Page 32 - Read Online

Page 8 of 14 Lozano-Rosas et al. Hepatoma Res 2018;4:19 I http://dx.doi.org/10.20517/2394-5079.2018.48

stemness and self-renewal characteristics in TICs and protect them from drug-induced cell death. Elevated
levels of ROS inhibit stemness genes by activation of the p38 MAPK pathway leading to polycomb suppressor
protein complex I (BMI) protein degradation and FOXO3 activation. NANOG also acts synergistically with
p53 inactivation and b-catenin activation to reprogram cellular metabolic pathways, since p53 promotes
glycolysis and OXPHOS . Other pluripotency transcription factors that are being studied that contribute
[88]
to TICs metabolism reprogramming are MYC and OCT4. MYC regulates the glutaminolysis and glycolysis
pathways and OCT4 also regulates OXPHOS [29,88] .

MtDNA copy number has a very important role in tumorigenesis. Depending on the cancer types, the
mtDNA copy number varies, an increase in prostate and endometrial cancer has been reported, whereas
a decrease has been shown in HCC and gastric cancer . Cancer stem like cells have a low mtDNA copy
[89]
number that promotes their high proliferation rate and shifts their energy production by glycolysis. This low
mtDNA copy number downregulates the expression of the catalytic subunit of the mitochondrial-specific
polymerase POLGA by hypermethylation at exon 2 . The reduced expression of POLGA is necessary to
[89]
maintain pluripotency of cancer stem like cells. Yamada et al. reported a reduced copy number of mtDNA
[90]
in patients with HCC, which correlated with malignant potential.

The removal of mtDNA from cells in culture induces alterations in nDNA methylation. For example, the
content of 5mC in the genomic DNA of HCC (tumor tissue) is negatively correlated with the content of
mtDNA . These changes are reversible upon re-establishment of mtDNA . One possible mechanism is
[56]
[91]
that the expression of the enzyme DNMT1, crucial in DNA methylation, is dependent on the copy number
[92]
of mtDNA .
miR122 is the most important miRNA in adult healthy liver and is associated with liver stem cells
differentiation towards hepatocytes. In HCC, miR122 expression is lost. When miR122 expression is
reestablished in a stem-like cell line derived from human HCC (BCLC9 cells), it decreases cell proliferation
rate and reduces tumor size in vivo. This effect is achieved by down-regulating MYC, KLF4, FOXM1, AKT2,
and AKT3 and up-regulating FOXO1 and FOXO3A gene expression .
[93]

POTENTIAL VALUE OF MITOEPIGENETICS AS BIOMARKERS FOR CANCER DIAGNOSIS AND
THERAPY
The main problem of HCC is the absence of early detection and effective therapies. The Asian Pacific
Association for the Study of the Liver has recommended the use of alpha-fetoprotein (AFP) as a diagnostic
biomarker for early detection of HCC complemented with orthodox imaging-based tools . There are
[94]
other candidates with clinical value for early HCC diagnosis; in this regard, glycoforms of AFP, des-γ-
carboxyprothrombin, glypican-3, cytokeratin 19, annexin A2, and circulating miRNAs have been proposed,
among others, to be used alone or in combination .
[95]

Cancer metabolic reprogramming regulated by mitochondrial enzymes is now one of the hallmarks of
cancer. Tumor cells can acquire functional mtDNA from healthy cells to restore respiratory function and
metabolic activity, which enabled them to proliferate .
[96]

The mtDNA acts as a critical message to travel and communicate between tumor cells and neighbor non-
tumor cells. The outcome of mtDNA horizontal transfer could induce chemoresistance in the treatment .
[97]

In addition to the above mentioned, the mitochondrial cellular content and mutations have also been
suggested as novel molecular markers . Moreover, reduced expression of OXPHOS complexes has been
[98]