Hypermethylation-associated Inactivation of the SOCS-1 Gene, a JAK/STAT Inhibitor, in Human Pancreatic Cancers

Komazaki, Toshiaki; Nagai, Hisaki; Emi, Mitsuru; Terada, Yayoi; Yabe, Aya; Jin, Enjing; Kawanami, Ooiti; Konishi, Noboru; Moriyama, Yoshinori; Naka, Tetsuji; Kishimoto, Tadamitsu

doi:10.1093/jjco/hyh035

Cited by 56 publications

(33 citation statements)

References 13 publications

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“…For example, inactivation of the SOCS gene by methylation has been previously described in hepatocellular, pancreatic, lung, ovarian, and breast carcinomas (25,35,51,66,75). Since CpG island methylation generally results in complete absence of transcription, and increased baseline SOCS1 synthesis was observed in RC3 relative to WT8 cells (see Fig.…”

Section: Discussionmentioning

confidence: 76%

JAK kinases promote invasiveness in VHL-mediated renal cell carcinoma by a suppressor of cytokine signaling-regulated, HIF-independent mechanism

Miao²,

Khan³

2007

American Journal of Physiology-Renal Physiology

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Wu KL, Miao H, Khan S. JAK kinases promote invasiveness in VHL-mediated renal cell carcinoma by a suppressor of cytokine signaling-regulated, HIF-independent mechanism. Am J Physiol Renal Physiol 293: F1836-F1846, 2007. First published September 26, 2007; doi:10.1152/ajprenal.00096.2007 disease is a cancer syndrome, which includes renal cell carcinoma (RCC), and is caused by VHL mutations. Most, but not all VHL phenotypes are due to failure of mutant VHL to regulate constitutive proteolysis of hypoxia-inducible factors (HIFs). Janus kinases (JAK1, 2, 3, and TYK2) promote cell survival and proliferation, processes tightly controlled by SOCS proteins, which have sequence and structural homology to VHL. We hypothesized that in VHL disease, RCC pathogenesis results from enhanced SOCS1 degradation, leading to upregulated JAK activity. We find that baseline JAK2, JAK3, and TYK2 activities are increased in RCC cell lines, even after serum deprivation or coincubation with cytokine inhibitors. Furthermore, JAK activity is sustained in RCC stably expressing HIF2␣ shRNA. Invasion through Matrigel and migration in woundhealing assays, in vitro correlates of metastasis, are significantly greater in VHL mutant RCC compared with wild-type cells, and blocked by dominant-negative JAK expression or JAK inhibitors. Finally, we observe enhanced SOCS2/SOCS1 coprecipitation and reduced SOCS1 expression due to proteasomal degradation in VHLnull RCC compared with wild-type cells. The data support a new HIF-independent mechanism of RCC metastasis, whereby SOCS2 recruits SOCS1 for ubiquitination and proteasome degradation, which lead to unrestricted JAK-dependent RCC invasion. In addition to commonly proposed RCC treatment strategies that target HIFs, our data suggest that JAK inhibition represents an alternative therapeutic approach. Janus kinase; suppressor of cytokine signaling; von Hippel-Lindau syndrome VON HIPPEL-LINDAU (VHL) disease is a heritable multisystem cancer syndrome caused by germline mutations in VHL, which is located on chromosome 3p25 (30). The main causes of death are complications linked to highly angiogenic renal carcinomas and hemangioblastomas within the central nervous system (45, 59). The VHL gene is ubiquitously expressed (60) and the role of the VHL gene product (pVHL) in renal cell carcinoma (RCC) has been extensively studied (31, 49). There are currently no established, successful therapies, e.g., radiation or chemotherapy, for RCC other than nephrectomy in situations with no evidence of metastases.pVHL contains an ϳ100-residue NH 2 terminus (␤-domain) and a smaller COOH-terminal ␣-helix (␣-domain). Under normoxic conditions, the pVHL ␤-domain interacts with ␣-subunits of hypoxia-inducible factors (HIF)-1 and -2 transcription factors (48, 60), while the VHL ␣-domain and a small portion of the ␤-domain interact with Elongin C, a component of an E3 ubiquitin ligase complex that targets HIF-1␣ subunits for proteasomal degradation (31, 43, 64) and thereby prevents HIF transcription factor binding to target gene...

