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Nuclear but not mitochondrial genome involvement in 3-methylcholanthrene-induced expression of tumorigenicity in
J I Hayashi1, H Yonekawa, Y Tagashira
1Department of Biochemistry, Saitama Cancer Center Research Institute, Japan.
Abstract:
The involvement of heritable modifications of mitochondrial DNA (mtDNA) in chemical carcinogenesis was examined by studies on the effects on tumorigenicity of interchange of mtDNA between 3-methylcholanthrene (MCA)-induced mouse tumor cells and nontumorigenic mouse cells by the cytoplast-to-cell fusion technique. The difference in propagating abilities of two types of mouse mtDNA, type 1 mtDNA of B10mtJ strain and type 2 mtDNA of C57BL/10 strain, was applied successfully for complete replacement of the host cell mtDNA by cytoplasmically transmitted mtDNA. Tumorigenicity was assayed in nude mice by inoculating 5 x 10(6) cells s.c. into the backs of the mice. The results showed that tumorigenicity was not induced in nontumorigenic cells by replacement of their mtDNA by that from MCA-induced tumor cells. Moreover, the tumorigenicity of MCA-induced tumor cells was still expressed when their mtDNA was replaced by that from normal cells with a limited life span. These observations suggest that, even if MCA treatment causes heritable modifications of mtDNA, modified mtDNA cannot induce chemical carcinogenesis and that modifications of nuclear DNA alone are sufficient for the expression of tumorigenicity.
Insights
Heritable mitochondrial DNA (mtDNA) modifications do not cause chemical carcinogenesis. Nuclear DNA changes alone are sufficient for tumor development, as shown by experiments with mouse tumor cells and non-tumorigenic cells.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Chemical carcinogenesis involves genetic alterations leading to tumor formation.
- Mitochondrial DNA (mtDNA) is susceptible to modifications, but its role in carcinogenesis is not fully understood.
- Previous studies suggest nuclear DNA mutations are key drivers of cancer.
Purpose of the Study:
- To investigate whether heritable modifications in mitochondrial DNA (mtDNA) can induce chemical carcinogenesis.
- To determine if mtDNA plays a causal role in the development of tumors initiated by 3-methylcholanthrene (MCA).
Main Methods:
- Utilized cytoplast-to-cell fusion to exchange mtDNA between MCA-induced mouse tumor cells and nontumorigenic mouse cells.
- Employed distinct mouse mtDNA types (B10mtJ and C57BL/10) based on propagation differences for complete mtDNA replacement.
- Assayed tumorigenicity by subcutaneous inoculation of modified cells into nude mice.
Main Results:
- Nontumorigenic cells receiving mtDNA from MCA-induced tumor cells did not develop tumors.
- MCA-induced tumor cells retained their tumorigenicity even after their mtDNA was replaced with mtDNA from normal cells.
- These findings indicate that mtDNA modifications alone are insufficient to induce or maintain tumorigenicity.
Conclusions:
- Heritable modifications of mtDNA, if induced by chemical carcinogens like MCA, do not appear to cause chemical carcinogenesis.
- Modifications in nuclear DNA are sufficient for the expression of tumorigenicity.
- The study highlights the primary role of nuclear DNA alterations in chemical carcinogenesis.