Sriuranpong Virote, Park Jong In, Amornphimoltham Panomwat, Patel Vyomesh, Nelkin Barry D, Gutkind J Silvio
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland, 20892-4330, USA.
Cancer Res. 2003 Jun 1;63(11):2948-56.
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.
头颈部鳞状细胞癌（HNSCC）的异常生长通常与信号转导及转录激活因子3（STAT3）的组成性激活有关，据信这是由于表皮生长因子受体（EGF受体）在鳞状细胞癌（SCC）细胞中高表达而受到持续刺激所致。为了研究HNSCC中STAT3失调的机制，我们使用一组HNSCC细胞系研究了STAT3与表皮生长因子受体（EGFR）信号通路之间的相互作用。尽管STAT3在大多数HNSCC细胞系中呈激活状态，但10个HNSCC细胞系中只有3个对激活的EGFR呈中度至强阳性。即使在EGFR阳性的细胞系中，STAT3的激活也不依赖于EGFR的激活，因为在用EGFR活性化学抑制剂AG1478处理后，STAT3酪氨酸磷酸化水平仍然持续存在。此外，我们发现，无论EGFR信号状态如何，从HNSCC细胞收获的条件培养基都能诱导永生化角质形成细胞中的STAT3酪氨酸磷酸化。相反，阻断细胞因子gp130共受体可消除HNSCC细胞中以及条件培养基诱导的STAT3酪氨酸磷酸化。免疫耗竭研究表明白细胞介素6（IL6）是STAT3激活的主要自分泌/旁分泌因子，这与这些癌细胞向培养基中高水平分泌IL6相一致。用JAK激酶特异性抑制剂AG490处理HNSCC细胞会导致活性STAT3减少，并引起显著的生长迟缓和细胞凋亡。因此，HNSCC中STAT3的组成性激活可能利用了由IL6和其他通过gp130受体家族起作用的细胞因子介导的自分泌/旁分泌激活环，这可能赋予这种恶性肿瘤增殖和生存潜力。
