Muir–Torre-like syndrome in Fhit-deficient mice

Fong, Louise Y.Y.; Fidanza, Vincenzo; Zanesi, Nicola; Lock, L. F.; Siracusa, Linda D.; Mancini, Rita; Siprashvili, Zurab; Ottey, Michelle; Martín, Sabrina; Druck, Teresa; McCue, Peter A.; Croce, Carlo M.; Huebner, Kay

doi:10.1073/pnas.080063497

Cited by 189 publications

(235 citation statements)

References 22 publications

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“…In the present study, MMR deficiency was mainly due to the loss of Mlh1 expression, suggesting that MLH1 hypermethylation is the predominant mechanism (Herman et al, 1998). Recently, it has been reported that by NMBA (N-nitrosomethylbenzylamine) exposure, Fhit-deficient mice developed a spectrum of visceral and skin tumours similar to Muir-Torre syndrome, caused by a deficiency in a MMR gene (Fong et al, 2000). A large subgroup of MTS cases exhibits MSI and germline mutations in the MLH1 or MSH2 gene (Kruse et al, 1998).…”

Section: Genetics and Genomicsmentioning

confidence: 99%

“…Recently, Fong et al (2000) have demonstrated that NMBA (Nnitrosomethylbenzylamine) exposure caused a spectrum of visceral and skin tumours similar to Muir-Torre syndrome, caused by a deficiency in a MMR gene, in Fhit-deficient mice, and suggested that the FHIT gene may be a target of damage in a fraction of mismatch deficient tumours. Moreover, Mori et al (2001) reported that the loss of Msh2 protein is significantly correlated with the loss of Fhit expression in human CRCs.…”

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confidence: 99%

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Reduced Fhit expression is associated with mismatch repair deficiency in human advanced colorectal carcinoma

et al. 2002

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The Fragile Histidine Triad gene, encompassing the FRA3B fragile site at chromosome 3p14.2, is a candidate tumour suppressor gene involved in multiple tumour types including colorectal carcinomas. Recently, it has been reported that the Fragile Histidine Triad gene may be a target of damage in a fraction of mismatch deficient tumours. To explore this hypothesis, we analysed both Fragile histidine triad and mismatch repair protein (Msh2 and Mlh1) expression using immumohistochemical methods in 52 advanced colorectal carcinomas (19 well-, 17 moderately-, and 16 poorly-differentiated). In addition, we examined whether the Fragile histidine triad and mismatch repair protein expression correlated with p53 expression and clinicopathological findings. Significant loss or reduction of Fragile histidine triad expression was noted in 18 of the 52 (34.6%) advanced colorectal carcinomas: 2 (10.5%) well-differentiated, 3 (17.6%) moderately-differentiated, 13 (81.3%) poorly-differentiated carcinomas, the frequency being significantly higher in the latter than that in the former two (P50.0001). Loss of mismatch repair protein (mainly, Mlh1) expression was detected in 21 of the 52 (40.4%) colorectal carcinomas. Moreover, reduced Fragile histidine triad expression was significantly associated with absence of mismatch repair protein expression in the advanced colorectal carcinomas (P50.0001). However, the Fragile histidine triad and mismatch repair protein expression was not significantly associated with p53 expression. These results suggested that reduced Fragile histidine triad expression might be correlated with mismatch repair expression, but not with p53 expression.

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Section: Genetics and Genomicsmentioning

confidence: 99%

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confidence: 99%

Reduced Fhit expression is associated with mismatch repair deficiency in human advanced colorectal carcinoma

et al. 2002

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“…We hypothesized that they would show enhanced sensitivity to induction of skin cancers versus the B6 strain. Fhit knockout mice have shown enhanced sensitivity to carcinogen induction of gastric and lung cancers 20, 21, 22, so we considered that this strain would provide a strong test of the Zn supplementation effect. Also, loss of expression of Fhit tumor suppressor protein occurs in >50% of human cancers 23.…”

Section: Introductionmentioning

confidence: 99%

“…Fhit also serves as a genome caretaker preventing the onset of global genome instability 24, 25. Fhit‐deficient and haploinsufficient mice spontaneously develop lung tumors, lymphomas and liver hemangiomas at slightly higher incidences than wt mice 21 and 100% of Fhit knockout mice developed NMBA‐induced forestomach tumors, significantly more than wt mice 20, 21. We hypothesized that wt and Fhit‐deficient mice would develop increased numbers of induced NMSCs and that Zn supplementation would reduce tumor burdens.…”

Section: Introductionmentioning

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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“…Inactivation of the FHIT protein plays an important role in the development of several human cancers, including lung cancer [5][6][7]. Several lines of in vitro and in vivo experimental evidence have demonstrated the tumor suppression function of the FHIT gene [8][9][10][11][12]. Exogenous expression of the FHIT gene in 3p14.2-deficient cancer cells induces apoptosis and alters cell cycle kinetics in various types of cancer cells [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Induction of apoptosis by tumor suppressor FHIT via death receptor signaling pathway in human lung cancer cells

Deng

Nishizaki

Fang

et al. 2007

Biochemical and Biophysical Research Communications

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FHIT is a novel tumor suppressor gene located at human chromosome 3p14.2. Restoration of wildtype FHIT in 3p14.2-deficient human lung cancer cells inhibits cell growth and induces apoptosis. In this study, we analyzed potential upstream/downstream molecular targets of the FHIT protein and found that FHIT specifically targeted and regulated death receptor (DR) genes in human non-smallcell lung cancer (NSCLC) cells. Exogenous expression of FHIT by a recombinant adenoviral vector (Ad)-mediated gene transfer upregulated expression of DR genes. Treatment with a recombinant TRAIL protein, a DR-specific ligand, in Ad-FHIT-transduced NSCLC cells considerably enhanced FHIT-induced apoptosis, further demonstrating the involvement of DRs in FHIT-induced apoptosis. Moreover, we also found that FHIT targeted downstream of the DR-mediated signaling pathway. FHIT overexpression disrupted mitochondrial membrane integrity and activated multiple proapoptotic proteins in NSCLC cell. These results suggest that FHIT induces apoptosis through a sequential activation of DR-mediated pro-apoptotic signaling pathways in human NSCLC cells.

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Muir–Torre-like syndrome in Fhit-deficient mice

Cited by 189 publications

References 22 publications

Reduced Fhit expression is associated with mismatch repair deficiency in human advanced colorectal carcinoma

Reduced Fhit expression is associated with mismatch repair deficiency in human advanced colorectal carcinoma

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

Induction of apoptosis by tumor suppressor FHIT via death receptor signaling pathway in human lung cancer cells

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