| 摘要: | 單胺氧化? (monoamine oxidases, MAOs) 是負責分解單胺類神經傳遞物質的酵素，分為MAOA和MAOB 兩種亞型。研究發現 MAOs在不同癌種的發展扮演著致癌或抑癌角色。近期研究已指出MAOA可促進前列腺癌的生長和轉移。本研究主要探究了MAOB 在泌尿系統癌症之角色，包括腎細胞癌和前列腺癌。我們透由分析TCGA和GEO臨床資料庫，發現腎細胞癌組織的MAOB表現量越高與病患的良好預後呈現正相關性，包括更長的存活期及更小的腫瘤體積。這種相關性在腎亮細胞癌 (clear cell renal cell carcinoma, ccRCC) 族群中特別顯著。在ccRCC細胞株中發現MAOB過度表現可以抑制細胞增殖、集落形成和遷移之能力且MAOB的抑癌能力是依賴其酵素活性。機制探討發現MAOB可以誘導活性氧化物 (ROS) 產生進而活化p53抑癌蛋白，最後導致細胞周期停?和細胞凋亡。在ccRCC原位移植動物模式中，我們發現MAOB大量表現能顯著抑制腫瘤生長和轉移。組織染色結果顯示MAOB可抑制細胞增殖標記Ki-67表現及促進p53表現。在前列腺癌研究中，我們發現帶有MAOB rs6324 A等位基因的患者顯示出有較高初始前列腺特異性抗原 (initial prostate-specific antigen, iPSA) (>10 ng/mL)。而帶MAOB rs3027452 A等位基因的患者則具有較高風險產生腫瘤遠端轉移，尤其是在具有高iPSA的亞族群中更為顯著。在術後未復發的亞族群中，我們發現具MAOB rs1799836 G等位基因患者其產生淋巴結轉移和腫瘤復發的風險高於帶A等位基因的患者。此外，在前列腺癌細胞株中，帶有MAOB rs1799836 G等位基因的細胞比攜帶A等位基因的細胞具有較低的MAOB表現。與腎癌細胞結果相似，MAOB大量表現也會抑制前列腺癌細胞的遷移和增生。MAOB 表現減少與前列腺癌晚期、腫瘤轉移和不良預後相關。本研究發現，MAOB於腎亮細胞癌及前列腺癌的進展及轉移皆扮演抑癌的角色。這項研究深入探討了MAOB在泌尿系統癌症中的多方面參與，包括其基因多型性、臨床意義、分子機制和細胞功能。闡明MAOB在泌尿系統癌症中的功能，可以為這些種類的惡性腫瘤提供新的治療見解。
Monoamine oxidases (MAOs) are enzymes responsible for the degradation of monoamine neurotransmitters, comprising two subtypes, MAOA and MAOB. Oncogenic or tumor suppressive roles of MAOs were reported in cancers, but their roles in urinary system cancers are still not fully understood. Recently, MAOA was shown to promote the growth and metastasis of prostate cancer (PCa). This study investigated the role of MAOB in urinary system-related cancers, including renal cell carcinoma (RCC) and PCa. Analysis of clinical data from the TCGA and GEO databases, we found a positive correlation between MAOB expression and favorable prognosis of RCC patients, including longer survival time and smaller tumor size. This correlation was particularly significant in clear cell RCC (ccRCC) subgroups. In vitro studies showed that overexpression of MAOB in ccRCC cell lines inhibited cell proliferation, colony formation, and migration, which depending on its enzymatic activity. Mechanically, we found that MAOB can induce the production of reactive oxygen species (ROS), which activates the p53 tumor suppressor protein, leading to cell cycle arrest and apoptosis. In a ccRCC orthotopic xenograft model the inhibition of tumor growth and metastasis was observed in cells overexpressing MAOB, accompanied by a decreased proliferation marker, Ki-67, and increased p53 expression. In the study of PCa, patients with the MAOB rs6324 A allele showed a higher risk of high initial prostate-specific antigen (iPSA) levels (>10 ng/mL). Those with the MAOB rs3027452 A allele had an increased risk of distant metastasis, particularly in the high iPSA subgroup. Additionally, PCa patients without postoperative biochemical recurrence but carrying the MAOB rs1799836 G allele had a higher risk of lymph node metastasis and tumor recurrence compared to those with the A allele. Additionally, PCa cell lines carrying the MAOB rs1799836 G allele exhibited lower MAOB expression than those carrying the A-allele. Similar to ccRCC, overexpression of MAOB in PCa cells inhibited migration and proliferation of cells. Analysis of TCGA data revealed that decreased MAOB expression was associated with progression and poor prognosis of PCa patients. This study identifies MAOB as a tumor suppressor in ccRCC and PCa. It explores MAOB's genetic polymorphism, clinical significance, molecular mechanisms, and cellular functions in urinary system-related cancers. Understanding MAOB role in ccRCC and PCa could offer new therapeutic insights for these malignancies. |
