ARD1在人類胃癌腫瘤血管新生之角色探討

胃癌高居世界十大癌症死因第二位，導致胃癌死亡率居高、治癒率低的原因，主要為癌細胞之轉移而造成治療失敗。因此研究抑制癌細胞轉移之機轉，在癌症治療領域佔有重要的角色。在像胃癌這樣的實體腫瘤中，腫瘤的增大進而轉移的過程亟需新生血管與週邊組織連結，以運輸腫瘤所需之養分。若能找出具抑制腫瘤血管新生作用之蛋白，並釐清其機制，可做為作為病理診斷上的新方法，及未來治療癌症的方向。 ARD1 在1985年即被發現在酵母菌中扮演著轉換細胞有絲分裂及發育機轉之角色，ARD1和其共同作用者NATH可形成一個穩定的結構，此結構具有N基乙醯轉移酵素之活性，並參與許多生物性功能如細胞分化，熱敏感性，細胞凋亡等。本篇研究結果顯示，臨床上分析ARD1蛋白表現量較低的病人，與較早癌病復發率、較短存活時間，以及癌病惡性度較高有正相關。在體外細胞株實驗當中，收集不同胃癌細胞株的細胞培養液處理內皮細胞，發現ARD1的mRNA及蛋白表現量和其影響內皮細胞之移動與新生血管能力有負相關性。在ARD1過度表現之轉殖細胞株中發現顯著降低內皮細胞的移動與新生血管能力；相反的，在ARD1表現降低的轉殖株中則促進內皮細胞的移動與新生血管能力。此外，雞胚胎卵黃囊試驗法(CAM)與小黑鼠體內血管新生(Matrigel Plug assay)中，同樣觀察到ARD1顯著降低血管生成與發育。最後藉由動物實驗，再次印證ARD1在活體實驗當中也有效抑制腫瘤血管新生。進一步探討ARD1所調控之轉移能力之機轉則發現，ARD1可減少ARNT (HIF-1β)的RNA與蛋白表現，進而抑制其所調控之基因啟動子上的缺氧反應元(HRE)活性，使下游基因(如血管內皮生成因子基因)表現減少。我們也證明了ARD1本身之N基乙醯轉移酵素活性並不影響其調控血管新生之能力。因此，ARD1為一個新發現之抑癌基因並可作為將來治療腫瘤血管新生的標的因子。

關鍵字

胃癌；血管新生

並列摘要

Gastric cancer is one of the leading causes of cancer-related death worldwide, and metastasis is the major cause of treatment failure and mortality in cancer patients. Angiogenesis, the formation of new blood vessels from the existing vessels, depends on the homeostasis of a variety of pro- and anti-angiogenic factors. Tumor angiogenesis is induced by the secretion of angiogenic factors from cancer cells, and is essential for the growth and progression of solid tumors, including gastric cancer. Identification of novel tumor angiogenesis-associated genes and elucidation of their mechanism of action may provide new insights into the pathogenesis and management of cancer metastasis. Arrest defective protein 1 (ARD1) is characterized as an N-acetyltransferase. It forms heterodimer with human N-acetyltransferase (NATH) and exerts N-acetyltransferase activity in many biological processes such as cell cycle regulation and cell proliferation. The purpose of this study is to investigate the regulatory role of ARD1 in tumor angiogenesis. In the present study, we found that ARD1 expression was inversely correlated with patients’ survival, stage and tumor status, as well as angiogenesis abilities in gastric cancer cell lines. By using cell wounding and capillary tube formation on a matrigel matrix, we found that ARD1 decreased gastric cancer cell-induced angiogenesis, migration and tube formation in endothelial cells. In addition, ARD1 also suppressed gastric cancer cell-induced angiogenesis in chick chorioallantoic membrane (CAM) assay and matrigel plug assay. Furthermore, in vivo xenograft mouse model showed that ARD1 inhibited tumor growth, tumor microvessel density, and distal organ metastasis. We further demonstrated that ARD1 suppressed cancer cell-induced angiogenesis through down regulating the expression of ARNT (HIF-1β) and decreasing the transcriptional activity of HIF-1α/HIF-1β, which may result in reduction of downstream genes. In conclusion, we considered ARD1 as an anti-angiogenesis gene and it inhibited cancer cell-induced angiogenesis through reducing ARNT expression. Therefore, ARD1 may be a potential target for cancer treatment.

並列關鍵字

Gastric cancer ； Angiogenesis

參考文獻

Adams, R. H. and K. Alitalo (2007). "Molecular regulation of angiogenesis and lymphangiogenesis." Nat Rev Mol Cell Biol 8(6): 464-478.

Arnesen, T., X. Kong, et al. (2005). "Interaction between HIF-1 alpha (ODD) and hARD1 does not induce acetylation and destabilization of HIF-1 alpha." FEBS Lett 579(28): 6428-6432.

Asaumi, M., K. Iijima, et al. (2005). "Interaction of N-terminal acetyltransferase with the cytoplasmic domain of beta-amyloid precursor protein and its effect on A beta secretion." J Biochem (Tokyo) 137(2): 147-155.

Aurello, P., R. Bellagamba, et al. (2009). "Apoptosis and microvessel density in gastric cancer: correlation with tumor stage and prognosis." Am Surg 75(12): 1183-1188.

Brown, L. F., B. Berse, et al. (1993). "Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract." Cancer Res 53(19): 4727-4735.

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ARD1在人類胃癌腫瘤血管新生之角色探討

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