The FHIT gene product: tumor suppressor and genome “caretaker”

Waters, Catherine E.; Saldivar, Joshua C.; Hosseini, Seyed Ali; Huebner, Kay

doi:10.1007/s00018-014-1722-0

Cited by 89 publications

(96 citation statements)

References 69 publications

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“…In line with our hypothesis, we found that Fhit − / − mice showed significantly more carcinogen‐induced tumors than wt mice ( P < 0.001). We expect that the skin of Fhit − / − mice treated with the DMBA/PMA induction protocol would also display increased single‐base substitutions, copy number alterations and aneuploidy, representative of the genome instability seen in Fhit knockout mice 25, 39, compared to the skin of the similarly treated control mice.…”

Section: Discussionmentioning

confidence: 99%

Reduction in squamous cell carcinomas in mouse skin by dietary zinc supplementation

Sun

Shen²,

Schrock

et al. 2016

Cancer Medicine

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Inadequate dietary Zn consumption increases susceptibility to esophageal and other cancers in humans and model organisms. Since Zn supplementation can prevent cancers in rodent squamous cell carcinoma (SCC) models, we were interested in determining if it could have a preventive effect in a rodent skin cancer model, as a preclinical basis for considering a role for Zn in prevention of human nonmelanoma skin cancers, the most frequent cancers in humans. We used the 7,12‐dimethyl benzanthracene carcinogen/phorbol myristate acetate tumor promoter treatment method to induce skin tumors in Zn‐sufficient wild‐type and Fhit (human or mouse protein) knockout mice. Fhit protein expression is lost in >50% of human cancers, including skin SCCs, and Fhit‐deficient mice show increased sensitivity to carcinogen induction of tumors. We hypothesized that: (1) the skin cancer burdens would be reduced by Zn supplementation; (2) Fhit −/−(Fhit, murine fragile histidine triad gene) mice would show increased susceptibility to skin tumor induction versus wild‐type mice. 30 weeks after initiating treatment, the tumor burden was increased ~2‐fold in Fhit −/− versus wild‐type mice (16.2 versus 7.6 tumors, P < 0.001); Zn supplementation significantly reduced tumor burdens in Fhit −/− mice (males and females combined, 16.2 unsupplemented versus 10.3 supplemented, P = 0.001). Most importantly, the SCC burden was reduced after Zn supplementation in both strains and genders of mice, most significantly in the wild‐type males (P = 0.035). Although the mechanism(s) of action of Zn supplementation in skin tumor prevention is not known in detail, the Zn‐supplemented tumors showed evidence of reduced DNA damage and some cohorts showed reduced inflammation scores. The results suggest that mild Zn supplementation should be tested for prevention of skin cancer in high‐risk human cohorts.

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Section: Discussionmentioning

confidence: 99%

Reduction in squamous cell carcinomas in mouse skin by dietary zinc supplementation

Sun

Shen²,

Schrock

et al. 2016

Cancer Medicine

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“…Fhit knockout mouse models are much more susceptible to develop both spontaneous and carcinogen-induced tumors than wild-type control mice [16, 52]. As a tumor suppressor, FHIT’s role in the DDR is mainly guarding genome integrity and regulating apoptosis (reviewed in [23]). Pioneering work by the Huebner group showed that FHIT protects genomic integrity by preventing spontaneous replication stress.…”

Section: Cfs Gene Products With Roles In the Ddrmentioning

confidence: 99%

“…Hemizygous deletions are frequent in CFS genes (CFS-Gs), suggesting that these genes are haploinsufficient [16, 17] or that the second allele could be epigenetically silenced, as is seen for many CFS-Gs [18–22]. Furthermore, emerging findings show that CFS-Ps are directly involved in the DNA damage response (DDR) and therefore participate in maintaining genomic integrity (reviewed in [23–25]). These studies reveal that expression and activity of several CFS-Ps are induced in response to DNA damage and contribute to proper cellular checkpoint response, including DNA repair, cell cycle arrest, and apoptosis ([24, 26] and sections below).…”

Section: Introductionmentioning

confidence: 99%

Tumor Suppressor Genes within Common Fragile Sites Are Active Players in the DNA Damage Response

2016

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The role of common fragile sites (CFSs) in cancer remains controversial. Two main views dominate the discussion: one suggests that CFS loci are hotspots of genomic instability leading to inactivation of genes encoded within them, while the other view proposes that CFSs are functional units and that loss of the encoded genes confers selective pressure, leading to cancer development. The latter view is supported by emerging evidence showing that expression of a given CFS is associated with genome integrity and that inactivation of CFS-resident tumor suppressor genes leads to dysregulation of the DNA damage response (DDR) and increased genomic instability. These two viewpoints of CFS function are not mutually exclusive but rather coexist; when breaks at CFSs are not repaired accurately, this can lead to deletions by which cells acquire growth advantage because of loss of tumor suppressor activities. Here, we review recent advances linking some CFS gene products with the DDR, genomic instability, and carcinogenesis and discuss how their inactivation might represent a selective advantage for cancer cells.

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“…The fragile histidine triad (FHIT) is a tumor suppressor gene and is located in FRA3B which is the most active common fragile site, where DNA damage leading to aberrant transcripts and translocations frequently occur [1][2][3][4][5]. Abnormal transcripts of FHIT have been detected in various types of cancer [6,7].…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical characterization of FHIT expression in normal human tissues

Kujan

Abuderman

Al-Shawaf

2016

IMAS

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Abstract:Background: Fragile histidine triad (FHIT) is a tumor suppressor gene that is commonly inactivated in human tumors. Interestingly, the normal pattern of FHIT expression is largely unknown. Aim: This study is aimed to characterize the expression of FHIT protein in normal human tissues. Materials and methods: A total of 119 normal human tissue specimens were analyzed for the FHIT expression using immunohistochemistry technique. The inclusion criteria included: normal/infl ammatory tissue with no evidence of cellular atypia. Results: All studied specimens were stained positively with FHIT and showed either nuclear or cytoplasmic expression. Interestingly, the pattern of FHIT staining was similar among diff erent specimens from each organ. FHIT is located predominantly in the nucleus, although cytoplasmic staining is also present in some cell types. Oral squamous epithelium, breast ductal epithelium, squamous and tubal metaplastic epithelium of the uterine cervix, esophageal squamous epithelium, salivary glands, and bronchial epithelia all strongly expressed the nuclear protein. In connective tissue, FHIT has shown strong cytoplasmic expression in histocytes including macrophages and dendritic cells, fi broblasts, and myofi broblasts. Conclusion: Documentation of the pattern of FHIT expression in normal tissues will contribute to our understanding of the normal function of this protein and to interpretation of potentially altered FHIT expression in human tumors.

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The FHIT gene product: tumor suppressor and genome “caretaker”

Cited by 89 publications

References 69 publications

Reduction in squamous cell carcinomas in mouse skin by dietary zinc supplementation

Reduction in squamous cell carcinomas in mouse skin by dietary zinc supplementation

Tumor Suppressor Genes within Common Fragile Sites Are Active Players in the DNA Damage Response

Immunohistochemical characterization of FHIT expression in normal human tissues

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