Introduction to the Role of Fragile Histidine Triad (fhit) Gene in Cancer: A Review of Literature with Special Emphasis on Cervical Carcinoma
The role of fragile histidine triad (fhit) gene in the etiology of cancer is a relatively recent area of research. The fhit gene has been investigated in most cancers; however, literature is not conclusive regarding its role in the pathophysiology of cancer. Many studies are now focusing on this gene and its potential relationship with cancers. Although, studies have shown an association between infection with Human Papillomavirus (HPV) and cervical neoplasia, evidence also suggests that this infection alone is not sufficient for development of cervical cancer. Other genetic factors like altered tumor suppressor gene activities are also thought to contribute to the carcinogenic process in cervical carcinomas. In this short review, we present the function, the potential role of fhit gene and its protein, influence of fhit gene in various cancers with specific emphasis on cervical cancer has been discussed. In addition, the present article also focuses on the biochemical and molecular nature of FHIT protein.
to cite this article:
S.A. Sultana, S. Kiranmayee, V.K. Bammidi, A.P. Shaik and K. Jamil, 2011. Introduction to the Role of Fragile Histidine Triad (fhit) Gene in Cancer: A Review of Literature with Special Emphasis on Cervical Carcinoma. International Journal of Cancer Research, 7: 99-113.
November 06, 2010; Accepted: November 12, 2010;
Published: April 22, 2011
Exposure to carcinogens and the associated FHIT inactivation was first observed
in lung cancers (Sozzi et al., 1998), suggesting
that the alteration of the fhit gene through damage to the associated
fragile region by carcinogens may contribute in a large part to the pathophysiology
of cancer. The loss of FHIT function was more frequently observed in cancers
developing in individuals with constitutional alterations to genes involved
in DNA repair (Mori et al., 2001). Epigenetic
changes to chromatin, such as DNA methylation and modifications in histone proteins
regulate transcription of several tumor suppressor genes (Hsieh
and Jones, 2003). Multiple genetic changes, including activation of protooncogenes
to oncogenes and epigenetic modification (inactivation) of tumor-suppressor
genes are involved in the pathogenesis of cancer (Hsieh
and Jones, 2003; Pichiorri et al., 2008).
Such genetic changes affect cell survival, cell proliferation and stability
of the genome. The 3p14.2 region in chromosome 3 which harbors the fhit
gene encompasses the most active common fragile sites of the human genome making
the region very sensitive to alterations by DNA damaging agents (Pichiorri
et al., 2008).
Aberrant transcripts of the fhit (fragile histidine triad) gene have
been reported in human cancers (Ohta et al., 1996;
Sozzi et al., 1996; Mao et
al., 1996), supporting evidence also indicates the role of FHIT protein
in the regulation of apoptosis and cell cycle (Sard et
al., 1999). Knockout mice models become highly susceptible to chemical
induction of tumors and cells without FHIT protein showed increased resistance
to ultra-violet radiation, mitomycin C and ionizing radiation (Ishii
et al., 2007). Ishii et al. (2006)
suggested that FHIT protects cells from accumulating DNA damages, through modulation
of checkpoint proteins Hus1 and phosphoChk1.
Protein biochemistry: FHIT belongs to the histidine triad superfamily
(HIT, characterized by the histidine triad motif, HxHxHxx (where, x is a hydrophobic
residue)) of nucleotide-binding proteins and is functionally a diadenosine triphosphate
hydrolase which under in vitro conditions cleaves diadenosine triphosphate
through a magnesium dependent hydrolysis to adenine diphosphate and adenine
monophosphate (Barnes et al., 1996). In humans,
this enzyme is composed of 147 amino acids (Ohta et al.,
1996; Pekarsky et al., 1998) and is involved
in purine metabolism. In the first step of enzymatic hydrolysis, it is hypothesized
that diadenosine triphosphateand Mg(2+) reacts with the His96 residue of the
enzyme to form a covalent FHIT-AMP intermediate releasing Mg-ADP; this intermediate
in the second step releases AMP (Barnes et al., 1996;
Abend et al., 1999). Barnes
et al. (1996) showed that the FHIT substrates, diadenosine triphosphate
and diadenosine tetraphosphate are involved in intracellular functions such
as regulation of DNA replication and signaling stress responses. Direct evidence
of this mechanism was provided by Huang et al. (2004),
who showed that FHIT protein mutated at His96 region is completely inactive
against Mg-diadenosine diphosphate indicating that conserved residues of the
histidine triad are required for activity of the enzyme.
The FHIT protein is homologous to the Aph1 enzyme of Saccharomyces pombe,
which has diadenosine triphosphate hydrolase activity, a function that is conserved
from yeast to human. Structural studies have shown that binding of the FHIT
dimer with two molecules of diadenosine triphoshate, results in highly phosphorylated
surfaces, with potential signaling activity (Pace et
al., 1998; Pekarsky et al., 2004). The
FHIT protein may exist is unphosphorylated, monophosphorylated and diphosphorylated
The 16.8 KDa protein produced by the expression of the fhit gene is
phosphorylated at tyrosine 114 residue by Src family proteins. The structure
of the FHIT protein along with active sites predicted by thematics is shown
in Fig. 1. The FHIT protein is expressed at the highest steady
state levels in the kidney and liver.
||FHIT protein with active sites. Active sites of the FHIT protein
as predicted by Thematics. Human fragile histidine triad protein (E.C. 220.127.116.11;
PDB: 5FIT). Adapted from: Wei et al. (2007)
The protein is primarily cytosolic, but is also found in the mitochondria.
Restoration of fhit gene expression in cancer cells deficient in this
gene causes death by apoptosis, involving the intrinsic caspase pathway, in
cancer-derived cells and in tumor xenografts. The tumor-specific loss or reduction
of FHIT protein has been detected immunohistochemically in cervical carcinoma
(Greenspan et al., 1997).
Interactions of FHIT with other proteins: The biological function of
FHIT protein was characterized using the yeast two-hybrid screen by Shi
et al. (2000). FHIT was shown to interact with the protein UBE2I,
this sequence was found to be identical to that of human ubiquitin-conjugating
enzyme 9 (hUBC9). A single amino acid substitution at codon 96 from histidine
to asparagine (His_Asn) or three amino acid substitutions (His_Asn) at codons
94, 96 and 98 did not affect this association. The enzymatic activity of FHIT
was eliminated by mutations in either of the histidine triad regions indicating
the potential role for this protein in controlling cell cycle.
Studies of Weiske et al. (2007) showed that
FHIT protein is associated with a lymphoid enhancer-binding factor-1, T-cell
factor and beta-catenin complex in human embryonic kidney cells. FHIT was shown
to be bound to the C-terminal domain of beta-catenin, a protein which plays
a vital role in the Wnt signalling pathway.
Mutations in fhit gene: The fhit (fragile histidine triad)
gene spanning more than 1.6 Mb of the genomic DNA is a tumor-suppressor gene
composed of 10 exons. The gene encodes a 1.1 kb mRNA. The most common fragile
site, FRA3B is located within the fhit gene (Ohta
et al., 1996). It has been shown that the degree of chromosomal fragility
at this particular site may determine the degree of susceptibility to cancer
(Yang et al., 2002). The fhit region also
encompasses the break point of the t(3:8) translocation (Fig.
2), identified in familial renal-cell carcinoma. Using transfection experiments
in 4 different cell line with homozygous deletions of the fhit gene,
Croce et al. (1999) demonstrated the tumor suppressor
activity of this gene. The FHIT-expressing transfectants when injected into
nude mice resulted in the loss of the ability to form tumors (Siprashvili
et al., 1997). Ohta et al. (1996)
showed that three 5-prime exons of FHIT are centromeric to the 3p14.2 breakpoint,
while the remaining exons are telomeric to this region (Fig. 3).
Using FHIT gene knock-out mouse embryonal stem cells, Fong
et al. (2000) and Zanesi et al. (2001)
have shown that the fhit -/- knockout mice depicted increased susceptibility
to spontaneous tumors and high sensitivity to carcinogens. Aberrant fhit gene
transcripts have been found in esophageal, stomach and other carcinomas. A pseudogene,
with sequences nearly identical to the 51UTR of FHIT, was found to
be located on chromosome 1 (www.atlasgeneticsoncology.org/Genes/FHITID192ch3p).
||Exons of fhit gene. Three 5-prime exons of FHIT are
centromeric to the 3p14.2 breakpoint, while the remaining exons are telomeric
to this region. The figure shows the fhit gene genomic locus with
exons and the position of t(3;8) translocation. Redrawn based on image from:
Corbin et al. (2002) suggested the probable
presence of multiple hot spots within the FHIT/FRA3B locus. Their experiments
involved microcell-mediated chromosome transfer to isolate hybrid cell clones
that retain chromosome 3 homologues followed by molecular mapping of the FHIT/FRA3B
locus. Their results also suggest that factors other than the DNA sequence alone
may be responsible for DNA breaks/gaps.
Implications of fhit gene mutations: Some of the fhit gene polymorphisms that have been most commonly observed in human cancers include the below:
Homozygous deletions in fhit gene in lung, gastrointestinal, breast
and head-and-neck cancers and aberrant fhit transcripts in cancer cell
lines have been reported (Ohta et al., 1996;
Sozzi et al., 1996; Negrini
et al., 1996; Virgilio et al., 1996;
Druck et al., 1997). However, aberrant fhit
transcripts have been seen in histologically normal tissues (Latil
et al., 1998). Although, Fong et al. (1997)
have reported that the point mutation of the fhit gene is rare in lung
cancer, Yoshino et al. (1998) in contrast found
9 point mutations (19%) in cervical carcinomas and showed that these are somatic
mutations rather than rare polymorphisms or germline mutations.
Animal models to investigate the role of fhit gene: After inactivation
of the fhit allele, the resultant mice carrying the inactivated fhit
allele (+/-) were treated with nitrosomethylbenzylamine. While only 25% of the
+/+ mice developed adenoma or papilloma, 100% of fhit deficient mice
developed multiple tumors. The visceral and sebaceous tumors, which lacked FHIT
protein, were similar to the tumors found in the Muir-Torre familial cancer
syndrome (Fong et al., 2000).
Zanesi et al. (2001) suggest that the fhit
gene may be a one-hit tumor suppressor gene in some tissues. Dumon
et al. (2001) inhibited tumor development by fhit gene transfer
using viral vectors suggesting that fhit gene therapy could be a novel
clinical approach in cancer. Shiraishi et al. (2001)
sequenced >600 kb of the mouse locus and determined the fhit deletion
breakpoints in a mouse kidney cancer cell line. Sequence alignment of the murine
and human FRA3B sequences showed that this region was stable in evolution. There
were also several unusual highly conserved regions.
Role of FHIT in various cancers: The inactivation of fhit gene
was shown in a variety of human malignancies indicating its the tumor suppressor
function. In approximately 50% of gastrointestinal carcinomas (esohageal, stomach
and colon) aberrant fhit transcripts have been identified (Ohta
et al., 1996). Huebner and Croce (2003) showed
that FHIT is altered in many human tumors caused by environmental carcinogens.
The same authors in a previous study (Huebner and Croce,
2001) showed that fhit-negative cancer cells were highly sensitive
to the fhit expression. Geurts et al. (1997)
reported that FHIT was involved in a translocation-derived fusion with the high-mobility
group (non histone chromosomal) protein isoform I-C, the causative gene in a
variety of benign tumors. Using sequencing and Southern blot analysis, Rassool
et al. (1996) found neither (CGG)n repeats nor other sequences associated
with rare fragile sites within the 85 kb contig.
By sequence analysis of fhit locus and 22 associated cancer cell deletion
endpoints, Inoue et al. (1997) demonstrated that
this locus is a frequent target of homologous recombination resulting in fhit
gene internal deletions. Corbin et al. (2002)
suggested the possibility of existence of the presence of multiple hot spots
within the fhit locus using microcell-mediated chromosome transfer.
Lung cancers: The expression of the FHIT protein and its relevance to
the diagnosis and prognosis of lung cancers were studied by Feng
et al. (2007) wherein a total loss or marked reduction of expression
was seen in 67% of the analyzed cases. This loss or marked reduction of fhit
gene expression was lung cancers of smokers. However, the expression of FHIT
was not associated with histopathologic grading of tumors and their clinical
staging, lymph node metastasis or survival time. The correlation between loss
of fhit gene expression with a large number of molecular genetic and
clinical parameters in Non-Small-Cell Lung Cancers (NSCLC) were studied using
a polyclonal antibody to FHIT protein. A complete loss of cytoplasmic FHIT staining
was seen in this immunohistochemical reaction in more than 50% of tumors.
Using reverse transcriptase polymerase chain reaction, Sozzi
et al. (1996) analyzed the structure of fhit gene in small
cell and non-small cell lung cancers. The authors noted abnormal-sized transcripts
in tumors and loss of heterozygosity for microsatellite markers in and regions
adjacent to fhit locus. In these tumors, inactivation of the fhit
gene occurred loss of 1 allele and altered expression of the remaining allele.
Studies have indicated a role of cigarette smoking in the etiology of lung
cancer. Microsatellite alterations within the fhit gene and at an independent
locus in chromosome 10 called D10S197 were assessed in lung tumors from heavy
smokers and in tumors from never smokers (Sozzi et al.,
1997a). Loss of heterozygosity affecting at least one locus of the fhit
gene was observed in 80% tumors from the smokers group and only in 22% tumors
from non-smokers. While, the loss of fhit in smokers and nonsmokers was
statistically significant, no difference in loss of heterozygosity rate was
observed at D10S197 locus. An analysis of lung cancer cell lines, small cell
lung carcinomas and pairs of non-small cell primary tumors and bronchial mucosa
specimen using molecular, genetic and histochemical methods showed concordance
between RNA abnormalities and lack of FHIT protein expression in lung tumors
and cell lines (Sozzi et al., 1997b). This study
also suggested that FHIT protein may be lost at very early stages of lung carcinogenesis.
In addition, Stein et al. (2002) showed that
active smokers had a significantly higher frequency of fragile site expression,
compared to nonsmokers and SCLC patients who stopped smoking. Active tobacco
exposure may thus increase the expression of fhit gene.
Head and neck cancers: Virgilio et al. (1996)
noted several regions of loss of heterozygosity in head and neck cancers. More
than 90% of the analysed head and neck squamous cell carcinoma cell lines showed
alterations of at least 1 allele of the fhit gene. Using immunohistochemical
analysis Paradiso et al. (2004) hypothesise that
decreasing levels of FHIT is directly involved in cancer development.
Thyroid tumors: A retrospective analysis of fhit mRNA transcripts
and genomic DNA from thyroid tumors showed the frequent present of truncated
fhit transcripts alongwith full-length transcripts (McIver
et al., 2000). The pathogenetic role for these aberrant transcripts
remains a possibility, but no correlation was found with stage, histological
grade or outcome in this study.
Colorectal cancers: Morikawa et al. (2000)
reported altered expression of FHIT protein in 47% of colorectal adenomas. The
amount of FHIT protein produced was inversely proportional to the degree of
dysplasia. Their findings suggest that altered expression of the fhit
gene is an early event in the etiology of colorectal cancer. Elnatan
et al. (1999) showed that the HIT family of genes were selectively
involved in tumorigenesis and also confirmed the early alterations in fhit
gene expression. The alteration of the fhit locus and loss of FHIT protein
expression were found to be significantly more frequent in sporadic colorectal
carcinomas (Mori et al., 2001).
Bladder cancer: Maruyama et al. (2001)
investigated the aberrant promoter methylation profile of bladder cancers and
correlated their data with clinicopathological findings. The methylation profile
was hypothesised to be a potential new biomarker of risk prediction in bladder
Esophageal cancer: In esophageal cancer, 50% of severe and moderate
dysplasias and 33% of mild dysplasias were fhit negative in most of the
in situ lesions (Mori et al., 2001). Mimori
et al. (2003) showed that microsatellite instability is significantly
related to the allelic loss in the fhit region and this was unrelated
to the progression of esophageal cancer.
Hepatocellular cancer: Zekri et al. (2005)
showed that the fhit gene is a frequent target in hepatitis C virus-associated
hepatocellular carcinoma and that alterations affecting this gene occurs as
an early event in this type of neoplasm. In addition, studies also showed abnormal
apoptosis-proliferation balance indicating an important role of fhit
gene expression in the carcinogenesis and development of hepatocellular carcinoma
(Nan et al., 2005).
Prostate cancer: A linkage analysis by of 80 candidate genes conducted
in prostatic adenocarcinoma showed that involvement of germline variations of
FHIT may increase the risk of prostate cancer risk (Larson
et al., 2005).
Breast cancer: The protective role of fhit gene was determined
by crossing in mice carrying one inactivated fhit allele with mice carrying
the rat neu proto-oncogene (Bianchi et al., 2007).
All fhit heterozygous mice developed mammary tumors, whereas when both
fhit alleles were present, tumor incidence was reduced in 27% of the
mice. Their findings suggest a protective role for FHIT in HER2-driven mammary
The loss of heterozygosity in D3S1300, an fhit intragenic marker with
concomitant loss of BRCA1 intragenic marker was reported (Santos
et al., 2004). In this study, no correlations were found between
loss of heterozygosity with the size of tumor, grade and axillary lymph node
metastasis. Guler et al. (2004) observed a strong
correlation between FHIT and Wwox expression, a result consistent with the increased
susceptibility of fragile sites to DNA damage. The reduced expression of fhit
expression was associated with adverse prognostic factors. In an additional
study Guler et al. (2009) showed that reduced
expression levels of FHIT, Wwox and nuclear AP2gamma have roles in basal-like
differentiation in breast cancer. In addition, Wang et
al. (2008) have shown that the expression of fhit gene and Wwox
and decreases along with progression from normal cells to cancer.
Gastric cancer: The absence of FHIT protein correlated with tumor stage
and histologic grade in gastric cancers (Capuzzi et al.,
2000). Lee et al. (2001a, b)
showed that a higher frequency of aberrant transcripts in gastric carcinomas.
Along with this, they observed a significant rate of loss of heterozygosity
indicating the important role of fhit gene in etiology of gastric carcinogenesis.
A study by Zheng et al. (2007) showed that in
gastric cancer, the expression of fhit and pten were lower compared
to the levels in normal mucosal cells. A negative association was found with
the extent of lymphatic invasion, lymph node metastasis, liver metastasis and
staging. However, a positive association was found between fhit and pten
Periocular sebaceous gland carcinoma: Holbach et
al. (2002) showed that the inactivation of the fhit gene or inactivation
of the mismatch-repair system may contribute to the development of periocular
sebaceous gland carcinoma in Muir-Torre syndrome.
Renal carcinoma: Gemmill et al. (1998)
showed that the reciprocal t (3;8) translocation was associated with multifocal
clear cell renal carcinoma. Such balanced and constitutional translocation was
also reported in bilateral clear cell renal cell carcinoma (Poland
et al., 2007), these translocations disrupt the trc8 and fhit
genes caused increased susceptibility to bilateral renal cell carcinoma. Strefford
et al. (2005) reported genomic imbalances and rearrangements in renal
cell carcinoma cell lines. The frequent loss or decrease in FHIT protein expression
was also observed by Gayrard et al. (2008) in
addition fhit inactivation was found to play a major role in renal cell
tumorigenesis by Velickovic et al. (2001) and
Sukosd et al. (2003).
Role of FHIT gene in cervical cancers: Loss of FHIT expression, was
found to be reported commonly in patients with stage IA1 to IB2 cervical squamous
cell carcinoma, this being significantly more common in cervical cancers of
smokers (Holschneider et al., 2005). Abnormal
protein expression fhit gene has been reported to play a pivotal role
in cervical cancers (www.cancerindex.org/clinks3h.htm),
a common type of malignancy accounting for about 6% of all cancers found in
women (Parkin et al., 1999). Cervical cancer
remains a major source of cancer-related morbidity and death for women throughout
the world (Bosch et al., 1995). The Human Papilloma
Viruses (HPV) are the principal cause of cervical cancer and HPV DNA has been
found in more than 95% of carcinoma cases. HPV are DNA viruses and affect the
nucleus and the cytoplasm of the infected cells. The DNA of these viruses may
or may not be intergrated in the epithelial cell nuclei. However, morphological
changes occur when HPV DNA is integrated into the epithelial cell nuclear DNA.
The HPV lesions are typically dysplastic and atypical and may be associated
with chromosome and ploidy alterations (Geradts et al.,
2000). Infection with certain high risk Human Papilloma Virus (HPV) types
is associated with cervical cancer probably by inactivation of p53 and pRB through
interactions with the HPV E6 and E7 proteins, respectively (Alani
and Munger, 1998). HPV infections are generally transient, but a small percentage
of women develop cervical cancer (Zur Hausen, 1990;
Evander et al., 1995).
Nevertheless, HPV infection alone may not be sufficient for the development
of cervical cancer since this does not explain the additional events that are
necessary for some infections to become chronic and undergo malignant transformation
(Neyaz et al., 2010). Genomic rearrangements,
aberrant mRNA transcripts and decreased or completed absence of FHIT protein
have been reported in cervical carcinomas (Noronha et
al., 1999; Lopez-Beltran and Munoz, 1995). These
aberrations may have a predictive role in the malignant transformation of lesions
in the cervix.
Becker et al. (2002) showed fragility of fhit
gene in cervical cancer. The fhit gene expression on a panel of cervical
tumor-derived cell lines showed aberrant regulation. In squamous-cell carcinomas
of the uterine cervix, 43% of tumors were found with aberrant transcripts and
32% tumors with point mutations (Yoshino et al.,
2000). Alterations in fhit were significantly associated with cervical
carcinogenesis. Further, this study analysed the alteration of fhit gene
in various grades of cervical intra-epithelial neoplasias and invasive cervical
carcinomas compared to normal cervical epithelium. A strong association of altered
FHIT protein expression with the disruption of normal fhit transcript
was observed. There was no correlation between fhit inactivation and
HPV infection. The fhit-gene inactivation was shown to be a late event
in cervical carcinogenesis. In addition, homozygous deletions of fhit
in cervical cancer and cervical carcinoma cell lines have been reported (Muller
et al., 1998). Aberrant fhit transcripts were seen only in
cervical tumor tissue and not in normal cervical tissue (Greenspan
et al., 1997; Muller et al., 1998;
Nakagawa et al., 1999; Segawa
et al., 1999; Yoshino et al., 2000),
however, some studies have reported the same levels of RNA expression pattern
in both tumors and normal cervical tissue (Chu et al.,
1998; Su et al., 1998; Yoshino
et al., 2000).
A reduced FHIT protein level compared to normal cervical epithelium has been
reported (Greenspan et al., 1997; Segawa
et al., 1999; Birrer et al., 1999;
Yoshino et al., 2000). 61% of squamous carcinomas
and 40% of adenocarcinomas of the cervix showed abnormal fhit expression
(Birrer et al., 1999). fhit expression
was abnormal in both glandular and squamous cervical cancers. Abnormal fhit
expression was also detected in some preneoplastic lesions of the ectocervix.
Alterations in fhit expression may be an important marker of early progression
in cervical cancer.
Connolly et al. (2000) suggest that loss of
fhit expression could serve as a useful marker of high-grade preinvasive
lesions that have an increased likelihood to progress to invasive carcinoma.
Baykal et al. (2003) showed that fhit
gene was lower in 53% of the cervical carcinomas. None of the clinicopathologic
prognostic parameters investigated in this study showed a correlation with FHIT
expression. FHIT was thus shown to play a carcinogenic role in tumoral progression
but not in the tumoral development.
Bahnassy et al. (2006) reported that aberrations
in the fhit gene frequent in HPV-associated cervical carcinoma can be
used as predictors of tumor recurrences. In addition to this, a decreased or
complete absence of FHIT protein expression was found in 65% cases. The difference
between the expression level of the fhit gene and the FHIT protein was
reported by Birrer et al. (1999) and Bahnassy
et al. (2006). Genomic rearrangements, altered mRNA transcripts and
absence or reduction of the FHIT protein have all been reported in numerous
epithelial tumors including cervical carcinomas (Lopez-Beltran
and Munoz, 1995; Munoz et al., 1995; Noronha
et al., 1999). These aberrations may play a predictive role in the
identification of the malignant potential of high-grade squamous intraepithelial
lesions of the uterine cervix (Schiffman et al.,
Kannan et al. (2000) identified 2 different
mutations in oral cancer (caused by chewing tobacco) and cervical cancer (caused
by HPV) infection. These mutations were at the second nucleotide 3' to the termination
codon (TGA) in exon 9 and at the ninth nucleotide upstream to the beginning
of exon 9. In addition to this, the authors also reported a single nucleotide
fhit gene polymorphism due to T/A replacement at 17 nucleotides upstream
to exon 9.
Neyaz et al. (2008) analysed cervical cancer
tissue biopsies of various clinical stages and histological grading. Aberrant
promoter methylation of the fhit gene was found in 28.3% of subjects
and was significantly (p<0.01) associated with the cervical cancer compared
with controls. Neyaz et al. (2010) also attempted
to study the role of point mutation in fhit gene in HPV mediated cervical
cancer and identified a novel mutation at codon 98 from with replacement of
the amino acid His by Arg in cervical cancer. The authors suggest that the His
to Arg substitution in the substrate-binding domain may generate catalytically
inactive protein with consequent loss of tumor suppressor activity. Promoter
hypermehylation and loss of heterozygosity of the fhit was investigated
in cervical cancer (Choi et al., 2007). While,
promoter hypermethylation was detected in 24% of tumors compared to noncancerous
tissues, no correlation was observed between loss of heterozygosity and promoter
hypermethylation for fhit gene.
From the reviewed studies it can be said that, in addition to HPV infection, mutations in fhit gene may be critical for the development and progression of cervical cancer. In addition, from the literature, it is also clear that fhit gene might play an important role in the etiology of several other cancers, although supporting literature is limited. Host factors like altered tumor suppressor gene and activation of protooncogenes to oncogenes that contribute to the carcinogenic process in cervical carcinomas and other cancers need to be further evaluated to understand the specific role of this protein. The present review article focused on the biochemical and molecular nature of FHIT protein the role of this gene as evident from literature in various cancers with special emphasis on cervical cancer. However, to better understand this protein, further studies in larger population sizes and sub-divided into groups based on stages of cancers in necessary.
The data presented here are from a non-homogeneous collection of information available about fhit gene. This is indeed a potential limitation of the study. However, the article tries to give a clear picture of the important role the fhit gene plays in the pathophysiology of cancers. The article therefore focused on the summary of the gene, its protein, expression and its role giving an overall understanding of this gene and its protein.
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