Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine/paracrine stimulation of the interleukin 6/gp130 cytokine system.
Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine/paracrine stimulation of the interleukin 6/gp130 cytokine system.
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发表时间：
2003-06
期刊：
影响因子：
11.2
通讯作者：
V. Sriuranpong;Jong In Park;Panomwat Amornphimoltham;V. Patel;B. Nelkin;J. Gutkind
中科院分区：
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作者：
V. Sriuranpong;Jong In Park;Panomwat Amornphimoltham;V. Patel;B. Nelkin;J. Gutkind
头颈部鳞状细胞癌的异常生长常与信号转导通路信号转导通路3(signal-transducer-and-activator-of-transcription-3，STAT3)的结构性激活有关，而信号转导通路3被认为是在鳞状细胞癌细胞中高表达的表皮生长因子受体持续刺激的结果。为了研究STAT3在HNSCC中失控的机制，我们用一组HNSCC细胞株检测了STAT3和表皮生长因子受体(EGFR)信号通路的相互作用。尽管STAT3在大多数HNSCC细胞系中都是活性的，但在10个HNSCC细胞系中只有3个细胞系的激活的EGFR呈中到强阳性。即使在EGFR阳性的细胞系中，STAT3的激活也不依赖于EGFR的激活，因为在EGFR活性的化学抑制剂AG1478处理后，STAT3的酪氨酸磷酸化水平持续存在。此外，我们发现从HNSCC细胞获得的条件培养液可以诱导永生化角质形成细胞中STAT3酪氨酸的磷酸化，而与EGFR信号转导状态无关。相反，阻断细胞因子gp130辅受体后，HNSCC细胞中STAT3酪氨酸磷酸化水平及条件培养液诱导的STAT3酪氨酸磷酸化水平均被阻断。免疫耗竭研究表明，白介素6(IL6)是STAT3激活的主要自分泌/旁分泌因子，这与这些癌细胞高水平地将IL6分泌到培养上清液中相吻合。在HNSCC细胞中，用Janus激酶的特异性抑制剂AG490处理后，STAT3活性降低，并导致显著的生长迟缓和细胞凋亡。因此，在HNSCC中，STAT3的结构性激活可能使用IL6和其他细胞因子通过gp130受体家族作用的自分泌/旁分泌激活环，这可能在HNSCC中具有增殖和生存潜力。
The aberrant growth of head and neck squamous cell carcinoma (HNSCC) is often associated with the constitutive activation of signal-transducer-and-activator-of-transcription-3 (STAT3), which is believed to result from the persistent stimulation of EGF receptors that are highly expressed in squamous cell carcinoma (SCC) cells. To investigate the mechanism underlying STAT3 deregulation in HNSCC, we examined the interplay of the STAT3 and epidermal growth factor receptor (EGFR) signaling pathways using a panel of HNSCC cell lines. Although STAT3 was active in most HNSCC cell lines, only 3 of 10 HNSCC cell lines were moderately to strongly positive for activated EGFR. Even in the EGFR-positive cell lines, STAT3 activation was not dependent on EGFR activation, as STAT3 tyrosine phosphorylation levels persisted after treatment with AG1478, a chemical inhibitor of EGFR activity. Furthermore, we found that conditioned medium harvested from HNSCC cells could induce STAT3 tyrosine phosphorylation in immortalized keratinocytes regardless of the status of EGFR signaling. In contrast, blocking the cytokine gp130 coreceptor abolished STAT3 tyrosine phosphorylation in HNSCC cells and that induced by the conditioned medium. Immunodepletion studies suggested interleukin 6 (IL6) as the major autocrine/paracrine factor for STAT3 activation, which coincided with high levels of secretion of IL6 into the culture medium by these cancer cells. Treatment with a specific inhibitor of Janus kinase, AG490, in HNSCC cells led to a reduction of active STAT3 and caused significant growth retardation and apoptosis. Thus, constitutive activation of STAT3 in HNSCC may use an autocrine/paracrine-activating loop mediated by IL6 and other cytokines acting through the gp130 receptor family, which may confer both proliferative and survival potential in this malignancy.