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prolific cells, stem cells and germline, is crucial for the C250T) showed very high frequency in HCC. Furthermore,
[34]
[43]
preservation of high populations and human health. large scale studies by Huang et al. identified TERT
Generally, point mutations that lead to single substitution promoter mutations to be 31.4% in HCC which shows high
of amino acid are more likely tolerated than frame shift frequency similar like other primary cancers.
and splicing junction mutations, limiting but not abolishing
the enzyme activity. The toleration of reduction and loss Cirrhosis is a disease in which liver cells become damaged
of telomerase function decreases with several subsequent and is replaced by scar tissues. People with cirrhosis have
generations. The telomeres of the parental generation an increased risk of liver cancer. Most people who develop
erode when passed to the offspring with shorter telomeres. liver cancer already have some evidence of cirrhosis.
The increase in severity of symptoms is linked with the Evidence supporting the role of genetic risk factors has been
progressive decrease to telomere length. [35] accumulating during the past years and recently it has been
also suggested that telomere shortening may represent a
HEPATOCARCINOMA WITH EXPRESSION OF genetic risk factor. Valenti et al. found that HCC arising
[48]
[12]
ACTIVE TELOMERASE from cirrhosis contained a TERT mutation in the neoplastic
tissue. Furthermore, studies from Hartmann et al. provides
[16]
The relationship between telomerase mutation and experimental evidence that telomerase gene mutations are
development of hepatocellular carcinoma is controversial present in patients who develop cirrhosis as a consequence
and inconclusive so far. Telomeres within HCC were shorter of chronic liver disease.
[13]
compared to normal liver cells suggesting that it could
escape the DNA damage response and subsequent cell cycle DRUG RESEARCH AND DEVELOPMENT FOR
arrest signal generated from short telomeres. It has been CANCER WITH TELOMERASE AS TARGET
suggested that telomere shortening may represent a genetic
risk factor for the development of cirrhosis. The beneficial A fundamental property of the cancer cells is to replicate
[36]
effects of the telomere and telomerase system plays a role for without limitation, which is achieved by telomerase-regulated
suppression of the development of liver cirrhosis and HCC telomere maintenance in most types of cancer cells. Since
in gene knock out mouse model which was performed by somatic cells do not utilize activated telomerase to keep the
Wiemann et al. and Kitada et al. [38] integrity of the telomere length, the telomerase inhibitors
[37]
have the potential to be a selective anti-cancer agents to
However, some studies of HBV-associated HCC have disrupt the proliferation of the telomerase-positive cancer
demonstrated that longer telomeres and higher telomerase cells. Oligonucleotide can interact with both telomerase
[11]
activity correlates with a worse prognosis. The expression of RNA and mRNA of telomerase proteins, therefore native or
dyskerin, the accessory component of telomerase complex, modified oligonucleotides are considered to be potential
showed a correlation with tumorigenic process, which might telomerase inhibitors that can influence the biogenesis of
be a prognostic factor in patients with HCC. A nuclear telomerase core components. A promising oligonucleotide,
[39]
ribonucleoprotein A2/B1, an hTERT-associated protein GRN163L, has been developed as telomerase inhibitor, which
was proposed as a marker and prognosis factor of HCC. acts as competitive inhibitor for the template region of the
[40]
[41]
The study by Lechel et al. provides direct evidence that hTR. [49,50] The compound has already completed phase I trials
telomerase is a critical component for in vivo progression HCC in patients and now being conducted for phase II trials. To
[51]
with short telomeres in the chronically damaged liver and trigger cancer cells death, it requires a period of treatment
telomerase limits the accumulation of telomere dysfunction of telomerase inhibitor to produce enough short telomeres.
thus suppressing hepatocarcinogenesis. Taken together, However, the therapy may be more effective when combined
short telomeres or telomere dysfunction appears permissive with conventional chemotherapies.
for the development of early stage neoplasia, but inhibitory
to later stage and more anaplastic lesions. [42] Some of the telomerase inhibitors have been found in
microbes, which target either telomerase holoenzyme
Transcriptional regulation of the TERT gene is a cause of cancer activity or regulatory pathways of telomerase expression.
specific increase in telomerase activity. Quaas et al. and Among anticancer compounds, the inhibitors are promising
[43]
[44]
other researchers have shown the mutations on promoter for the chemotherapy by virtue of differential expression
region of hTERT in hepatocellular carcinoma. Meanwhile, of telomerase in cancer cells. Synthetic preparation or
several reports have shown that increase in telomerase modification of already screened natural telomerase inhibitor
activity was detected in nearly 90% of HCC as compared to will become useful weapons in the war against cancer
only 21% of non-tumor tissue which resulted in increased e.g. BIBR 1532. Most recently the co-crystal structure of
[52]
levels of TERT mRNA implying that TERT mRNA expression telomerase inhibitor BIBR 1532 with Tribolium castaneum
could predict or be a marker of HCC. [45,46] Recent study from telomerase catalytic subunit showed a novel motif on the
Cevik et al. hTERT promoter is one of most frequent thumb domain could be a target for inhibiting telomerase
[47]
mutational targets in liver cancer regardless of the function. Kellermann et al. identified a compound that
[53]
[54]
geographical location and two site mutation (C228T AND prevent the assembling of the core enzyme and revealed a
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