GPR4 in the pH‐dependent migration of melanoma cells in the tumor microenvironment
GPR4 in the pH‐dependent migration of melanoma cells in the tumor microenvironment
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DOI：
10.1111/exd.14735
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发表时间：
2022-12
影响因子：
3.6
通讯作者：
J. Stolwijk;S. Wallner;J. Heider;B. Kurz;Lisa Pütz;S. Michaelis;Barbara Goricnik;Julia Erl;Linda Frank;M. Berneburg;F. Haubner;J. Wegener;S. Schreml
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作者：
J. Stolwijk;S. Wallner;J. Heider;B. Kurz;Lisa Pütz;S. Michaelis;Barbara Goricnik;Julia Erl;Linda Frank;M. Berneburg;F. Haubner;J. Wegener;S. Schreml
由于其高转移潜力，恶性黑色素瘤是最致命的皮肤癌之一。在黑色素瘤和其他癌症中，肿瘤微环境的酸化（=TME，逆pH梯度）是肿瘤进展和转移的一个众所周知的驱动因素。膜结合受体，如质子敏感GPCR (pH - GPCR) GPR4，被认为是与恶性转化相关的信号级联反应的潜在启动物。在这项研究中，我们使用基于阻抗的电损伤和迁移实验和经典的Boyden室实验研究了GPR4野生型/过表达SK‐Mel‐28细胞的pH依赖性迁移。在基于阻抗的电损伤和迁移实验中，与对照组相比，过表达SK‐Mel‐28的GPR4细胞在pH 6.5-7.5范围内的迁移增强。在Boyden实验中，GPR4过表达仅在pH为7.5时增加了迁移，而在pH为6.5时则没有。结果表明，GPR4参与黑色素瘤细胞的迁移，特别是肿瘤周围的迁移，并且这一过程受TME中pH的影响。
Due to its high metastatic potential, malignant melanoma is one of the deadliest skin cancers. In melanoma as well as in other cancers, acidification of the tumor microenvironment (=TME, inverse pH‐gradient) is a well‐known driver of tumor progression and metastasis. Membrane‐bound receptors, such as the proton‐sensitive GPCR (pH‐GPCR) GPR4, are considered as potential initiators of the signalling cascades relevant to malignant transformation. In this study, we investigated the pH‐dependent migration of GPR4 wildtype/overexpressing SK‐Mel‐28 cells using an impedance‐based electrical wounding and migration assay and classical Boyden chamber experiments. Migration of GPR4 overexpressing SK‐Mel‐28 cells was enhanced in a range of pH 6.5–7.5 as compared to controls in the impedance‐based electrical wounding and migration assay. In Boyden chamber experiments, GPR4 overexpression only increased migration at pH 7.5 in a Matrigel‐free setup, but not at pH 6.5. Results indicate that GPR4 is involved in the migration of melanoma cells, especially in the tumor periphery, and that this process is affected by pH in the TME.