Reduced Fhit Expression Occurs in the Early Stage of Esophageal Tumorigenesis: No Correlation with p53 Expression and Apoptosis

Kitamura, Akihiro; Yashima, Kazuo; Okamoto, Eiji; Andachi, H; Hosoda, Asao; Kishimoto, Yosuke; Shiota, Goshi; Ito, Hisao; Kaibara, Nobuaki; Kawasaki, Hironaka

doi:10.1159/000055376

Cited by 28 publications

(26 citation statements)

References 18 publications

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“…In this study, consistent with other studies (29,39,40), we have shown that FHIT is down-regulated early during carcinogenesis and that its down-regulation is associated with increasing dysplasia grade in POLs. In addition, the loss of FHIT expression was observed more frequently in precursor lesions that developed invasive SCC.…”

Section: Discussionsupporting

confidence: 93%

Fragile Histidine Triad Expression in Oral Squamous Cell Carcinoma and Precursor Lesions

Kujan

Oliver

Roz

et al. 2006

Clinical Cancer Research

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Pupose: Fragile histidine triad (FHIT) expression in precursor oral lesions (POL) and oral squamous cell carcinomas (OSCC) was studied with regard to (a) the frequency of loss of FHIT expression, (b) whether loss of FHITexpression correlates with degree of dysplasia in POLs, (c) whether FHIT loss predicts high-risk POLs that are more likely to transform, and (d) whether FHIT loss in OSCCs correlates with survival. Experimental Design: Ninety-four POLs and 86 OSCCs were immunostained for FHIT. Survival analysis was done for cases with validated clinical outcomes. Results: By optimizing the immunostaining protocol, we found that FHIT is expressed in a distinctive strong nuclear and weak cytoplasmic pattern in oral tissues. Loss of FHIT expression was found in 42 of 94 (45%) POLs and in 66 of 86 (77%) OSCCs. We observed a statistically significant positive correlation between frequency of FHIT loss and increasing grade of dysplasia (m 2 = 13.8; degrees of freedom = 4; P = 0.008). Loss of FHITexpression in POLs that progressed to malignancy was more frequent than in those that did not [17 of 25 (68%) versus 12 of 29 (41.4%), respectively]. This difference was statistically significant (m 2 = 3.8; degrees of freedom = 1; P = 0.046). In OSCCs, loss of FHIT staining indicated a worse prognosis (survival rate, 36.2%) than when positive FHIT staining was observed (survival rate, 50%), but the difference was not statistically significant (P = 0.546, Kaplan-Meier, log-rank). Conclusions: FHITseems to localize to both nuclear and cytoplasmic domains. FHIT inactivation occurs early in oral carcinogenesis and may be useful molecular marker for progressive dysplastic oral lesions.

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Section: Discussionsupporting

confidence: 93%

Fragile Histidine Triad Expression in Oral Squamous Cell Carcinoma and Precursor Lesions

Kujan

Oliver

Roz

et al. 2006

Clinical Cancer Research

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“…Alterations and abnormal transcripts of the FHIT gene have been reported in a number of primary human tumours, including CRCs (Ohta et al, 1996;Croce et al, 1999;Kitamura et al, 2001). However, some of the data are conflicting in CRCs (Hao et al, 2000;Hibi et al, 1997;Luceri et al, 2000;Mori et al, 2001;Thiagalingam et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…The Fragile histidine triad (Fhit) protein has been characterised as an Ap 3 A hydrolase molecule, which cleaves the Ap 4 A substrate that may be involved in the control of DNA replication and the cell cycle (Ohta et al, 1996). Frequent abnormal transcripts were found in a variety of human cancers including those of the digestive tract, lung, breast, and head and neck (Ohta et al, 1996;Croce et al, 1999;Kitamura et al, 2001). The majority of these abnormalities include aberrant mRNA transcripts, with the absence of one or more exons within the mRNA.…”

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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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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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“…However, conflicting results from reverse transcription (RT) -PCR analysis and genomic analysis have been reported (Ohta et al, 1996;Gemma et al, 1997;Tamura et al, 1997). In general, in tumours (lung and oesophagus) associated with environmental carcinogens, alterations in the FHIT gene occur early in cancer development, but are thought to be a late event in other cancers and possibly associated with cancer progression to more aggressive neoplasia (Croce et al, 1999;Kitamura et al, 2001). Moreover, little is known about Fhit expression in early gastric neoplasia.…”

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confidence: 99%

Fhit expression in human gastric adenomas and intramucosal carcinomas: correlation with Mlh1 expression and gastric phenotype

et al. 2004

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The fragile histidine triad (FHIT) gene, encompassing the FRA3B fragile site at chromosome 3p14.2, is a candidate tumour suppressor gene involved in a variety of tumours, including gastric carcinomas. Recently, it has been reported that the FHIT gene may be a target of damage in some of mismatch-deficient tumours. To clarify further the role of the Fhit protein in gastric carcinogenesis, we investigated whether Fhit expression in early gastric neoplasia is associated with mismatch repair protein expression and cellular phenotype. Fhit, Mlh1 and phenotypic expression were evaluated immunohistochemically in 87 early gastric neoplasias, comprising 32 adenomas and 55 intramucosal carcinomas, resected by endoscopic mucosal resection therapy. Significant loss or reduction of Fhit expression was noted in four (12.5%) of the 32 adenomas and 21 (38.2%) of the 55 intramucosal carcinomas. The rate of abnormal Fhit expression was significantly higher in intramucosal carcinomas than in adenomas (P ¼ 0.021). Moreover, reduced Fhit expression was found to be significantly associated with loss of Mlh1 expression in early gastric neoplasia (P ¼ 0.0011). Furthermore, we also detected a significant association between reduced Fhit expression and gastric phenotype (P ¼ 0.0018). These results suggested that reduced Fhit expression occurs in the early stage of gastric carcinogenesis and could be correlated with a lack of Mlh1 expression and gastric phenotype.

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Reduced Fhit Expression Occurs in the Early Stage of Esophageal Tumorigenesis: No Correlation with p53 Expression and Apoptosis

Cited by 28 publications

References 18 publications

Fragile Histidine Triad Expression in Oral Squamous Cell Carcinoma and Precursor Lesions

Fragile Histidine Triad Expression in Oral Squamous Cell Carcinoma and Precursor Lesions

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

Fhit expression in human gastric adenomas and intramucosal carcinomas: correlation with Mlh1 expression and gastric phenotype

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