Overexpression of hRFI (human ring finger homologous to inhibitor of apoptosis protein type) inhibits death receptor-mediated apoptosis in colorectal cancer cells.
The acquisition of antiapoptotic properties is one of the essential mechanistic steps in colorectal carcinogenesis and is closely correlated with a loss of chemosensitivity and radiosensitivity. Human ring finger homologous to inhibitor of apoptosis protein type (hRFI) is a newly discovered gene encoding a ring finger domain highly homologous to that of X chromosome-linked inhibitor of apoptosis protein. Immunohistochemistry has revealed that the expression of hRFI increased in transition from normal colorectal mucosas to adenomas and from adenomas to carcinomas, suggesting an essential role in the early stage of colorectal carcinogenesis. However, the function role of hRFI in colorectal carcinoma has not been elucidated. To determine whether hRFI possesses an antiapoptotic function in colorectal cancer cells, HCT116 colorectal cancer cells stably overexpressing hRFI were established. The hRFI transfectant exhibited significant resistance to apoptosis induced by tumor necrosis factor-alpha or tumor necrosis factor-related apoptosis-inducing ligand compared with control. This antiapoptotic response was associated with decreased activity of caspase-3, -8, and -9. We also established an antisense down-regulation of hRFI, which effectively reversed the antiapoptotic activity of the hRFI transfectant. This confirmed that the antiapoptotic property of the hRFI transfectant was not due to the clonal effect but in fact dependent on hRFI function. In conclusion, hRFI possesses an antiapoptotic function in HCT116 colorectal cancer cells. Considering the progressive increase of hRFI expression in the advance of the colorectal adenoma-carcinoma sequence, hRFI is one of the important players in colorectal carcinogenesis through its effect on apoptosis regulation.
Konishi
Tsuyoshi
T
Department of Surgical Oncology, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. SASAKI-1SU@h.u-tokyo.ac.jp.
Sasaki
Shin
S
Watanabe
Toshiaki
T
Kitayama
Joji
J
Nagawa
Hirokazu
H
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016373:DNA, Antisense / Q000494:pharmacology; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000473:pathology; D045325:HCT116 Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D016373:DNA, Antisense; D008562:Membrane Glycoproteins; C461219:RNF34 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases