X-linked inhibitor of apoptosis protein expression level in colorectal cancer is regulated by hepatocyte growth factor/C-met pathway via Akt signaling

Hiroya Takeuchi, Joseph Kim, Akihide Fujimoto, Naoyuki Umetani, Takuji Mori, Anton Bilchik, Rod Turner, Andy Tran, Christine Kuo, Dave S.B. Hoon

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Abstract

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-MET enhances 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.

Original languageEnglish
Pages (from-to)7621-7628
Number of pages8
JournalClinical Cancer Research
Volume11
Issue number21
DOIs
Publication statusPublished - 2005 Nov 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Takeuchi, H., Kim, J., Fujimoto, A., Umetani, N., Mori, T., Bilchik, A., Turner, R., Tran, A., Kuo, C., & Hoon, D. S. B. (2005). X-linked inhibitor of apoptosis protein expression level in colorectal cancer is regulated by hepatocyte growth factor/C-met pathway via Akt signaling. Clinical Cancer Research, 11(21), 7621-7628. https://doi.org/10.1158/1078-0432.CCR-05-0479