Gene expression of WWOX, FHIT and p73 in acute lymphoblastic leukemia

Chen, Xu; Zhang, Hui; Li, Ping; Yang, Zheng; Qin, Lingyan; Mo, Wuning

doi:10.3892/ol.2013.1514

Cited by 21 publications

(20 citation statements)

References 31 publications

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“…Previous studies have indicated that the methylation status of FHIT may lead to the silencing of gene expression, promoting the occurrence and development of acute lymphoblastic leukemia (17). In the present study, the FHIT gene was found to be expressed in FMSCs, but not in F6 cells.…”

Section: Discussionsupporting

confidence: 54%

Methylation status of the FHIT gene in the transformed human mesenchymal F6 stem cell line

Gao

Wang

et al. 2015

Oncology Letters

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Abstract. The fragile histidine triad (FHIT) gene is known to be a tumor suppressor gene and the abnormal methylation of FHIT has been identified in leukemia and several solid tumors. The transformation of the tumor F6 cell line from human fetal mesenchymal stem cells (FMSCs) was first reported in a previous study that also identified the presence of a population of cancer stem cells in the F6 cell line. However, the existence of the epigenetic changes during the transformation process have yet to be elucidated. To confirm the role of the FHIT gene in the transformation process of FMSC, the expression level and methylation status of the FHIT gene was examined in F6 tumor cells and FMSCs. Additionally, the alteration in cell morphology, the cell cycle and apoptosis in F6 cells following 5-Aza-CdR treatment was assessed. It was found that the FHIT gene was expressed in FMSCs, but not in F6 cells. The methylation-specific PCR results demonstrated that the promoter methylation of FHIT genes existed in the F6 cell line. Subsequent to treatment with 5-Aza-CdR the expression of FHIT genes was restored in F6 cells. In addition, the morphology of F6 cells was altered, and the cell cycle was arrested in the G 2 phase, with the initiation of apoptosis.Overall, the present findings demonstrated that the FHIT gene was methylated in F6 cells and demethylation treatment lead to changes in the biological characteristics, thereby promoting the apoptosis of F6 cells. FHIT gene methylation may be one of the molecular events involved in the development and transformation of FMSCs into F6 tumor cells. IntroductionMesenchymal stem cells (MSCs) are pluripotent adult stromal cells that possess the ability to differentiate into bone, cartilage and adipose tissues, and the cells exhibit promising potential for regenerative medicine (1). An increasing number of studies have demonstrated that MSCs demonstrate potential therapeutic effects for multiple diseases, including liver injury, ischemia/reperfusion-induced acute kidney injury and acute myocardial infarction (2-4). However, transplantation therapy using MSCs continues to be subject to investigation, particularly into the safety of MSCs in clinical application. In a previous study that aimed to determine the induction of MSC differentiation and immune function, tumorigenesis was observed unexpectedly and a cloned a novel tumor cell line, the F6 cell line, transformed from human fetal bone marrow MSCs (5). These findings initiated interest into investigating the mechanism of mutation in fetal MSCs (FMSCs).Previous studies have demonstrated that epigenetic and genetic alterations markedly contribute to tumorigenesis. The hypermethylation of tumor suppressor genes has been detected in various types of tumors (6). Ohta et al first reported the tumor suppressor gene fragile histidine triad (FHIT), providing the molecular evidence for the association between fragile sites and cancer (7). The loss or reduction of FHIT expression has been revealed to be important in the initiation of tumorige...

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Section: Discussionsupporting

confidence: 54%

Methylation status of the FHIT gene in the transformed human mesenchymal F6 stem cell line

Gao

Wang

et al. 2015

Oncology Letters

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“…In addition, Chen et al (36) reported that mRNA expression of FHIT was significantly lower and methylation frequency of FHIT was significantly higher in ALL samples compared with controls.…”

