Mitochondrial metabolism
Enzymes produced from cytochrome P450 genes
(CYP) are involved in the formation (synthesis) and breakdown (metabolism) of
various molecules and chemicals within cells. Cytochrome P450 enzymes are
primarily found in liver cells. Because the differential expression of CYP2E1
may play a pleiotropic role in the multistep process of liver carcinogenesis,
Yang and colleagues (54) examined the effect of trichostatin A (TSA) on CYP2E1
expression and the role of CYP2E1 in inducing apoptosis of HepG2 cells; they
found that TSA selectively induced CYP2E1 in human HCC cell lines (Huh7,
PLC/PRF/5, Hep3B, and HepG2), but not in normal primary human hepatocytes.
Moreover, TSA-mediated up-regulation of CYP2E1 expression was associated with
histone H3 acetylation and recruitment of HNF-1 and HNF-3beta to the CYP2E1
promoter in HepG2 cells (54). These findings suggested that histone modification
is involved in CYP2E1 gene expression and that CYP2E1-dependent mitochondrial
oxidative stress plays a role in TSA-induced apoptosis. In addition, the
adeno-associated virus (AAV)3-mediated transfer and expression of the pyruvate
dehydrogenase E1 alpha subunit gene could cause metabolic remodeling and
apoptosis of human liver cancer cells (55).
Mutated expression of microRNAs (miRNAs) may
contribute to HCC. MiRNA-122 is a regulator of mitochondrial metabolic gene
network in HCC. Increased expression of miR-122 seed-matched genes leads to a
loss of mitochondrial metabolic function. In
vitro miR-122 data further provide a direct link between induction of
miR-122-controlled genes and impairment of mitochondrial metabolism (56).
Because miR-122 regulates mitochondrial metabolism, its loss may be detrimental
to sustaining critical liver function and may contribute to morbidity and
mortality of liver cancer patients. Further elucidation of the miRNAs
regulating mitochondrial metabolism, or other pathways in mitochondria, could
potentially help with the development of novel HCC therapies.
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