Hypermethylation associated with inactivation of the SOCS-1 gene, a JAK/STAT inhibitor, in human hepatoblastomas

Nagai, Hisaki; Naka, Tetsuji; Terada, Yayoi; Komazaki, Toshiaki; Yabe, Aya; Jin, Enjing; Kawanami, Oichi; Kishimoto, Tadamitsu; Konishi, Noboru; Nakamura, Mitsutoshi; Kobayashi, Yasuhito; Emi, Mitsuru

doi:10.1007/s100380300008

Cited by 73 publications

(52 citation statements)

References 24 publications

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“…Inactivation of phosphatases such as SHP1 or SHP2, which dephosphorylate JAKs and STATs, might explain JAK deregulation. Other hypotheses include inactivation of negative regulators of the JAK-STAT pathway, such as the SOCS proteins, that were shown to be transcriptionally repressed by hypermethylation in different types of cancer (He et al, 2003;Nagai et al, 2003). However, we did not detect any decrease in SOCS1, 2, 3 and CISH expression in the five autonomous clones tested (data not shown).…”

Section: Activated Signaling Pathways In Autonomous Clonesmentioning

confidence: 71%

JAK kinases overexpression promotes in vitro cell transformation

et al. 2007

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Constitutive activation of the JAK-STAT pathway is frequent in cancer and contributes to oncogenesis. Here, we took advantage of the Ba/F3 cell line, a murine proB cell line dependent on IL-3 for growth, to analyse mechanisms of constitutive STAT activation in vitro. Cytokineindependent and tumorigenic Ba/F3 cell lines were derived from a two-step selection process. Cells transfected with a defective IL-9 receptor acquire IL-9 responsiveness during a first step of selection, and progress after a second selection step to autonomously growing tumorigenic cells. Microarray analysis pointed to JAK1 overexpression as a key genetic event in this transformation. Overexpression of JAK1 not only increased the sensitivity to IL-9 but also allowed a second selection step toward cytokine-independent growth with constitutive STAT activation. This progression was dependent on a functional FERM and kinase JAK1 domain. Similar results were observed after JAK2, JAK3 and TYK2 overexpression. All autonomous cell lines showed an activation of STAT5, ERK1-2 and AKT but only TYK2-overexpressing cell lines showed a constitutive activation of STAT3. Thus, JAK overexpression can be considered as one of the oncogenic events leading to the constitutive activation of the JAK-STAT pathway.

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Section: Activated Signaling Pathways In Autonomous Clonesmentioning

confidence: 71%

JAK kinases overexpression promotes in vitro cell transformation

et al. 2007

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“…The present and previous studies evaluated the methylation status of at least 20 genes in hepatoblastoma and found that only 3 genes were methylated (Table IV). 9,34,35 The limited number of methylated genes suggest that this profile may be specific for hepatoblastoma, 38 and the survival and stage distribution analyses disclosed that combined RASSF1A and SOCS1 or CASP8 methylation, or joint methylation of the 3 genes are not correlated with the advanced stage of disease or a poor outcome, contrary to the findings that methylation of multiple genes were correlated with a poor outcome, reported in neuroblastoma. 39 The present multivariate analysis identified unresectable tumor stages of disease (3B and 4) as the most significant factor predicting overall survival, followed by RASSF1A methylation.…”

Section: Discussionmentioning

confidence: 92%

The methylation status of RASSF1A promoter predicts responsiveness to chemotherapy and eventual cure in hepatoblastoma patients

