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Oncol Rep. 2014 Nov;32(5):2093-103. doi: 10.3892/or.2014.3462. Epub 2014 Sep 3.

DNA methyltransferases 3a and 3b are differentially expressed in the early stages of a rat liver carcinogenesis model.

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Department of Cell Biology Center for Research and Advanced Studies (CINVESTAV) IPN, Basic Research Branch, Mexico, D.F., Mexico.
National Cancer Institute, Basic Research Branch, Mexico, D.F., Mexico.
Department of Physics, Center for Research and Advanced Studies (CINVESTAV) IPN, Basic Research Branch, Mexico, D.F., Mexico.


Carcinogenesis is driven by the accumulation of mutations and abnormal DNA methylation patterns, particularly the hypermethylation of tumor‑suppressor genes. Changes in genomic DNA methylation patterns are established by the DNA methyltransferases (DNMTs) family: DNMT1, DNMT3a and DNMT3b. The DNMTs are known to be overexpressed in tumors. However, when the DNMTs expression profile is altered in earlier stages of carcinogenesis remains to be elucidated. The resistant hepatocyte model (RHM) allows the analysis of the hepatocellular carcinoma (HCC) from the formation of altered cell foci to the appearance of tumors in rats. To investigate the DNMTs expression in this model, we first observed that timp3, rassf1a and p16 genes became methylated during cancer development by methylation‑specific PCR (MSP) and the bisulphate sequencing PCR (BSP) of timp3. The differential expression at the RNA and protein level of the three DNMTs was also assessed. dnmt1 expression was higher in tumors than in normal and early cancer stages. However, no evident overexpression of the enzyme was identified by immunohistochemistry. By contrast, DNMT3a and DNMT3b were consistently subexpressed in tumors. In the present study, we report a carcinogenesis model that does not feature the overexpression of DNMT1 but exhibits a transient expression of DNMT3a and DNMT3b.

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