Laboratoire de Physiologie Cellulaire et Moléculaire - UR UPJV 4667, UFR Sciences, Université de Picardie Jules Verne (UPJV), 80039, Amiens, France.
UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA), 51095, Amiens, France.
Arch Toxicol. 2020 Mar;94(3):735-747. doi: 10.1007/s00204-020-02674-w. Epub 2020 Feb 20.
Cadmium is a xenobiotic involved in neoplastic transformation. Cadmium enters the cells through divalent cation transporters including the Transient Receptor Potential Melastatin-related 7 (TRPM7) which is known to be involved in cancer cell fate. This work aimed to study the role of TRPM7 in neoplastic transformation induced by cadmium exposure in non-cancer epithelial cells. Non-cancer epithelial cells were chronically exposed to low-dose of cadmium. TRPM7 expression and function were studied by Western-Blot, Patch-Clamp and calcium and magnesium imaging. Finally, cell migration and invasion were studied by Boyden chamber assays. Chronic cadmium exposure induced TRPM7 overexpression and increased the membrane currents (P < 0.001). Cells exposed to cadmium had higher intracellular calcium and magnesium levels (P < 0.05). TRPM7 silencing restored calcium levels but strongly decreased intracellular magnesium concentration (P < 0.001). Moreover, cadmium exposure enhanced both cell migration and invasion, but TRPM7 silencing strongly decreased these features (P < 0.001). Furthermore, mammary epithelial cells exposed to cadmium became rounded and had less cell-to-cell junctions. Cadmium exposure decreased epithelial markers while the mesenchymal ones were increased. Importantly, TRPM7 silencing was able to reverse these phenotypic modifications (P < 0.05). To summarize, our data show that chronic cadmium exposure enhanced TRPM7 expression and activity in non-cancer epithelial cells. TRPM7 overexpression induced intracellular magnesium increase and stimulated cell migration and invasion. These neoplastic properties could be linked to a TRPM7-dependent epithelial-to-mesenchymal transition reprogramming in cell exposed to cadmium. These findings provide new insights into the regulation of cell fates by cadmium exposure.
镉是一种参与肿瘤转化的异生物质。镉通过二价阳离子转运体进入细胞，包括瞬态受体电位 melastatin 相关 7 型（TRPM7），已知其参与癌细胞命运。本工作旨在研究 TRPM7 在非癌细胞上皮细胞暴露于镉诱导的肿瘤转化中的作用。非癌细胞上皮细胞长期暴露于低剂量镉下。通过 Western-Blot、膜片钳和钙镁成像研究 TRPM7 的表达和功能。最后，通过 Boyden 室测定研究细胞迁移和侵袭。慢性镉暴露诱导 TRPM7 过表达并增加膜电流（P<0.001）。暴露于镉的细胞具有更高的细胞内钙和镁水平（P<0.05）。TRPM7 沉默恢复了钙水平，但强烈降低了细胞内镁浓度（P<0.001）。此外，镉暴露增强了细胞迁移和侵袭，但 TRPM7 沉默强烈降低了这些特征（P<0.001）。此外，暴露于镉的乳腺上皮细胞变圆，细胞间连接减少。镉暴露降低了上皮标志物，而间充质标志物增加。重要的是，TRPM7 沉默能够逆转这些表型改变（P<0.05）。总之，我们的数据表明，慢性镉暴露增强了非癌细胞上皮细胞中 TRPM7 的表达和活性。TRPM7 过表达诱导细胞内镁增加，并刺激细胞迁移和侵袭。这些肿瘤特性可能与暴露于镉的细胞中 TRPM7 依赖性上皮-间充质转化重编程有关。这些发现为镉暴露对细胞命运的调控提供了新的见解。
