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Biological significance of gene amplification in carcinogenesis
M Terada1, H Sakamoto, Y Ohmura
1National Cancer Center Research Institute, Tokyo, Japan.
Abstract:
K-SAM gene was originally isolated as an amplified gene in a stomach cancer cell line by in-gel DNA renaturation method. K-SAM encodes a membrane receptor with tyrosine kinase and is often amplified in poorly differentiated type of stomach cancer, while c-ERBB-2 is often amplified in well differentiated type of stomach cancer. There are several forms of K-SAM mRNAs which are generated by alternative splicing, and two types of K-SAM protein without transmembrane region. The ligand of K-SAM is considered to be growth factor(s) belonging to fibroblast growth factor (FGF) or heparin binding growth factor (HBFG) family. We have also frequently found amplification of HST-1 or HSTF1 gene in esophageal cancer. HST-1 gene, originally found as a transforming gene, is located on human chromosome 11q13, and it locates 35 kbp apart from its related gene, INT-2. Neither of the genes was expressed even in cancer cells with the co-amplification. By cosmid walking, we have identified at least two genes, designated tentatively as EXP1 and EXP2, on the same amplicon as HST-1 and INT-2, and the mRNAs for EXP1 and EXP2 genes were increased in amounts proportional to the degree of amplification.
Insights
The K-SAM gene, amplified in stomach cancer, encodes a tyrosine kinase receptor. Amplification of HST-1 and related genes, including EXP1 and EXP2, was also found in esophageal cancer.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- K-SAM gene amplification is linked to poorly differentiated stomach cancer.
- c-ERBB-2 amplification is associated with well-differentiated stomach cancer.
- Fibroblast growth factor (FGF) or heparin-binding growth factor (HBFG) are potential K-SAM ligands.
Purpose of the Study:
- To investigate gene amplification in stomach and esophageal cancers.
- To identify novel genes within amplified regions.
- To understand the relationship between gene amplification and cancer subtypes.
Main Methods:
- In-gel DNA renaturation for gene isolation.
- Cosmid walking for gene identification.
- Analysis of mRNA expression levels.
Main Results:
- K-SAM gene, encoding a tyrosine kinase receptor, is amplified in stomach cancer.
- HST-1 and INT-2 genes are frequently amplified in esophageal cancer.
- Two novel genes, EXP1 and EXP2, were identified on the same amplicon as HST-1 and INT-2, with increased mRNA levels correlating with amplification degree.
Conclusions:
- Gene amplification plays a significant role in stomach and esophageal cancers.
- K-SAM and HST-1/INT-2 amplifications may serve as biomarkers for specific cancer types.
- EXP1 and EXP2 are novel genes within the HST-1/INT-2 amplicon, potentially involved in esophageal tumorigenesis.