Honda

Haruta

Sugawara

et al. 2008

Intl Journal of Cancer

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Despite the progress of therapy, outcomes of advanced hepatoblastoma patients who are refractory to standard preoperative chemotherapy remain unsatisfactory. To improve the mortality rate, novel prognostic markers are needed for better therapy planning. We examined the methylation status of 13 candidate tumor suppressor genes in 20 hepatoblastoma tumors by conventional methylation-specific PCR (MSP) and found hypermethylation in 3 of the 13 genes. We analyzed the methylation status of these 3 genes (RASSF1A, SOCS1 and CASP8) in 97 tumors and found hypermethylation in 30.9, 33.0 and 15.5%, respectively. Univariate analysis showed that only the methylation status of RASSF1A but not the other 2 genes predicted the outcome, and multivariate analysis showed a weak contribution of RASSF1A methylation to overall survival. Using quantitative MSP, we found RASSF1A methylation in 44.3% of the 97 tumors. CTNNB1 mutation was detected in 67.0% of the 97 tumors. While univariate analysis demonstrated RASSF1A methylation, CTNNB1 mutation and other clinicopathological variables as prognostic factors, multivariate analysis identified RASSF1A methylation (p 5 0.043; relative risk 9.39) and the disease stage (p 5 0.002; relative risk 7.67) but not CTNNB1 mutation as independent prognostic factors. In survival analysis of 33 patients in stage 3B or 4, patients with unmethylated tumor had better overall survival than those with methylated tumor (p 5 0.035). RASSF1A methylation may be a promising moleculargenetic marker to predict the treatment outcome and may be used to stratify patients when clinical trials are carried out. ' 2008 Wiley-Liss, Inc.Key words: RASSF1A; CTNNB1; quantitative MSP; hepatoblastoma; prognostic factor Hepatoblastoma is a rare malignant neoplasm of the liver, with an incidence of 0.5-1.5 per million children. 1 Remarkable progress in clinical outcome has been achieved in the past 20 years due to advances in chemotherapy and surgical procedures; however, the mortality rate remains 20-30% and treatment results in patients in advanced stages who are refractory to standard preoperative chemotherapy regimens are unsatisfactory. 2,3 To improve the mortality of these patients, innovative treatment and potent prognostic markers for better therapy planning are needed. The present clinical factors predicting outcome include the level of alpha-feto protein, histology, disease stage and growth pattern of the tumor. 2-4 Chromosomal gains of 2q, 8q and 20 and high expression of telomerase or PLK1 were shown to be moleculargenetic markers predicting poor outcome 5-8 ; however, none have been proven to be independent prognostic factors by multivariate analysis.We previously reported that RASSF1A (RAS association domain family protein 1) methylation, found in 39% of 39 hepatoblastoma tumors, was correlated with poor outcome by univariate analysis. 9 Nevertheless, the article had some limitations that the number of tumors was not enough, the method used to detect the hypermethylation was suboptimal, and the prognostic signifi...

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“…After the bisulphate treatment, the samples were amplified both for the promoter and Exon 2 regions by MS-PCR. The primers for the promoter region was reported previously [6] and Exon 2 primers were redesigned by us. The PCR yields were analyzed on 4% agarose gel.…”

Section: Bisulphate Treatment and Ms-pcrmentioning

confidence: 99%

“…Loss of SOCS1 gene could play an important role in the regulation and progression of leukomogenesis in CML. Thus, we aimed to study the methylation status of SOCS1 gene, which has been shown to be methylated in different tumor types [5][6][7], in CML patients.…”

Section: Introductionmentioning

confidence: 99%

The SOCS‐1 gene methylation in chronic myeloid leukemia patients

Hatırnaz¹,

Üre

et al. 2007

American J Hematol

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SOCS-1, an important protein in the JAK/STAT pathway, has a role in the down stream of BCR-ABL protein kinase. We investigated 56 CML patients and 16 controls for the methylation status of SOCS-1 gene promoter and Exon 2 regions. Exon 2 was found to be methylated in 58.9% of the patients and 93.8% of the controls [P 5 0.020, OR 5 0.121(0.015-0.957)%95CI]. The promoter region was found unmethylated in all patient samples and controls. Although previous studies revealed a relation between SOCS1 gene Exon-2 hypermethylation and CML development or progression, the results of this study showed no such correlation. On the contrary, our results might be indicating hypomethylation in CML patients, this hypothesis need to be studied in larger study population. Am. J. Hematol. 82:729-730, 2007. V

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Hypermethylation associated with inactivation of the SOCS-1 gene, a JAK/STAT inhibitor, in human hepatoblastomas

Cited by 73 publications

References 24 publications

JAK kinases overexpression promotes in vitro cell transformation

JAK kinases overexpression promotes in vitro cell transformation

The methylation status of RASSF1A promoter predicts responsiveness to chemotherapy and eventual cure in hepatoblastoma patients

The SOCS‐1 gene methylation in chronic myeloid leukemia patients

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