X-linked inhibitor of apoptosis protein expression level in colorectal cancer is regulated by hepatocyte growth Factor/C-Met pathway via Akt signaling
X-linked inhibitor of apoptosis protein expression level in colorectal cancer is regulated by hepatocyte growth Factor/C-Met pathway via Akt signaling
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DOI：
10.1158/1078-0432.ccr-05-0479
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发表时间：
2005-11-01
影响因子：
11.5
通讯作者：
Hoon, DSB
中科院分区：
文献类型：
--
作者：
Takeuchi, H;Kim, J;Hoon, DSB
目的：凋亡蛋白（IAP）家族成员的抑制剂，如X-linked IAP （XIAP）、survivin和livin，对结直肠癌细胞的存活和抗凋亡至关重要。我们假设肝细胞生长因子（HGF）在结直肠癌中通过c-Met受体激活，通过Akt信号调节IAP蛋白。实验设计：采用实时定量逆转录- pcr （RT-PCR）方法评估结直肠正常粘膜（n = 13）、腺瘤（n = 6）和结直肠癌肿瘤（n = 50）的IAPs水平和C-Met mRNA表达。采用小干扰RNA （small interfering RNA, siRNA）和定量RT-PCR分析结直肠癌细胞系，研究HGF/C-Met通路通过Akt和XIAP的作用。结果：在iap中，只有XIAP与肿瘤的发生发展有显著的相关性。原发性结直肠癌组织中XIAP mRNA水平显著高于结直肠正常粘膜组织（P = 0.01）；肝转移率显著高于原发结直肠癌（P = 0.04）；原发性结直肠癌N1/N2病例显著高于NO病例（P = 0.008）。HGF刺激结直肠癌细胞系可增强XIAP mRNA的表达，而其他iap的表达不受影响。靶向Akt1和Akt2的si RNA可抑制HGF对XIAP表达的激活。结论：c - meb的激活通过Akt通路增强XIAP。XIAP上调与结直肠癌肿瘤进展相关。Akt-XIAP通路可能是调节结直肠癌进展的潜在分子靶点。
Purpose: The inhibitor of the apoptosis protein (IAP) family members, such as the X-linked IAP (XIAP), survivin, and livin, are essential for cell survival and antiapoptosis in colorectal cancer cells. We hypothesized that the hepatocyte growth factor (HGF) activation in colorectal cancer via c-Met receptor regulates IAP proteins through Akt signaling.Experimental Design: The level of IAPs and C-Met mRNA expression was assessed using a quantitative real-time reverse transcriptase-PCR (RT-PCR) assay on colorectal normal mucosa (n = 13), adenomas (n = 6), and colorectal cancer tumors (n = 50). The role of HGF/C-Met pathway through Akt and XIAP was investigated by small interfering RNA (siRNA) and quantitative RT-PCR analysis of colorectal cancer lines.Results: Of the IAPs, only XIAP showed significant correlation to tumor development and progression. XIAP mRNA level in primary colorectal cancer was significantly higher than that in colorectal normal mucosa (P = 0.01); liver metastases was significantly higher than primary colorectal cancer tumors (P = 0.04); and primary colorectal cancer N1/N2 cases were significantly higher than NO cases (P = 0.008). HGF stimulation of colorectal cancer lines enhanced XIAP mRNA expression but not other IAPs. Activation of XIAP expression by HGF was inhibited by si RNA targeting Akt1 and Akt2.Conclusions: Activation of C-METenhances XIAP through the Akt pathway. XIAP up-regulation was shown to be correlated to colorectal cancer tumor progression. The Akt-XIAP pathway may be a potential molecular target for regulating colorectal cancer progression.