma, and KMO mRNA expression is high in many malignant statuses such as TNBC, nodal positive, and higher grade NPI patients. In the clinical outcome, we found that breast cancer patients with higher KMO expression were associated with significantly shorter relapse-free survival (RFS) and overall survival (OS). The KMO correlated genes were used to construct a protein-protein interaction (PPI) network and further identified 10 hub genes in the PPI network. These 10 hub genes contain chemokines and pro-inflammatory proteins. Many studies have shown that chemokines and inflammation are involved in the progression of various human cancers. Taken together, this study investigated the molecular characteristics of KMO in clinical breast cancer patients through various bioinformatic tools, and the results indicate that KMO may play a critical role in cancer.