Tumor-suppressive effect of S-adenosylmethionine supplementation in a murine model of inflammation-mediated hepatocarcinogenesis is dependent on treatment longevity

Evgeniy Stoyanov, Lina Mizrahi, Devorah Olam, Temima Schnitzer-Perlman, Eithan Galun, Daniel S. Goldenberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Chronic inflammation precedes the majority of hepatocellular carcinoma (HCC) cases. We investigated the chemopreventive potential of S-adenosylmethionine (SAM), an essential donor for all methylation reactions in the cell, at the late precancerous stage of HCC development using the Mdr2-knockout (Mdr2-KO, Abcb4-/-) mice, a model of inflammation-mediated hepatocarcinogenesis. Previously, we revealed down-regulation of the genes regulating SAM metabolism in the liver of these mice at the precancerous stages. Now, we have supplied Mdr2-KO mice at the late precancerous stage with SAM during either a short-term (17 days) or a longterm (51 days) period and explored the effects of such supplementation on tumor development, DNA methylation and gene expression in the liver. The short-term SAM supplementation significantly decreased the number of small tumor nodules, proliferating hepatocytes and the total DNA methylation level, while it increased expression of the tumor suppressor proteins Mat1a and p21. Surprisingly, the longterm SAM supplementation did not affect tumor growth and hepatocyte proliferation, while it increased the total liver DNA methylation. Our results demonstrate that the short-term SAM supplementation in the Mdr2-KO mice inhibited liver tumor development potentially by increasing multiple tumor suppressor mechanisms resulting in cell cycle arrest. The long-term SAM supplementation resulted in a bypass of the cell cycle arrest in this HCC model by a yet unknown mechanism.

Original languageAmerican English
Pages (from-to)104772-104784
Number of pages13
JournalOncotarget
Volume8
Issue number62
DOIs
StatePublished - 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© Stoyanov et al.

Keywords

  • Abcb4
  • Hepatocellular carcinoma
  • Mdr2
  • Methionine adenosyltransferase
  • S-adenosylmethionine

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