SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer

He, Biao; Li, You; Uematsu, Kazutsugu; Zang, Keling; Xu, Zhidong; Lee, Amie Y.; Costello, J; McCormick, Frank; Jablons, David M.

doi:10.1073/pnas.2232790100

Cited by 344 publications

(300 citation statements)

References 43 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: 70%

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: 70%

JAK kinases overexpression promotes in vitro cell transformation

et al. 2007

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“…The question arises as to the possible cause of differential activation of these genes. Epigenetic changes in the course of prolonged cultivation of cells have been well described (Chow and Rubin, 2000;Fojtova et al, 2003) and both SOCS genes were shown to be inactivated by methylation of their promoters (He et al, 2003). However, we consider this possibility unlikely since the IFN-insensitive WM 1158R subline expressed SOCS 3, suggesting that the promoter is transcriptionally active.…”

Section: Expression Profiles Of Socss In Melanoma Cellsmentioning

confidence: 77%

“…For example, silencing of SOCS 1 and/or SOCS 3 genes by methylation of promoter has been correlated with the loss of growth control inhibition in lung (Yoshikawa et al, 2001), pancreatic (Komazaki et al, 2004), breast and ovarian (Sutherland et al, 2004) carcinomas. Similar epigenetic block apparently affected SOCS 3 gene expression in lung (He et al, 2003) and head and neck carcinomas (Weber et al, 2005). These studies indicated that aberrant silencing could be a cause for constitutive activation of JAK/STAT pathway in cancer cells.…”

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confidence: 70%

Development of IFN-γ resistance is associated with attenuation of SOCS genes induction and constitutive expression of SOCS 3 in melanoma cells

et al. 2007

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The resistance to interferons (IFNs) limits their anticancer therapeutic efficacy. Here we studied the evolution of an IFN-resistant state in vitro using melanoma cell lines. We found that the cells became less sensitive to antiproliferative effect of IFN-g after prolonged cultivation enabling us to isolate sensitive and resistant subclones of the parental line. We investigated transcription of signal transducer and activator of transcription (STAT) 1 -6 and suppressor of cytokine signalling (SOCS) 1 -3 genes, and phosphorylation of STAT 1 protein. The resistant subline (termed WM 1158R) differed from the sensitive subline (WM 1158S) by a constitutive expression of SOCS 3, lack or weak SOCS 1 -3 activation following IFN-g, and short duration of cytokine activatory signal. Similar correlations were observed in additional melanoma lines differing in IFN sensitivities. At the protein level, IFN-g induced strong and prolonged STAT 1 activation at serine 727 (S727) in WM 1158R while in WM 1158S cells phosphorylation of this amino acid was much less pronounced. On the other hand, phosphorylation of tyrosine 701 (Y701) was stimulated regardless of the sensitivity phenotype. In conclusion, constitutive expression of SOCS 3 is correlated with attenuation of its induction following IFN treatment. These results suggest that progression of melanoma cells from IFN sensitivity to IFN insensitivity associates with changes in SOCS expression.

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“…SOCS-3 works in a negative-feedback loop to suppress STAT-3 signaling; therefore, it is reasonable to suggest that loss of SOCS-3 may contribute to STAT-3 activation and tumor progression. Indeed, reports describing SOCS-3 hypermethylation and subsequent loss of expression in a variety of cancers support the idea that SOCS-3 may have a tumor-suppressing function (94)(95)(96)(97). In contrast, elevated SOCS-3 expression was reported in human breast cancer and melanoma tissues, as well as in a subset of classic Hodgkin's lymphoma cell lines and primary lymphoma cells (98)(99)(100)(101)(102)(103)(104).…”

Section: Involvement Of Socs-3 In Gliomasmentioning

confidence: 94%