Section: Discussionmentioning

confidence: 99%

FHIT promoter DNA methylation and expression analysis in childhood acute lymphoblastic leukemia

et al. 2017

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Abstract. Fragile histidine triad (FHIT) is a tumor suppressor gene, which is involved in several malignancies. Epigenetic alterations in FHIT have been hypothesized to contribute to tumorigenesis. The present study aimed to examine DNA promoter methylation and gene expression levels of FHIT in childhood acute lymphoblastic leukemia (ALL), in a sample of Iranian patients. The promoter methylation status of FHIT was analyzed in 100 patients diagnosed with ALL and 120 healthy control patients. mRNA expression levels were assessed in 30 new cases of ALL compared with 32 healthy controls. Hypermethylation of the FHIT promoter was significantly more frequent in patients with ALL than in healthy controls (OR=3.83, 95% CI=1.51-9.75, P=0.007). Furthermore, FHIT mRNA expression levels were significantly reduced in childhood ALL patients compared with healthy controls (P=0.032). The results of the present study revealed that dysregulation of the FHIT gene may contribute to the pathogenesis of childhood ALL. Future studies investigating a larger sample population with greater ethnic diversity would be beneficial, to confirm the results from the present study.

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“…The bulk of the data documented have shown that the expression of WWOX/WWOX was lost or reduced in various types of solid cancers (2)(3)(4)(5)(6)(7)(8)(9)(10). Similarly, the aberration or absence of WWOX/WWOX expression in primary hematopoietic malignancies has also been reported (11)(12)(13)(14)(15)(16). A recently published study detected the expression of WWOX/WWOX in a small cohort of 38 primary leukemia patients and observed low expression levels (14).…”

Section: A B Cmentioning

confidence: 99%

“…A recently published study detected the expression of WWOX/WWOX in a small cohort of 38 primary leukemia patients and observed low expression levels (14). Chen et al (13) recently validated the expression of WWOX in ALL, and observed that the mRNA expression of WWOX, fragile histidine triad and tumor protein p73 was significantly lower in the ALL samples compared with the controls. Correspondingly, the current study showed that WWOX/WWOX expression was reduced or lost in a range of different leukemia types and cell lines in comparison to the normal controls.…”

Section: A B Cmentioning

confidence: 99%

“…The role of WWOX/WWOX in leukemia has also been reported, suggesting that WWOX may exert antineoplastic activity in human hematopoietic malignancies (11)(12)(13)(14)(15)(16). Our previous studies have demonstrated that WWOX exerts a role as an tumor suppressor gene in leukemia, inhibiting cell proliferation and promoting apoptosis via binding with p73 and triggering of the mitochondrial pathway (14,15).…”

Section: Introductionmentioning

confidence: 99%

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Reduced expression of the WW domain-containing oxidoreductase in human hematopoietic malignancies

et al. 2016

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Abstract. The role of the WW domain-containing oxidoreductase (WWOX) gene in multiple types of solid human cancers has been documented extensively thus far. Recently, we investigated the in vitro effects of WWOX overexpression and observed marked growth arrest in human leukemia cells; however, the clinical characterization of WWOX in leukemia remains poorly investigated. The present study evaluated the WWOX expression profiles of 182 patients with leukemia of different types and 5 leukemic cell lines, using reverse transcription-polymerase chain reaction and immunofluorescence analysis. The results found that WWOX mRNA and WWOX protein expression was significantly reduced or absent in the leukemia cases and cell lines compared with paired controls. The WWOX-positive rate was also lower in the leukemia cases compared with the rate of the normal controls. Notably, the WWOX level was reduced in newly diagnosed and relapsed cases, or in chronic myelogenous leukemia in the blastic phase, yet elevated in remission samples. Moreover, WWOX-negative cases exhibited WWOX expression restoration following induced remission. These findings suggest that WWOX may contribute to the occurrence and development of leukemia, and that it has potential to be a good biomarker or predictor for leukemia therapy.

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Gene expression of WWOX, FHIT and p73 in acute lymphoblastic leukemia

Cited by 21 publications

References 31 publications

Methylation status of the FHIT gene in the transformed human mesenchymal F6 stem cell line

Methylation status of the FHIT gene in the transformed human mesenchymal F6 stem cell line

FHIT promoter DNA methylation and expression analysis in childhood acute lymphoblastic leukemia

Reduced expression of the WW domain-containing oxidoreductase in human hematopoietic malignancies

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