Epigenetic modification of SOCS-1 differentially regulates STAT3 activation in response to interleukin-6 receptor and epidermal growth factor receptor signaling through JAK and/or MEK in head and neck squamous cell carcinomas
Epigenetic modification of SOCS-1 differentially regulates STAT3 activation in response to interleukin-6 receptor and epidermal growth factor receptor signaling through JAK and/or MEK in head and neck squamous cell carcinomas
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DOI：
10.1158/1535-7163.mct-05-0069
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发表时间：
2006-01-01
影响因子：
5.7
通讯作者：
Chen, Z
中科院分区：
文献类型：
--
作者：
Lee, TL;Yeh, J;Chen, Z
据报道，在头颈部鳞状细胞癌（HNSCC）中，信号转导和转录激活因子3（STAT 3）被白细胞介素-6受体（IL-6 R）或表皮生长因子受体（EGFR）激活，这可能对靶向EGFR、IL-6 R或中间激酶的治疗的反应性具有重要意义。细胞因子信号转导抑制因子-1（SOCS-1）最近被认为参与了IL-6 R/Janus激活激酶（JAK）介导的STAT 3激活的负调节，表明SOCS-1可以影响EGFR、IL-6 R和相关激酶对STAT 3的替代激活。我们研究了SOCS-1的表观遗传修饰是否影响STAT 3对IL-6 R-、EGFR-、JAK-或丝裂原活化蛋白激酶/细胞外信号调节激酶激酶（MEK）介导的信号激活的响应。在HNSCC系UMSCC-9和UMSCC-38中，STAT 3主要通过Jak 1/Jak 2被IL-6 R激活，与SOCS-1的转录沉默相关。在具有未甲基化SOCS-1的USCC-11 A细胞中，STAT 3活化通过涉及MEK的JAK非依赖性途径由EGFR和IL-6 R两者调节。JAK和MEK的药理学抑制剂以及去甲基化或瞬时转染后SOCS-1的表达抑制了相应细胞系中STAT 3的活化和细胞增殖并诱导细胞凋亡。在约三分之一的人类HNSCC组织中发现SOCS-1的高甲基化，使其成为HNSCC患者中STAT靶向治疗的潜在相关标志物。我们得出结论，SOCS-1甲基化状态可以通过JAK或MEK在不同的HNSCC中不同地影响IL-6 R和EGFR对STAT 3的激活以及对药物拮抗剂的反应。明确STAT 3激活的潜在因素和调控途径对HNSCC分子靶向治疗的发展和选择具有重要意义。
Signal transducer and activator of transcription 3 (STAT3) has been reported to be activated by interleukin-6 receptor (IL-6R) or epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinomas (HNSCC), which may have important implications for responsiveness to therapeutics targeted at EGFR, IL-6R, or intermediary kinases. Suppressor of cytokine signaling-1 (SOCS-1) has been implicated recently in the negative regulation of IL-6R/Janus-activated kinase (JAK)-mediated activation of STAT3, suggesting that SOCS-1 could affect alternative activation of STAT3 by EGFR, IL-6R, and associated kinases. We investigated whether epigenetic modification of SOCS-1 affects STAT3 activation in response to IL-6R-, EGFR-, JAK-, or mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)-mediated signal activation. STAT3 was predominantly activated by IL-6R via Jak1/Jak2 in HNSCC lines UMSCC-9 and UMSCC-38 in association with transcriptional silencing of SOCS-1 by hypermethylation. In UMSCC-11A cells with unmethylated SOCS-1, STAT3 activation was regulated by both EGFR and IL-6R via a JAK-independent pathway involving MEK. Pharmacologic inhibitors of JAK and MEK and expression of SOCS-1 following demethylation or transient transfection inhibited STAT3 activation and cell proliferation and induced cell apoptosis in corresponding cell lines. Hypermethylation of SOCS-1 was found in about one-third of human HNSCC tissues, making it a potentially relevant marker for STAT-targeted therapy in HNSCC patients. We conclude that SOCS-1 methylation status can differentially affect STAT3 activation by IL-6R and EGFR through JAK or MEK in different HNSCC and response to pharmacologic antagonists. Identifying the potential factors and the regulatory pathways in STAT3 activation has important implications for the development and selection of molecularly targeted therapy in HNSCC.