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Section: Discussionmentioning

confidence: 76%

JAK kinases promote invasiveness in VHL-mediated renal cell carcinoma by a suppressor of cytokine signaling-regulated, HIF-independent mechanism

Miao²,

Khan³

2007

American Journal of Physiology-Renal Physiology

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“…Because loss of expression of SOCS molecules has been reported in several human malignancies (18)(19)(20)(21)(22), we tested whether this could be the case of thyroid tumors, whose cytokine pathways were previously shown constitutively activated. For such purpose, purified epithelial cells from 10 PTC, 10 FTC, and 5 UTC, previously examined for positivity to IL-4 and IL-10 (data not shown), were analyzed by Real-Time PCR analysis for mRNA expression of SOCS1, SOCS3, and SOCS5, potent inhibitors of JAK/STAT activation.…”

Section: Resultsmentioning

confidence: 99%

Suppressor of Cytokine Signaling 3 Sensitizes Anaplastic Thyroid Cancer to Standard Chemotherapy

et al. 2009

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We previously showed that cancer cells from papillary, follicular, and anaplastic thyroid carcinomas produce interleukin-4 and interleukin-10, which counteract the cytotoxic activity of conventional chemotherapy through the upregulation of antiapoptotic molecules. Here, we identify Janus kinase/signal transducers and activators of transcription (STAT) and phosphatidyl inositol 3-kinase (PI3K)/AKT as the down-stream pathways through which these cytokines confer resistance to cell death in thyroid cancer. We found that the absence of suppressors of cytokine signaling (SOCS) molecules allows the propagation of the survival signaling. Exogenous expression of SOCS1, SOCS3, and SOCS5 in the highly aggressive anaplastic thyroid cancer cells reduces or abolishes STAT3 and 6 phosphorylation and PI3K/Akt pathway activation resulting in alteration in the balance of proapoptotic and antiapoptotic molecules and sensitization to chemotherapeutic drugs in vitro. Likewise, exogenous expression of SOCS3 significantly reduces tumor growth and potently enhances the efficacy of chemotherapy in vivo. Our results indicate that SOCS3 regulation of cytokines-prosurvival programs might represent a new strategy to overcome the resistance to chemotherapy-induced cell death of thyroid cancer. [Cancer Res 2009;69(15):6141-8]

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“…The recent research data also showed that SOCS-1 negatively regulated the response of chronic hepatitis C (CHC) to a-interferon (IFN-α) [12,13] . Methylation of SOCS-1 is implicated to be correlated with carcinoma, including hepatocarcinoma, pancreatic cancer, multiple myeloma and myeloid leukemia [14][15][16][17][18][19] . Expression of SOCS-1 was regulated by many factors.…”

Section: Introductionmentioning

confidence: 99%

Expression of SOCS-1 in the liver tissues of chronic hepatitis B and its clinical significance

Zhao¹,

Qing-xian²,

Peng³

et al. 2008

WJG

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Hypermethylation-associated Inactivation of the SOCS-1 Gene, a JAK/STAT Inhibitor, in Human Pancreatic Cancers

Abstract: The results suggested that this gene is silenced in a substantial portion of pancreatic cancers through mechanisms that cause methylation in the promoter region.

Cited by 56 publications

References 13 publications

JAK kinases promote invasiveness in VHL-mediated renal cell carcinoma by a suppressor of cytokine signaling-regulated, HIF-independent mechanism

JAK kinases promote invasiveness in VHL-mediated renal cell carcinoma by a suppressor of cytokine signaling-regulated, HIF-independent mechanism

Suppressor of Cytokine Signaling 3 Sensitizes Anaplastic Thyroid Cancer to Standard Chemotherapy

Expression of SOCS-1 in the liver tissues of chronic hepatitis B and its clinical significance

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