A disintegrin and metalloproteinase domain 17-epidermal growth factor receptor signaling contributes to oral cancer pain.
A disintegrin and metalloproteinase domain 17-epidermal growth factor receptor signaling contributes to oral cancer pain.
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癌细胞会分泌促痛介质，使邻近的感觉神经元敏感化并引发疼痛。对这些介质的识别与特性分析，可能会为癌症疼痛治疗找到新靶点。在本研究中，我们在癌细胞系中确定了一些候选基因，这些基因编码的分泌蛋白或细胞表面蛋白可能会引发痛觉感受。为开展这项研究，我们采用了急性癌痛小鼠模型、对公开的人类肿瘤衍生细胞系数据进行转录组分析，以及文献综述。根据急性癌痛小鼠模型中诱发的伤害感受行为，对癌细胞系上清液进行表型分类。我们比较了伤害感受性和非伤害感受性细胞系的基因表达数据。分析结果揭示了差异表达的基因和信号通路；许多已确定的基因此前并未与癌症疼痛信号传导相关联。在差异表达基因中，表皮生长因子受体（EGFR）和去整合素金属蛋白酶结构域17（ADAM17）被确定为潜在靶点。我们发现，与非伤害感受性细胞系相比，伤害感受性细胞系的细胞培养上清液中ADAM17蛋白含量显著更高。在小鼠中，几乎所有（>90%）舌部初级传入神经元中都存在细胞质EGFR。在急性口腔癌痛小鼠模型中，抗EGFR单克隆抗体西妥昔单抗抑制了细胞系上清液诱导的伤害感受行为。从这些数据我们推断，ADAM17 - EGFR信号传导参与了癌症介质诱导的痛觉感受。差异表达基因及其分泌的蛋白质产物，可能成为口腔癌疼痛的候选治疗靶点，值得进一步评估。
Cancer cells secrete pronociceptive mediators that sensitize adjacent sensory neurons and cause pain. Identification and characterization of these mediators could pinpoint novel targets for cancer pain treatment. In this study, we identified candidate genes in cancer cell lines that encode for secreted or cell surface proteins that may drive nociception. To undertake this work, we used an acute cancer pain mouse model, transcriptomic analysis of publicly available human tumor-derived cell line data, and a literature review. Cancer cell line supernatants were assigned a phenotype based on evoked nociceptive behavior in an acute cancer pain mouse model. We compared gene expression data from nociceptive and nonnociceptive cell lines. Our analyses revealed differentially expressed genes and pathways; many of the identified genes were not previously associated with cancer pain signaling. Epidermal growth factor receptor (EGFR) and disintegrin metalloprotease domain 17 (ADAM17) were identified as potential targets among the differentially expressed genes. We found that the nociceptive cell lines contained significantly more ADAM17 protein in the cell culture supernatant compared to nonnociceptive cell lines. Cytoplasmic EGFR was present in almost all (>90%) tongue primary afferent neurons in mice. Monoclonal antibody against EGFR, cetuximab, inhibited cell line supernatant-induced nociceptive behavior in an acute oral cancer pain mouse model. We infer from these data that ADAM17-EGFR signaling is involved in cancer mediator-induced nociception. The differentially expressed genes and their secreted protein products may serve as candidate therapeutic targets for oral cancer pain and warrant further evaluation.
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影响因子：
3.5
作者：
Das S;McCaffrey PG;Talkington MW;Andrews NA;Corlosquet S;Ivinson AJ;Clark T
通讯作者：
Clark T
影响因子：
158.5
作者：
Jonker, Derek J.;O'Callaghan, Chris J.;Moore, Malcolm J.
通讯作者：
Moore, Malcolm J.
影响因子：
20.3
作者：
Fong, Karen P.;Barry, Colin;Brass, Lawrence F.
通讯作者：
Brass, Lawrence F.
影响因子：
3.7
作者：
Kaganoi, Junichi;Watanabe, Go;Sakai, Yoshiharu
通讯作者：
Sakai, Yoshiharu
影响因子：
14.9
作者：
The UniProt Consortium
通讯作者：
The UniProt Consortium