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


METHODS
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 N0 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 siRNA 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.
Takeuchi
Hiroya
H
Department of Molecular Oncology, Gastrointestinal Section, Santa Monica, CA 90404, USA.
Kim
Joseph
J
Fujimoto
Akihide
A
Umetani
Naoyuki
N
Mori
Takuji
T
Bilchik
Anton
A
Turner
Rod
R
Tran
Andy
A
Kuo
Christine
C
Hoon
Dave S B
DS
D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D017931:DNA Primers / Q000737:chemistry; D018450:Disease Progression; D005260:Female; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis*; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014162:Transfection; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis*
D017931:DNA Primers; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051636:X-Linked Inhibitor of Apoptosis Protein; D012313:RNA; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt