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Objective: Deletions or loss of heterozygosity in chromosome 3p are very common in small-cell lung cancer (SCLC) and lung adenocarcinoma (ADC) cases. These are typically found in tumor cells but rarely observed in lymphocytes. This study aimed to evaluate the frequency of 3p deletions and/or abnormalities in the blood of lung cancer patients using conventional cytogenetics and fluorescence in situ hybridization (FISH), by targeting the fragile histidine triad diadenosine triphosphatase (FHIT) gene located at the commonly deleted region of 3p14.2, in lung cancers. Materials and Methods: The study examined 24 SCLC patients, 30 ADC patients, and 20 healthy controls. It used standard procedures to perform a 72-h lymphocyte culture, G-banding, and FISH. Results: All patient group cases showed multiple numerical and structural abnormalities, with numerical abnormalities being more prominent and involving all chromosomes. The following two 3p abnormalities were detected in one patient: del(3)(p22) and t(3;5) (p25;q31). FISH showed positive results regarding FHIT deletion in 9 (30%) ADC, and 7 (29%) SCLC patients. Conclusion: Regardless of the rarity of 3p abnormalities in lymphocytes, a high frequency of chromosomal aberrations may indicate genomic instability. Nevertheless, due to being a time-consuming and expertise-requiring technique, conventional cytogenetics is not recommended for lung cancer monitoring. However, the FISH results suggested that using FISH to examine FHIT gene status in lymphocytes could be a promising biomarker for lung cancer. [ABSTRACT FROM AUTHOR]

The Fragile Histidine Triad Diadenosine Triphosphatase (FHIT) gene is located in the Common Fragile Site FRA3B and encodes an enzyme that hydrolyzes the dinucleotide Ap3A. Although FHIT loss is one of the most frequent copy number alterations in cancer, its relevance for cancer initiation and progression remains unclear. FHIT is frequently lost in cancers from the digestive tract, which is compatible with being a cancer driver event in these tissues. However, FHIT loss could also be a passenger event due to the inherent fragility of the FRA3B locus. Moreover, the physiological relevance of FHIT enzymatic activity and the levels of Ap3A is largely unclear. We have conducted here a systematic pan-cancer analysis of FHIT status in connection with other mutations and phenotypic alterations, and we have critically discussed our findings in connection with the literature to provide an overall view of FHIT implications in cancer. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) play a critical role in a variety of human diseases such as cancer. Here, to elucidate a novel function of a lncRNA called LINC00173, we investigated its binding partner, target gene, and its regulatory mechanism in lung adenocarcinoma, including the A549 cell line and patients. In the A549 cell line, RNA immunoprecipitation (RIP) assays revealed that LINC00173 efficiently binds to SNAIL. RNA-seq and RT-qPCR analyses revealed that the expression of FHIT was decreased upon LINC00173 depletion, indicating that FHIT is a target gene of LINC00173. Overexpression of SNAIL suppressed and depletion of SNAIL increased the expression of FHIT, indicating that SNAIL negatively regulates FHIT. The downregulation of FHIT expression upon LINC00173 depletion was restored by additional SNAIL depletion, revealing a LINC00173-SNAIL-FHIT axis for FHIT regulation. Data from 501 patients with lung adenocarcinoma also support the existence of a LINC00173-SNAIL-FHIT axis, as FHIT expression correlated positively with LINC00173 (p = 1.75 × 10−6) and negatively with SNAIL (p = 7.00 × 10−5). Taken together, we propose that LINC00173 positively regulates FHIT gene expression by binding to SNAIL and inhibiting its function in human lung adenocarcinoma. Thus, this study sheds light on the LINC00173-SNAIL-FHIT axis, which may be a key mechanism for carcinogenesis and progression in human lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Aim: To determine the test and retest reliability of the functional head impulse test (fHIT) in healthy young adults. Materials and methods: Thirty-three healthy participants (17 women, 16 men) aged 18–30 years were included in the study. Each participant underwent the fHIT twice, 1 week apart, by the same experienced clinician. Intraclass correlation coefficients (ICCs) were used to determine test–retest reliability. Results: There was no statistically significant difference between the results of total percentage of correct answer (CA%) of the fHIT obtained in session 1 and session 2 measurements in the lateral, anterior, and posterior semicircular canals (SCCs) (p > 0.05). ICC values for test–retest reliability were found to range from 0.619 to 0.665 for the three semicircular canals (SCCs). Conclusion: The test–retest reliability of the fHIT device was moderate. Attention, cognition, and fatigue may be the factors reducing reliability. In the diagnosis, follow-up, and rehabilitation processes of vestibular diseases in clinics, changes in the fHIT CA% can be used to assess vestibulo-ocular reflex (VOR) functionality. [ABSTRACT FROM AUTHOR]

Genetic alterations in fragile histidine triad (FHIT) play a pivotal role in various cancers of head, neck, lung, kidney, gastrointestinal, and breast including oral which leads to abnormal transcripts in vivo during the development of oral cancer. Owing to the importance of FHIT gene in cell proliferation, tumor suppression and survival, the structural, functional, non-synonymous SNPs (nsSNPs), and network study was conducted to look at the potential relationship between phenotypic variations and genetic variations. In silico genomic analysis of FHIT was initiated with the identification of 18 rare variants from dbSNP database followed by PredictSNP 1.0 web server analysis for predicting the deleterious and neutral mutants. A total of 11 mutations i.e. P33T, P33A, V97F, S22A, T19I, T61M, D57N, P101A, P101S, S81P and R46H corresponding to 9 nsSNPs were found to be deleterious which affects the protein. The interacting genes with FHIT were found by analyzing protein–protein interactions network using a STRING database. Gene ontology and Disease Association functional analysis of FHIT was obtained by WebGestalt. The mutational positions and amino acid variations have been mapped onto native FHIT. Structural and docking analysis of native and mutant FHIT with ER 27319 Maleate was performed using Auto Dock 4.2, GLIDE, SRide server, structural visualizers, and MD simulations to check their binding energies, stabilizing residues, and to investigate their dynamic behavior, mode of binding action and inhibitor specificity. Our in-silico analysis suggested that screening of P101S (rs533270218), S81P (rs536941406) and D57N (rs375883257) variants of FHIT could be useful for molecular diagnosis and development of vital molecular inhibitors of FHIT pathways. The diagnostic and prognostic approach of these molecular biomarkers can intrude on the predisposition to oral cancer.

In previous studies, we have identified the tumor suppressor proteins Fhit (fragile histidine triad) and Nit1 (Nitrilase1) as interaction partners of β-catenin both acting as repressors of the canonical Wnt pathway. Interestingly, in D. melanogaster and C. elegans these proteins are expressed as NitFhit fusion proteins. According to the Rosetta Stone hypothesis, if proteins are expressed as fusion proteins in one organism and as single proteins in others, the latter should interact physically and show common signaling function. Here, we tested this hypothesis and provide the first biochemical evidence for a direct association between Nit1 and Fhit. In addition, size exclusion chromatography of purified recombinant human Nit1 showed a tetrameric structure as also previously observed for the NitFhit Rosetta Stone fusion protein Nft-1 in C. elegans. Finally, in line with the Rosetta Stone hypothesis we identified Hsp60 and Ubc9 as other common interaction partners of Nit1 and Fhit. The interaction of Nit1 and Fhit may affect their enzymatic activities as well as interaction with other binding partners. [ABSTRACT FROM AUTHOR]

Introduction: In recent decades, the development of immunotherapy and targeted therapies has considerably improved the outcome of non-small cell lung cancer (NSCLC) patients. Despite these impressive clinical benefits, new biomarkers are needed for an accurate stratification of NSCLC patients and a more personalized management. We recently showed that the tumor suppressor fragile histidine triad (FHIT), frequently lost in NSCLC, controls HER2 receptor activity in lung tumor cells and that tumor cells from NSCLC patients harboring a FHITlow/pHER2high phenotype are sensitive to anti-HER2 drugs. Here, we sought to identify the transcriptomic signature of this phenotype and evaluate its clinical significance. Materials and methods: We performed RNA sequencing analysis on tumor cells isolated from NSCLC (n=12) according to FHIT/pHER2 status and a functional analysis of differentially regulated genes. We also investigated the FHITlow/pHER2high signature in The Cancer Genome Atlas (TCGA) lung adenocarcinoma (LUAD) (n=489) and lung squamous cell carcinoma (LUSC) (n=493) cohorts and used the tumor immune dysfunction and exclusion (TIDE) model to test the ability of this signature to predict response to immune checkpoint inhibitors (ICI). Results: We showed that up-regulated genes in FHITlow/pHER2high tumors were associated with cell proliferation, metabolism and metastasis, whereas down-regulated genes were related to immune response. The FHITlow/pHER2high signature was associated with the higher size of tumors, lymph node involvement, and late TNM stages in LUAD and LUSC cohorts. It was identified as an independent predictor of overall survival (OS) in LUAD cohort. FHITlow/pHER2high tumors were also predictive of poor response to ICI in both LUAD and LUSC cohorts. Conclusion: These data suggest that ICI might not be a relevant option for NSCLC patients with FHITlow/pHER2high tumors and that anti-HER2 targeted therapy could be a good therapeutic alternative for this molecular subclass with poorer prognosis. [ABSTRACT FROM AUTHOR]

IntroductionIn recent decades, the development of immunotherapy and targeted therapies has considerably improved the outcome of non-small cell lung cancer (NSCLC) patients. Despite these impressive clinical benefits, new biomarkers are needed for an accurate stratification of NSCLC patients and a more personalized management. We recently showed that the tumor suppressor fragile histidine triad (FHIT), frequently lost in NSCLC, controls HER2 receptor activity in lung tumor cells and that tumor cells from NSCLC patients harboring a FHITlow/pHER2high phenotype are sensitive to anti-HER2 drugs. Here, we sought to identify the transcriptomic signature of this phenotype and evaluate its clinical significance.Materials and methodsWe performed RNA sequencing analysis on tumor cells isolated from NSCLC (n=12) according to FHIT/pHER2 status and a functional analysis of differentially regulated genes. We also investigated the FHITlow/pHER2high signature in The Cancer Genome Atlas (TCGA) lung adenocarcinoma (LUAD) (n=489) and lung squamous cell carcinoma (LUSC) (n=493) cohorts and used the tumor immune dysfunction and exclusion (TIDE) model to test the ability of this signature to predict response to immune checkpoint inhibitors (ICI).ResultsWe showed that up-regulated genes in FHITlow/pHER2high tumors were associated with cell proliferation, metabolism and metastasis, whereas down-regulated genes were related to immune response. The FHITlow/pHER2high signature was associated with the higher size of tumors, lymph node involvement, and late TNM stages in LUAD and LUSC cohorts. It was identified as an independent predictor of overall survival (OS) in LUAD cohort. FHITlow/pHER2high tumors were also predictive of poor response to ICI in both LUAD and LUSC cohorts.ConclusionThese data suggest that ICI might not be a relevant option for NSCLC patients with FHITlow/pHER2high tumors and that anti-HER2 targeted therapy could be a good therapeutic alternative for this molecular subclass with poorer prognosis.

Abstract Background Human T cell Leukemia virus type 1 (HTLV-I) is etiologically linked to adult T cell leukemia/lymphoma (ATL) and an inflammatory neurodegenerative disease called HTLV-I-associated myelopathy or tropical spastic paraparesis (HAM/TSP). The exact genetic or epigenetic events and/or environmental factors that influence the development of ATL, or HAM/TSP diseases are largely unknown. The tumor suppressor gene, Fragile Histidine Triad Diadenosine Triphosphatase (FHIT), is frequently lost in cancer through epigenetic modifications and/or deletion. FHIT is a tumor suppressor acting as genome caretaker by regulating cellular DNA repair. Indeed, FHIT loss leads to replicative stress and accumulation of double DNA strand breaks. Therefore, loss of FHIT expression plays a key role in cellular transformation. Methods Here, we studied over 400 samples from HTLV-I-infected individuals with ATL, TSP/HAM, or asymptomatic carriers (AC) for FHIT loss and expression. We examined the epigenetic status of FHIT through methylation specific PCR and bisulfite sequencing; and correlated these results to FHIT expression in patient samples. Results We found that epigenetic alteration of FHIT is specifically found in chronic and acute ATL but is absent in asymptomatic HTLV-I carriers and TSP/HAM patients’ samples. Furthermore, the extent of FHIT methylation in ATL patients was quantitatively comparable in virus-infected and virus non-infected cells. We also found that longitudinal HTLV-I carriers that progressed to smoldering ATL and descendants of ATL patients harbor FHIT methylation. Conclusions These results suggest that germinal epigenetic mutation of FHIT represents a preexisting mark predisposing to the development of ATL diseases. These findings have important clinical implications as patients with acute ATL are rarely cured. Our study suggests an alternative strategy to the current “wait and see approach” in that early screening of HTLV-I-infected individuals for germinal epimutation of FHIT and early treatment may offer significant clinical benefits.

Objective: The aim of this study was to assess the functional head impulse test on migraine patients without vertigo. fHIT is a new vestibular test which evaluates the ability to see and read clearly during head movement as a functional measurement of the vestibulo-ocular reflex. Materials and methods: The study included 20 patients suffering from migraine without vertigo between the ages of 20 and 30-years-old who were diagnosed by a neurologist and 20 individuals with non-migraine headaches (control group), with similar demographic characteristics. The functional head impulse test was applied to both groups, and the migraine disability assessment test was applied to migraine patients. Results: There was no statistically significant difference in the general fHIT results between the migraine group and the control group (p > 0.05). However, a statistically significant decrease was obtained in migraine patients in the left lateral (p = 0.018) and right posterior (p = 0.029) semicircular canals at 4000 Hz and the right anterior semicircular canal at 6000 Hz (p = 0.019). When compared by the degree of migraine disability assessment test, no significant difference in the fHIT results were observed (p > 0.05). Conclusion: The semicircular canals may be affected at high head acceleration (4000–6000 Hz) in migraine patients without a history of vertigo. It should be considered that fHIT results between 4000 and 6000 Hz in migraine patients without vertigo can be pathologic. [ABSTRACT FROM AUTHOR]

Background/aim: The main aim of the study is to assess expression levels of CDH1, FHIT, PTEN, and TTPAL genes in tumors and peripheral bloods of colorectal cancer patients in staged I-IV. Materials and methods: Gene expression analysis of related genes were performed for tumor tissues and peripheral blood samples of 51 colorectal cancer patients and colon tissues and blood samples of 5 healthy individuals. The real-time-PCR reaction method was used for the analysis. Results: Alteration of mRNA levels of related genes in tumor tissues of colorectal cancer cases was determined compared to control tissues. GAPDH and TBP were used for the normalization. While the mRNA levels of CDH1 decreased, the mRNA level of the FHIT and TTPAL genes increased in the tumor tissues. There was no PTEN gene expression difference in tumor tissues (total). The mRNA levels of the CDH1 and PTEN genes were increased while the mRNA levels of FHIT and TTPAL genes decreased in the blood (total). The mRNA levels of the CDH1 gene decreased at each stage (I-IV) in the tumor tissues and increased at each stage (I-IV) in the blood. The PTEN gene mRNA levels at each stage were controversial. The mRNA levels of the FHIT gene increased at stage I-II-III, decreased at stage IV in the tissues and decreased at each stage (I-IV) in the blood. The mRNA levels of TTPAL gene increased at each stage (I-IV) in the tissues and decreased at each stage (I-IV) in the blood. Conclusion: Although related expression levels in tissue did not correlate with its expression in blood, consistent with previous studies FHIT and TTPAL genes upregulation and CDH1 downregulation, in especially tumoral tissues, may serve as predictive determinants for the patients with colorectal cancer. [ABSTRACT FROM AUTHOR]

Background: Human T cell Leukemia virus type 1 (HTLV-I) is etiologically linked to adult T cell leukemia/lymphoma (ATL) and an inflammatory neurodegenerative disease called HTLV-I-associated myelopathy or tropical spastic paraparesis (HAM/TSP). The exact genetic or epigenetic events and/or environmental factors that influence the development of ATL, or HAM/TSP diseases are largely unknown. The tumor suppressor gene, Fragile Histidine Triad Diadenosine Triphosphatase (FHIT), is frequently lost in cancer through epigenetic modifications and/or deletion. FHIT is a tumor suppressor acting as genome caretaker by regulating cellular DNA repair. Indeed, FHIT loss leads to replicative stress and accumulation of double DNA strand breaks. Therefore, loss of FHIT expression plays a key role in cellular transformation. Methods: Here, we studied over 400 samples from HTLV-I-infected individuals with ATL, TSP/HAM, or asymptomatic carriers (AC) for FHIT loss and expression. We examined the epigenetic status of FHIT through methylation specific PCR and bisulfite sequencing; and correlated these results to FHIT expression in patient samples. Results: We found that epigenetic alteration of FHIT is specifically found in chronic and acute ATL but is absent in asymptomatic HTLV-I carriers and TSP/HAM patients' samples. Furthermore, the extent of FHIT methylation in ATL patients was quantitatively comparable in virus-infected and virus non-infected cells. We also found that longitudinal HTLV-I carriers that progressed to smoldering ATL and descendants of ATL patients harbor FHIT methylation. Conclusions: These results suggest that germinal epigenetic mutation of FHIT represents a preexisting mark predisposing to the development of ATL diseases. These findings have important clinical implications as patients with acute ATL are rarely cured. Our study suggests an alternative strategy to the current "wait and see approach" in that early screening of HTLV-I-infected individuals for germinal epimutation of FHIT and early treatment may offer significant clinical benefits. [ABSTRACT FROM AUTHOR]

ObjectivePatients with head and neck squamous cell carcinoma (HNSCC) containing TP53 mutation and 3p deletion ("double-hit") have poorer prognosis compared to patients with either event alone ("single-hit"). The etiology for worse clinical outcomes in patients with "double-hit" cancers is unclear. We compared radiosensitivity of cell lines containing both TP53 mutations and deletion of Fragile Histidine Triad (FHIT, the gene most commonly associated with 3p deletion) to "single-hit" lines with only TP53 mutation. We compared radiosensitivity in a "single-hit" cell line with TP53 mutation converted to "double-hit" using RNA interference targeting FHIT. Finally, we compared matrixmetalloproteinase-2/9 (MMP-2/9) activity, a previously-established biomarker for tumor aggressiveness, in xenograft tumors derived from these cell lines.Materials/methodsTP53 mutation and FHIT deletion profiles of HNSCC lines were established using Cancer Cell Line Encyclopedia (CCLE). We used RNA-interference to convert a "single-hit" cell line (SCC4) to "double-hit". Cultured cells were examined for radiosensitivity and cisplatin sensitivity. MMP-2/9 activity was evaluated in "double-hit" versus "single-hit" tumors using ratiometric activatable cell-penetrating peptide (RACPP) in tongue (n=17) and flank xenografts (n=4).ResultsRadiotherapy caused greater double-stranded DNA breaks in "single-hit" vs naturally occurring and engineered "double-hit" cells. In-vivo, "double-hit" xenografts demonstrated higher MMP-2/9 activity compared to "single-hit" xenografts (p

The fragile histidine triad (FHIT) protein is a member of the large and ubiquitous histidine triad (HIT) family of proteins. On the basis of genetic evidence, it has been postulated that the FHIT protein may function as tumor suppressor, implying a role for the FHIT protein in carcinogenesis. Recently, Gaudio et al. reported that FHIT binds and delocalizes annexin A4 (ANXA4) from plasma membrane to cytosol in paclitaxel-resistant lung cancer cells, thus restoring their chemosensitivity to the drug. They also identified the smallest protein sequence of the FHIT still interacting with ANXA4, ranging from position 7 to 13: QHLIKPS. This short sequence of FHIT protein was not only able to bind ANXA4 but also to hold its target in the cytosol during paclitaxel treatment, thus avoiding ANXA4 translocation to the inner side of the cell membrane. Starting from these results, to obtain much information about structure requirements involved in the interaction of the peptide mentioned above, we synthetized a panel of seven peptides through an Ala-scan approach. In detail, to study the binding of FHIT derived peptides with ANXA4, we applied a combination of different biophysical techniques such as differential scanning fluorimetry (DSF), surface plasmon resonance (SPR), and microscale thermophoresis (MST). Circular dichroism (CD) and nuclear magnetic resonance (NMR) were used to determine the conformational structure of the lead peptide (7–13) and peptides generated from ala-scan technique. The application of different biophysical and structural techniques, integrated by a preliminary biological evaluation, allowed us to build a solid structure activity relationship on the synthesized peptides.

Previously, we evaluated the effect of trichostatin A (TSA) on the expression of DNA methyltransferase 1 (DNMT1) in Hepatocellular Carcinoma (HCC). Fragile histidine triad (FHIT) and WW domain-containing oxidoreductase (WWOX) are two of the most common down-regulated genes in many cancers located on chromosome 3p14.2 and 16q23.3-24.1 respectively. The aim of the current study was to assess the effect of TSA on these genes expression, cell growth, and apoptosis in HCC WCH 17 cell. The cells were seeded and treated with TSA at different times. Then, MTT assay, flow cytometry, and qRT-PCR were achieved to determine viability, apoptosis and gene expression respectively. Cell growth was significantly inhibited, 92 to 36% after 24 h, 86 to 28% after 48 h, and 78 to 24% after 72 h. The results of flow cytometry confirmed that TSA increased apoptosis compared to the control group, the apoptosis percentage increased to 12%, 16%, and 18% in comparison to control groups (2%). Significant up-regulation of the genes was observed in all treated groups. We concluded that re-expression of silenced WWOX and FHIT genes could be achieved by TSA resulting in cell growth inhibition and apoptosis induction in WCH 17 cell.

BackgroundSince tumor suppressor gene function may be lost through hypermethylation, we assessed whether the demethylating agent decitabine could increase tumor suppressor gene expression clinically. For fragile histidine triad (FHIT), WW domain-containing oxidoreductase (WWOX), fused in sarcoma-1 (FUS1) and phosphatase and tensin homolog (PTEN), immunohistochemistry scores from pre- and post-decitabine tumor biopsies (25 patients) were correlated with methylation of the long interspersed nuclear element-1 (LINE-1) repetitive DNA element (as a surrogate for global DNA methylation) and with tumor regression.ResultsWith negative staining pre-decitabine (score = 0), the number of patients converting to positive staining post-decitabine was 1 of 1 for FHIT, 3 of 6 for WWOX, 2 of 3 for FUS1 and 1 of 10 for PTEN. In tumors with low pre-decitabine tumor suppressor gene scores (≤150), expression was higher post-treatment in 8 of 8 cases for FHIT (P = 0.014), 7 of 17 for WWOX (P = 0.0547), 7 of 12 for FUS1 (P = 0.0726), and 1 of 16 for PTEN (P = 0.2034). If FHIT, WWOX and FUS1 were considered together, median pre- versus post-decitabine scores were 60 versus 100 (P = 0.0002). Overall, tumor suppressor gene expression change did not correlate with LINE-1 demethylation, although tumors converting from negative to positive had a median decrease in LINE-1 methylation of 24%, compared to 6% in those not converting (P = 0.069). Five of 15 fully evaluable patients had reductions in tumor diameter (range 0.2% to 33.4%). Of these, three had simultaneous increases in three tumor suppressor genes (including the two patients with the greatest tumor regression) compared to 2 of 10 with tumor growth (P = 0.25).ConclusionsIn tumors with low tumor suppressor gene expression, decitabine may be associated with increased expression of the tumor suppressor genes FHIT, FUS1, and WWOX, but not PTEN.

Osteosarcoma is the most common malignant bone tumor, and although there has been significant progress in its management, metastases often herald incurable disease. Here we defined genes differentially expressed between primary and metastatic osteosarcoma as metastasis-related genes (MRGs) and used them to construct a novel six-MRG prognostic signature for overall survival of patients with osteosarcoma. Validation in internal and external datasets confirmed satisfactory accuracy and generalizability of the prognostic model, and a nomogram based on the signature and clinical variables was constructed to aid clinical decision-making. Of the six MRGs, FHIT is a well-documented tumor suppressor gene that is poorly defined in osteosarcoma. Consistent with tumor suppressor function, FHIT was downregulated in osteosarcoma cells and human osteosarcoma samples. FHIT overexpression inhibited osteosarcoma proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, FHIT overexpression upregulate the epithelial marker E-cadherin while repressing the mesenchymal markers N-cadherin and vimentin. Our six-MRG signature represents a novel and clinically useful prognostic biomarker for patients with osteosarcoma, and FHIT might represent a therapeutic target by reversing epithelial to mesenchymal transition.

Breast cancer is the most common cancer in women worldwide with remarkable proportion of the patients in advanced stage. Recently the importance of genetic mutations in cancers are well established and also the role of tumor suppressor genes such as FHIT gene in both heritable and non-heritable cancer. MicroRNAs are a class of non-coding RNAs which can interfere with cellular regulation. In this study, the association of rs73092672 which is located within the FHIT gene and the 3'UTR of hsa-miR-509-5p with the susceptibility to breast cancer risk has been studied in the Iranian population. By using the PCR_RFLP, the genotype rs73092672 was determined in 90 patients and 100 control subjects. The genotypes of the individuals were analyzed statistically to find the association between rs73092672 and the breast cancer incidence. The results revealed that due to the dominance of the C allele, the frequency of CC + CT genotypes, as compared with TT, had a significant correlation with the incidence of this disease in controls and cases (p = 0.02; OR= 3.6). Moreover, Bioinformatics analysis suggests rs73092672 as a polymorphism in the 3'UTR of hsa-miR-509-5p with higher binding affinity in the presence of T allele than C allele. [ABSTRACT FROM AUTHOR]

Despite its efficacy in solid tumours, in particular HER2+ breast cancer, HER2‐targeted therapy has given rise to disappointing results in non‐small cell lung cancer (NSCLC). With the aim of refining the target population for anti‐HER2 therapies in NSCLC, we investigated the relationships between HER2 and the tumour suppressor fragile histidine triad (FHIT) in lung tumour cells. First, we observed a negative correlation between FHIT expression and the activated form of HER2 (pHER2) in NSCLC samples and in lung tumour cell lines. Moreover, the silencing or overexpression of FHIT in lung cell lines led to an increase or decrease of HER2 activity, respectively. We also demonstrated that two anti‐HER2 drugs, irbinitinib and trastuzumab, restore a more epithelial phenotype and counteract cell invasiveness and growth of FHIT‐silenced tumour cell lines. Finally, we showed that the FHITlow/pHER2high phenotype predicts sensitivity to an anti‐HER2 therapy in primary tumour cells from NSCLC patients. Our results show that FHIT regulates the activity of HER2 in lung tumour cells and that FHIT‐inactivated tumour cells are sensitive to HER2 inhibitors. A new subclass of patients with NSCLC may be eligible for an anti‐HER2 therapy. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract Background FHIT is a genome caretaker/tumor suppressor that is silenced in >50% of cancers. Although it was identified more than 20 years ago, questions remain as to how FHIT loss contributes to cancer, and conversely, how FHIT acts to maintain genome integrity and suppress malignancy. Fhit belongs to the histidine triad family of enzymes that catalyze the degradation of nucleoside 5′,5′-triphosphates, including the m7GpppN ‘caps’ that are generated when mRNAs undergo 3′-5′ decay. This raised the possibility that Fhit loss might affect changes in the translation of cancer-associated mRNAs, possibly as a consequence of increased intracellular concentrations of these molecules. Results Ribosome profiling identified several hundred mRNAs for which coding region ribosome occupancy changed as a function of Fhit expression. While many of these changes could be explained by changes in mRNA steady-state, a subset of these showed changes in translation efficiency as a function of Fhit expression. The onset of malignancy has been linked to changes in 5’-UTR ribosome occupancy and this analysis also identified ribosome binding to 5′-untranslated regions (UTRs) of a number of cancer-associated mRNAs. 5’-UTR ribosome occupancy of these mRNAs differed between Fhit-negative and Fhit-positive cells, and in some cases these differences correlated with differences in coding region ribosome occupancy. Conclusions In summary, these findings show Fhit expression impacts the translation of a number of cancer associated genes, and they support the hypothesis that Fhit’s genome protective/tumor suppressor function is associated with post-transcriptional changes in expression of genes whose dysregulation contributes to malignancy.

Abstract Objectives In > 50% of cancers tumor development involves the early loss of Fhit (fragile histidine triad) protein expression, yet the mechanistic pathway(s) by which Fhit mediates its tumor suppressor functions are not fully understood. Earlier attempts to identify a Fhit-deficient gene expression profile relied on total cellular RNA and microarray analysis. The data here used RNA sequencing (RNA-Seq) of Fhit-negative and Fhit-positive cells as proof of principle for the impact of Fhit on specific mRNAs, and to lay the foundation for a study using ribosome profiling to identify mRNAs whose translation is affected by FHIT loss. Data description RNA-Seq was performed on RNA from lines of Fhit-expressing and Fhit-deficient lung cancer cells. This identified changes in the levels of mRNAs for a number of cell survival and cell cycle progression genes. Polysome profile analysis performed on cytoplasmic extracts from Fhit-negative and Fhit-positive cells showed changes in the sedimentation of select mRNAs consistent with changes in translation efficiency. The impact of differential Fhit expression on the turnover of selected cancer-linked mRNAs was determined by RT-qPCR of cytoplasmic RNA isolated at intervals after treating cells with a transcription inhibitor.

In this research, we represented the structural characterization and preparation of two La(III)-based coordination polymers {[La(TATAB)(H2O)](H2O)2}n (1, H3TATAB = 4,4,4″-s-triazine-1,3,5-triyltri-m-aminobenzoic acid) and {[La(TCA)(H2O)](H2O)4}n (2, H3TCA = 1,3,5-tris (4-carbonylphenyloxy) benzene) by the usage of two flexible tricarboxylate ligand with different donor sites as the joints along with the different functional backbones. Furthermore, the nanostructures of complexes 1 and 2 (denoted as nano 1 and nano 2 hereafter) have been prepared via a sonochemical synthesis approach. The results indicated that nano 1 can block the SCC-25 cancer cells' proliferation. Moreover, Annexin V-FITC/PI assay was carried out to discover the SCC-25 (Phosphorus cancer cells of human tongue) cancer cells' apoptosis after compounds treatment. The data showed that nano 1 significantly improve the apoptotic cells numbers rather than nano 2. In addition, nano 1 facilitated the ROS's (ROS = reactive oxygen species) accumulation which are important in cell apoptosis. The western blot showed that nano 1 induce cell apoptosis via up-regulating FHIT expression. [ABSTRACT FROM AUTHOR]

Two suppressor genes which often undergo epigenetic silencing during the early stages of lung carcinogenesis are those encoding retinoic acid receptor-β (RARβ) and Fhit protein (FHIT). RARβ expression is regulated by miRNA-34a and miRNA-141, and FHIT expression by miRNA-143 and miRNA-217. The aim of the study was to assess how selected miRNAs regulate the expression of their targeted genes in bronchoalveolar lavage fluid (BALf), obtained from patients with SCC of the lung. It also examines the relationship between the genetic findings and the clinical and pathomorphological features of the tumor. A total of 50 BALf samples were taken: 25 from patients with SCC and 25 from healthy donors. The expression (RQ) of the selected genes was analyzed by qPCR, as well as the miRNA level, with a particular emphasis on the relationship between the expression of the genes themselves and their corresponding miRNAs; in addition, the expression of the genes and miRNAs were compared with the pathomorphological features of the tumor and the clinical features of patients. Analysis of the RQ values showed downregulation of RARß, FHIT and miRNA-34a and increased expression of miRNA-141, miRNA-143 and miRNA-217 in all BALf samples (P > 0.05). No correlation was found between the expression of the selected genes and corresponding miRNAs, history of smoking, cancer stage, age and sex of the patients. The presence of the selected genes and miRNAs in BALf material does not seem to have diagnostic potential in patients with SCC; however, the results should be verified on a larger group of patients. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to investigate the predictive value of the biomarkers FHIT, p27, and pERK1/ERK2 in salivary gland carcinomas. Material and methods: Immunohistochemical staining of FHIT, p27, and pERK1/ERK2 of 265 patients with salivary gland carcinomas was conducted, and associations with clinico-histopathological data, overall survival, and disease-specific survival were examined. Results: Expression of FHIT (quick score 98.7 vs. 206.4) and p27 (QS 187.3 vs. 244.8) was significantly lower in carcinomas compared to non-tumor control tissue. Loss of FHIT frequently occurred in ACC (55.2%), SDC (68.2%), and SCC (100%). In the totality of tumors, loss of FHIT expression was found in 46.7% (106/227) and was significantly associated with advanced T stage and UICC stage, high-grade histology, loss of p27, PI3K, and survivin. FHIT positivity went along with significantly better overall and disease-specific survival. Negativity of p27 occurred in 28.7% (70/244) of tumors, particularly in SDC (54.4%) and SCC (50%). In the totality of tumors, p27 was associated with advanced patient age, high-grade histology, PI3K, survivin as well as better overall and disease-specific survival (p < 0.05). Positive pERK1/ERK2 expression correlated with positive survivin expression but did not affect overall survival in the totality of tumors. In mucoepidermoid carcinomas, pERK1/ERK2 expression was associated with low-grade malignancy, positive nuclear survivin, and better disease-specific survival. Conclusions: Loss of FHIT and p27 characterizes aggressive tumor growth and unfavorable prognosis in salivary gland cancer. Clinical relevance: The results may help to stratify patient-specific therapies according to individual tumor characteristics. [ABSTRACT FROM AUTHOR]

Xiaoyu Wu,1,* Guannan Wu,1,* Xuequan Yao,1 Gang Hou,2 Feng Jiang3 1Department of Surgical Oncology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, 2Department of Respiratory Medicine, The First Hospital of China Medical University, Shenyang, 3Department of Thoracic Surgery, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, People’s Republic of China *These authors contributed equally to this work Abstract: Emerging evidence indicates that FHIT is a candidate tumor suppressor in many types of tumors including non-small-cell lung carcinoma (NSCLC). However, the prognostic value and correlation between FHIT hypermethylation and clinicopathological characteristics of NSCLC remains unclear. In this report, we performed a meta-analysis to evaluate the effects of FHIT hypermethylation on the incidence of NSCLC and clinicopathological characteristics of human NSCLC patients. Final analysis of 1,801 NSCLC patients from 18 eligible studies was performed. FHIT hypermethylation was found to be significantly higher in NSCLC than in normal lung tissue. The pooled odds ratio (OR) from ten studies included 819 NSCLC and 792 normal lung tissues (OR =7.51, 95% confidence interval [CI] =2.98–18.91, P

Objective: The aim of this study was to determine the expression levels of CDH1, FHIT, and TTPAL genes and to determine the genotype and allele frequencies of the IL7Rα gene polymorphism rs6897932 in patients with breast cancer., Methods: The expression levels of genes and the distribution of the IL7Rα gene polymorphism rs6897932 were analyzed by real-time polymerase chain reaction., Results: No differences in genotype ratios or allele frequencies were observed between the 2 groups for the IL7Rα gene polymorphism rs6897932. The frequency of the IL7Rα rs6897932 T risk allele was found to be similar between breast cancer patients and controls. CDH1 messenger RNA (mRNA) levels decreased (0.714-fold and 0.834-fold, respectively), and TTPAL mRNA levels increased (2.675-fold [P < .05] and 1.169-fold, respectively) in tumor tissues and peripheral blood samples. FHIT mRNA levels decreased (0.559-fold) in tumor tissue samples and increased (2.21-fold) in peripheral blood samples., Conclusion: Our results are compatible with those reported in the literature. It can be suggested that the upregulation observed in the TTPAL gene might be a marker for breast cancer. The downregulation of CDH1 and FHIT gene expression has been validated in our study. An increase in the copy numbers of FHIT mRNA in blood samples and a decrease in the tumor samples can also be considered an abnormal condition.

The functional head impulse test is a new test of vestibular function based on the ability to recognize the orientation of a Landolt C optotype that briefly appears on a computer screen during passive head impulses imposed by the examiner over a range of head accelerations. Here, we compare its results with those of the video head impulse test on a population of vestibular neuritis patients recorded acutely and after 3 months from symptoms onset. The preliminary results presented here show that while both tests are able to identify the affected labyrinth and to show a recovery of vestibular functionality at 3 months, the two tests are not redundant, but complementary. [ABSTRACT FROM AUTHOR]

Background: FHIT is a genome caretaker/tumor suppressor that is silenced in >50% of cancers. Although it was identified more than 20 years ago, questions remain as to how FHIT loss contributes to cancer, and conversely, how FHIT acts to maintain genome integrity and suppress malignancy. Fhit belongs to the histidine triad family of enzymes that catalyze the degradation of nucleoside 5',5'-triphosphates, including the m7GpppN 'caps' that are generated when mRNAs undergo 3'-5' decay. This raised the possibility that Fhit loss might affect changes in the translation of cancer-associated mRNAs, possibly as a consequence of increased intracellular concentrations of these molecules. Results: Ribosome profiling identified several hundred mRNAs for which coding region ribosome occupancy changed as a function of Fhit expression. While many of these changes could be explained by changes in mRNA steady-state, a subset of these showed changes in translation efficiency as a function of Fhit expression. The onset of malignancy has been linked to changes in 5'-UTR ribosome occupancy and this analysis also identified ribosome binding to 5'-untranslated regions (UTRs) of a number of cancer-associated mRNAs. 5'-UTR ribosome occupancy of these mRNAs differed between Fhit-negative and Fhit-positive cells, and in some cases these differences correlated with differences in coding region ribosome occupancy. Conclusions: In summary, these findings show Fhit expression impacts the translation of a number of cancer associated genes, and they support the hypothesis that Fhit's genome protective/tumor suppressor function is associated with post-transcriptional changes in expression of genes whose dysregulation contributes to malignancy. [ABSTRACT FROM AUTHOR]

Background: There have been suggestions that fragile histidine triad protein (FHIT) expression and FHIT gene hypermethylation were crucial to the pathogenesis of liver cancer. However, the conclusions remained unclear because of small sample size, disease subtype, and different detection techniques. Therefore, we performed a meta-analysis to estimate the associations of FHIT expression and FHIT gene hypermethylation with liver cancer pathogenesis. Methods: Studies that were published in electronic databases, such as PubMed, Web of Knowledge, China National Knowledge Infrastructure (CNKI), VIP, and WanFang, were retrieved and selected for the meta-analysis. Relative risk (RR) and 95% confidence interval (CI) were calculated to determine the correlations of FHIT expression and FHIT gene hypermethylation with liver cancer pathogenesis with Stata 12.0 software. Results: A total of 17 papers that evaluated the associations of FHIT expression (14 articles) and FHIT gene methylation (3 articles) with liver cancer pathogenesis were included in this metaanalysis. In the overall analysis, the pooled relative risk was 1.93 (95% CI =1.72-2.17), which indicated a significant association between FHIT low expression and liver cancer risk. According to the results of clinical information, there were significant associations of FHIT expression with TNM-stage (RR =2.13, 95% CI =1.72-2.64), tumor size (RR =1.67, 95% CI =1.36-2.05), and merger of cirrhosis (RR =1.34, 95% CI =1.06-1.69) of liver cancer in the Chinese population. In addition, the FHIT gene hypermethylation was significantly associated with the risk of liver cancer (RR =1.45, 95% CI =1.08-1.93). Conclusion: The FHIT expression and hypermethylation of FHIT gene were significantly associated with the risk of liver cancer, especially in the Chinese population. Furthermore, the results indicated significant associations between FHIT low expression and TNM-stage, tumor size, and merging of cirrhosis of liver cancer in the Chinese population. [ABSTRACT FROM AUTHOR]

