Section of Experimental Medicine, School of Pharmacy, University of Camerino, Camerino, Italy.
Int J Cancer. 2012 Oct 1;131(7):E1067-77. doi: 10.1002/ijc.27588. Epub 2012 Apr 27.
Malignant transformation of cells resulting from enhanced proliferation and aberrant differentiation is often accompanied by changes in transient receptor potential vanilloid (TRPV) channels expression. In gliomas, recent evidence indicates that TRPV type 2 (TRPV2) negatively controls glioma cell survival and proliferation. In addition, cannabinoids, the ligands of both cannabinoid and TRPV2 receptors, promote glioblastoma stem-like cells (GSCs) differentiation and inhibit gliomagenesis. Herein, we provide evidence on the expression of TRPV2 in human GSCs and that GSCs differentiation reduces nestin and progressively increases both the glial fibrillary acidic protein (GFAP) and TRPV2 expression. Therefore, we evaluated the role of TRPV2 cation channel in GSC lines differentiation. Treatment of GSC lines with the TRPV antagonist Ruthenium Red, with ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid or knockdown of TRPV2 gene during differentiation, decreases GFAP and class III beta-tubulin (β(III)-tubulin) expression; conversely, phorbol-12-myristate-13-acetate stimulates GSCs proliferation, reduces TRPV2 expression and partially reverts astroglial differentiation. In addition, forced TRPV2 expression in GSC lines by stable TRPV2 transfection increases GFAP and β(III)-tubulin expression and parallelly reduces proliferation. Finally, TRPV2 overexpression inhibits GSCs proliferation in a xenograft mouse model, as shown by reduced tumor diameter and mitotic index, and promotes the differentiation of GSCs toward a more mature glial phenotype. Overall, our results demonstrate that TRPV2 promotes in vitro and in vivo GSCs differentiation and inhibits their proliferation. Better understanding of the molecular mechanisms that regulate the balance between proliferation and differentiation of GSCs would lead to more specific and efficacious pharmacological approaches.
细胞的恶性转化是由于增殖增强和异常分化所致，通常伴随着瞬时受体电位香草素（TRPV）通道表达的变化。在神经胶质瘤中，最近的证据表明 TRPV 型 2（TRPV2）负向控制神经胶质瘤细胞的存活和增殖。此外，大麻素，即大麻素和 TRPV2 受体的配体，可促进神经胶质瘤干细胞（GSCs）分化并抑制神经胶质瘤发生。在此，我们提供了 TRPV2 在人 GSCs 中的表达证据，并且 GSCs 分化降低了巢蛋白并逐渐增加了神经胶质纤维酸性蛋白（GFAP）和 TRPV2 的表达。因此，我们评估了 TRPV2 阳离子通道在 GSC 系分化中的作用。用 TRPV 拮抗剂 Ruthenium Red、乙二醇双（2-氨基乙基醚）-N，N，N'，N'-四乙酸或在分化过程中敲低 TRPV2 基因处理 GSC 系，会降低 GFAP 和 III 型 β-微管蛋白（β（III）-微管蛋白）的表达；相反，佛波醇-12-肉豆蔻酸-13-乙酸刺激 GSCs 增殖，降低 TRPV2 表达，并部分逆转星形胶质分化。此外，通过稳定的 TRPV2 转染使 GSC 系中 TRPV2 过表达会增加 GFAP 和 β（III）-微管蛋白的表达，并平行降低增殖。最后，TRPV2 过表达在异种移植小鼠模型中抑制 GSCs 的增殖，表现为肿瘤直径和有丝分裂指数减小，并促进 GSCs 向更成熟的神经胶质表型分化。总的来说，我们的结果表明 TRPV2 促进了体外和体内 GSCs 的分化并抑制了它们的增殖。更好地了解调节 GSCs 增殖和分化平衡的分子机制将导致更特异和有效的药物治疗方法。
