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Met/HGF receptor modulates bcl-w expression and inhibits apoptosis in human colorectal cancers
S Kitamura1, S Kondo, Y Shinomura
1Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Abstract:
The met proto-oncogene is the tyrosine kinase growth factor receptor for hepatocyte growth factor. In the present study, we investigated the role of met expression on the modulation of apoptosis in colorectal tumours. The gene expressions of c-met and the anti-apoptotic bcl-2 family, including bcl-2, bcl-x(L)and bcl-w, were analysed in human colorectal adenomas and adenocarcinomas by using a quantitative polymerase chain-reaction combined with reverse transcription. In seven of 12 adenomas and seven of 11 carcinomas, the c-met gene was overexpressed. The bcl-w, bcl-2 and bcl-x(L)genes were over-expressed in nine, five and six of 12 adenomas and in five, two and seven of 11 carcinomas, respectively. The c-met mRNA level in human colorectal adenomas and carcinomas was correlated with bcl-w but not with bcl-2 or with bcl-x(L)mRNA level. The administration of c-met-antisense oligonucleotides decreased Met protein levels in the LoVo human colon cancer cell line. In the case of c- met -antisense-treated cells, apoptotic cell death induced by serum deprivation was more prominent, compared to control or c-met -nonsense-treated cells. Treatment with c-met-antisense oligonucleotides inhibits the gene expression of bcl-w in LoVo cells. On the other hand, the gene expression of bcl-2 or bcl-x(L)was not affected by treatment with c-met-antisense oligonucleotides. These findings suggest that Met expression modulates apoptosis through bcl -w expression in colorectal tumours.
Insights
Met proto-oncogene (c-MET) expression influences apoptosis in colorectal tumors by regulating bcl-w. Inhibiting c-MET increases apoptosis and decreases bcl-w, suggesting a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The MET proto-oncogene encodes a receptor tyrosine kinase crucial for cell growth and survival.
- Dysregulation of MET signaling is implicated in various cancers, including colorectal tumors.
- Apoptosis, or programmed cell death, is a key process often altered in cancer development.
Purpose of the Study:
- To investigate the role of MET proto-oncogene expression in modulating apoptosis within colorectal tumors.
- To analyze the correlation between c-MET gene expression and the expression of anti-apoptotic bcl-2 family members (bcl-2, bcl-x(L), bcl-w).
- To determine the functional impact of MET inhibition on apoptosis and bcl-w expression in a human colon cancer cell line.
Main Methods:
- Quantitative polymerase chain-reaction combined with reverse transcription (RT-qPCR) was used to analyze gene expression.
- c-MET and bcl-2 family gene expression levels were measured in human colorectal adenomas and adenocarcinomas.
- The effect of c-MET-antisense oligonucleotides on Met protein levels, apoptosis, and gene expression was assessed in the LoVo colon cancer cell line.
Main Results:
- Overexpression of c-MET was observed in a significant proportion of both adenomas and adenocarcinomas.
- c-MET mRNA levels positively correlated with bcl-w mRNA levels, but not with bcl-2 or bcl-x(L).
- Inhibition of c-MET using antisense oligonucleotides led to increased apoptosis and decreased bcl-w gene expression in LoVo cells.
Conclusions:
- MET proto-oncogene expression plays a role in the modulation of apoptosis in colorectal tumors.
- The observed effect of MET on apoptosis appears to be mediated through the regulation of bcl-w gene expression.
- Targeting MET signaling, potentially via bcl-w modulation, could represent a therapeutic strategy for colorectal cancer.