Aberrant Fhit expression characterizes a large proportion of primary pancreatic ductal adenocarcinomas (PDACs), but fragmentary information is available on Fhit expression during the phenotypic changes of pancreatic ductal epithelium during multistep transformation. We assessed Fhit expression by immunohistochemistry in two different multistep pancreatic carcinogenic processes: pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). We considered 105 surgically treated PDACs/IPMNs and selected 30 samples of non-neoplastic pancreatic parenchyma, 50 PanIN lesions, 30 IPMNs, 15 IPMNs with associated invasive carcinoma, and 60 adenocarcinomas. Normal pancreatic ducts and surrounding acinar cells consistently showed moderate to strong Fhit immunoreactivity. Significant down-regulation of Fhit expression was observed in association with increasing severity of dysplastia/neoplastia in both carcinogenic processes. This was further confirmed by studying multiple lesions obtained from the same surgical specimen. Of 60 PDACs, only 14 showed Fhit expression comparable to normal pancreatic ductal epithelium, while the remainder (77%) showed clearly negative or reduced Fhit expression. This study demonstrates that Fhit down-regulation is an early event in both multistep carcinogenic processes leading to PDAC. [ABSTRACT FROM AUTHOR]

The RARβ and FHIT promoter methylation are observed in some cervical carcinoma. However, the association between RARβ and FHIT promoter methylation and cervical carcinogenesis remains unclear. This study was carried out to evaluate the correlation between RARβ or FHIT promoter methylation and cervical carcinogenesis. Eligible publications were searched via online databases. The combined odds ratios and corresponding 95% confidence intervals were calculated and summarized. In all, 17 eligible articles on RARβ and FHIT promoter methylation were identified in the study. RARβ promoter methylation was significantly higher in cervical cancer than in cervical intraepithelial neoplasia lesions and normal cervical tissues (odds ratio = 3.90, p = 0.018; odds ratio = 12.98, p < 0.001, respectively). There was more FHIT promoter methylation in cervical cancer than in cervical intraepithelial neoplasia lesions and normal controls (odds ratio = 8.0, p = 0.055; odds ratio = 10.75, p < 0.001, respectively). In addition, FHIT promoter methylation was correlated with clinical stage (advanced stage vs early stage: odds ratio = 2.69, p = 0.056) and tumor grade (high grade vs low grade: odds ratio = 4.11, p < 0.001). RARβ and FHIT promoter methylation may be associated with the carcinogenesis of cervical cancer. FHIT promoter methylation may play a crucial role in cervical cancer progression. Additional studies with large sample sizes are essential to confirm our findings. [ABSTRACT FROM AUTHOR]

FHIT, located at FRA3B, is one of the most commonly deleted genes in human cancers, and loss of FHIT protein is one of the earliest events in cancer initiation. However, location of FHIT at a chromosomal fragile site, a locus prone to breakage and gap formation under even mild replication stress, has encouraged claims that FHIT loss is a passenger event in cancers. We summarize accumulated evidence that FHIT protein functions as a genome "caretaker" required to protect the stability of genomes of normal cells of most tissues from agents causing intrinsic and extrinsic DNA damage. FHIT loss leads to intracellular replication stress and subsequent genome instability, which provides an opportunistic mutational landscape in preneoplasias for selection of a variety of other cancer-driving mutations. We also review evidence showing that FHIT loss leads to enhanced activation of other common fragile sites, including the FRA16D/ WWOX locus, and creates optimal single-stranded DNA substrates for the hypermutator enzyme, APOBEC3B. [ABSTRACT FROM AUTHOR]

FHIT is a genome caretaker gene that is silenced in > 50% of cancers. Loss of Fhit protein expression promotes accumulation of DNA damage, affects apoptosis and epithelial-mesenchymal transition, though molecular mechanisms underlying these alterations have not been fully elucidated. Initiation of genome instability directly follows Fhit loss and the associated reduced Thymidine Kinase 1 (TK1) protein expression. The effects on TK1 of Fhit knockdown and Fhit induction in the current study confirmed the role of Fhit in regulating TK1 expression. Changes in Fhit expression did not impact TK1 protein turnover or transcription from the TK1 promoter, nor steady-state levels of TK1 mRNA or turnover. Polysome profile analysis showed that up-regulated Fhit expression resulted in decreased TK1 RNA in non-translating messenger ribonucleoproteins and increased ribosome density on TK1 mRNA. Fhit does not bind RNA but its expression increased luciferase expression from a transgene bearing the TK1 5′-UTR. Fhit has been reported to act as a scavenger decapping enzyme, and a similar result with a mutant (H96) that binds but does not cleave nucleoside 5′,5′-triphosphates suggests the impact on TK1 translation is due to its ability to modulate the intracellular level of cap-like molecules. Consistent with this, cells expressing Fhit mutants with reduced activity toward cap-like dinucleotides exhibit DNA damage resulting from TK1 deficiency, whereas cells expressing wild-type Fhit or the H96N mutant do not. The results have implications for the mechanism by which Fhit regulates TK1 mRNA, and more broadly, for its modulation of multiple functions as tumor suppressor/genome caretaker. [ABSTRACT FROM AUTHOR]