- 學位論文
褪黑激素治療腎細胞癌轉移之臨床前研究
The Therapeutic Potential of Melatonin on Renal Carcinoma Cell Metastasis - A Preclinical Study
摘要
腎細胞癌時常發生鄰近器官侵犯甚至遠處轉移，因此在所有泌尿系統惡性腫瘤中最容易引發癌症相關死亡。褪黑激素因可以調控生理時鐘，具有直接或間接清除自由基，抑制正常細胞凋亡等生理活性外，同時具有多種抑制腫瘤活性，例如對抗腫瘤增殖、誘發細胞凋亡，抗血管生成及免疫調控的作用。先前研究發現褪黑激素可以抑制肝癌細胞，骨肉瘤細胞，及神經膠質瘤細胞的侵犯能力，也有研究報告指出褪黑激素可以促進咖啡白脂或直接抑制腎癌細胞增生，然而褪黑激素在腎細胞癌抗腫瘤轉移的能力及機制尚不清楚。在此研究中，我們證明褪黑激素在藥物濃度(0.5-2 mM)能有效的減少腎細胞癌細胞（Caki-1 和Achn）的遷移和侵襲的能力。此外我們發現在原位性和實驗性轉移動物模式中褪黑激素能抑制Caki-1腎癌細胞轉移。進一步探討褪黑激素抑制的機制顯示，褪黑激素能減少基質金屬蛋白酶-9(MMP-9)的生合成是透過抑制基因轉錄，而此作用經實驗證實，主要是而減少轉錄因子NF-κB與啟動子間的結合，而NF-κB家族中的p65和p52蛋白與MMP-9染色體的結合能力及細胞核的移位最為重要。除此之外，Akt主導絲裂原活化蛋白激酶MAPK中JNK1/2和ERK1/2的訊息路徑參與褪黑激素調控基質金屬蛋白酶-9基因啟動和細胞運動。基因資料庫顯示褪黑激素受體1A(MTNR1A)與MMP-9基因在正常腎臟組織及腎細胞癌腫瘤組織中的表現呈負相關性。並且發現在腎細胞癌患者基因表現MTNR1A高/MMP-9低比MTNR1A低/MMP-9高的患者有較高的存活率。總體而言，我們的研究結果提供的新的觀點在褪黑激素抑制抑制腎癌細胞轉移的調控，並提供褪黑激素潛在的治療應用在轉移型腎細胞癌。
並列摘要
Renal cell carcinoma (RCC) causes most cancer death among urologic malignancy because of its metastatic potential to vital organs. Melatonin own multiple oncostatic activities through tumor growth inhibition, induction of apoptosis, and anti-angiogenic actions in various cancers. However, the anti-metastatic activity of melatonin and its mechanism in RCC are poorly elucidated. In this study, we revealed that the pharmacologic concentration (0.5–2 mM) of melatonin inhibited the migration and invasion of RCC cells (Caki-1 and Achn). Furthermore, we demonstrated that melatonin suppressed tumor growth and metastasis of Caki-1 cells in orthotopic and experimental metastatic animal models. Further investigations revealed that melatonin inhibited matrix metalloproteinase-9 (MMP-9) transcription by reducing p65- and p52-DNA-binding activities and nucleus translocation. Moreover, the Akt-mediated mitogen-activated protein kinase (MAPK) signaling pathways were participated in melatonin-regulated MMP-9 transactivation and cancer cell motility in RCC. According to The Cancer Genome Atlas database, there was an inverse correlation between melatonin receptor 1A (MTNR1A) and MMP-9 expression in normal kidney and RCC tissues. Furthermore, a higher survival rate was found in MTNR1Ahigh/MMP-9low patients than in MTNR1Alow/MMP-9high patients. In summary, this study provide new insights into the role of melatonin-mediated regulation in suppressing RCC metastasis and suggest that melatonin has potential therapeutic applications for metastatic RCC.