Functional expression of calcium-permeable canonical transient receptor potential 4-containing channels promotes migration of medulloblastoma cells.
Functional expression of calcium-permeable canonical transient receptor potential 4-containing channels promotes migration of medulloblastoma cells.
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DOI：
10.1113/jp274659
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发表时间：
2017-08-15
期刊：
影响因子：
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通讯作者：
Glitsch MD
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文献类型：
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作者：
Wei WC;Huang WC;Lin YP;Becker EBE;Ansorge O;Flockerzi V;Conti D;Cenacchi G;Glitsch MD
质子敏感卵巢癌G蛋白偶联受体1（OGR 1，又名GPR68）促进正常和转化小脑颗粒前体（DAOY）细胞中典型瞬时受体电位通道亚基TRPC 4的表达。OGR 1和TRPC 4在整个出生后发育的健康小脑组织和原发性小脑髓母细胞瘤组织中显著表达。在伤口愈合和transwell迁移试验中，DAOY细胞（而非转化颗粒前体细胞）中含TRPC 4通道的激活导致[Ca2+]i显著增加，并促进细胞运动性。不是由颗粒前体细胞产生的髓母细胞瘤细胞既不显示[Ca2+]i的显著升高，也不显示对TRPC 4激活的响应的运动性增强，除非它们过表达TRPC 4。我们的研究结果表明，OGR 1增强了含TRPC 4通道的表达，这些通道有助于增强颗粒前体衍生的人髓母细胞瘤的侵袭和转移。异常的细胞内Ca2+信号传导有助于包括癌症在内的一系列不同病理的形成和进展。细胞内Ca2+浓度的升高响应于通过质膜通道的Ca2+内流和来自细胞内Ca2+储存的Ca2+释放而发生，所述细胞内Ca2+储存可响应于细胞表面受体的活化而被动员。卵巢癌G蛋白偶联受体1（OGR 1，又名GPR68）是一种质子敏感Gq偶联受体，在小脑中表达最高。髓母细胞瘤（MB）是最常见的儿科脑肿瘤，起源于小脑前体细胞。我们发现，9个不同的人MB样本都表达OGR 1。在正常颗粒细胞和转化的人小脑颗粒细胞系DAOY中，OGR 1促进了典型瞬时受体电位（TRPC）通道家族的质子增强成员TRPC 4的表达。与TRPC 4在MB中的作用一致，我们发现所有MB样品也表达TRPC 4。在DAOY细胞中，含TRPC 4通道的激活导致大量Ca2+内流和增强的迁移，而在正常小脑颗粒（前体）细胞和不来源于颗粒前体的MB细胞中，仅观察到少量Ca2+内流和未观察到增强的迁移。我们的研究结果表明，TRPC 4表达的OGR 1依赖性增加可能有利于形成高Ca2+渗透性的TRPC 4通道，促进转化颗粒细胞迁移。癌细胞运动性的增加是癌症侵袭和转移的先决条件，我们的研究结果可能指向TRPC 4在某些类型MB进展中的关键作用。质子敏感卵巢癌G蛋白偶联受体1（OGR 1，又名GPR68）促进正常和转化小脑颗粒前体（DAOY）细胞中典型瞬时受体电位通道亚基TRPC 4的表达。OGR 1和TRPC 4在整个出生后发育的健康小脑组织和原发性小脑髓母细胞瘤组织中显著表达。在伤口愈合和transwell迁移试验中，DAOY细胞（而非转化颗粒前体细胞）中含TRPC 4通道的激活导致[Ca2+]i显著增加，并促进细胞运动性。不是由颗粒前体细胞产生的髓母细胞瘤细胞既不显示[Ca2+]i的显著升高，也不显示对TRPC 4激活的响应的运动性增强，除非它们过表达TRPC 4。我们的研究结果表明，OGR 1增强了含TRPC 4通道的表达，这些通道有助于增强颗粒前体衍生的人髓母细胞瘤的侵袭和转移。
The proton sensing ovarian cancer G protein coupled receptor 1 (OGR1, aka GPR68) promotes expression of the canonical transient receptor potential channel subunit TRPC4 in normal and transformed cerebellar granule precursor (DAOY) cells. OGR1 and TRPC4 are prominently expressed in healthy cerebellar tissue throughout postnatal development and in primary cerebellar medulloblastoma tissues. Activation of TRPC4‐containing channels in DAOY cells, but not non‐transformed granule precursor cells, results in prominent increases in [Ca2+]i and promotes cell motility in wound healing and transwell migration assays. Medulloblastoma cells not arising from granule precursor cells show neither prominent rises in [Ca2+]i nor enhanced motility in response to TRPC4 activation unless they overexpressTRPC4. Our results suggest that OGR1 enhances expression of TRPC4‐containing channels that contribute to enhanced invasion and metastasis of granule precursor‐derived human medulloblastoma. Aberrant intracellular Ca2+ signalling contributes to the formation and progression of a range of distinct pathologies including cancers. Rises in intracellular Ca2+ concentration occur in response to Ca2+ influx through plasma membrane channels and Ca2+ release from intracellular Ca2+ stores, which can be mobilized in response to activation of cell surface receptors. Ovarian cancer G protein coupled receptor 1 (OGR1, aka GPR68) is a proton‐sensing Gq‐coupled receptor that is most highly expressed in cerebellum. Medulloblastoma (MB) is the most common paediatric brain tumour that arises from cerebellar precursor cells. We found that nine distinct human MB samples all expressed OGR1. In both normal granule cells and the transformed human cerebellar granule cell line DAOY, OGR1 promoted expression of the proton‐potentiated member of the canonical transient receptor potential (TRPC) channel family, TRPC4. Consistent with a role for TRPC4 in MB, we found that all MB samples also expressed TRPC4. In DAOY cells, activation of TRPC4‐containing channels resulted in large Ca2+ influx and enhanced migration, while in normal cerebellar granule (precursor) cells and MB cells not derived from granule precursors, only small levels of Ca2+ influx and no enhanced migration were observed. Our results suggest that OGR1‐dependent increases in TRPC4 expression may favour formation of highly Ca2+‐permeable TRPC4‐containing channels that promote transformed granule cell migration. Increased motility of cancer cells is a prerequisite for cancer invasion and metastasis, and our findings may point towards a key role for TRPC4 in progression of certain types of MB. The proton sensing ovarian cancer G protein coupled receptor 1 (OGR1, aka GPR68) promotes expression of the canonical transient receptor potential channel subunit TRPC4 in normal and transformed cerebellar granule precursor (DAOY) cells. OGR1 and TRPC4 are prominently expressed in healthy cerebellar tissue throughout postnatal development and in primary cerebellar medulloblastoma tissues. Activation of TRPC4‐containing channels in DAOY cells, but not non‐transformed granule precursor cells, results in prominent increases in [Ca2+]i and promotes cell motility in wound healing and transwell migration assays. Medulloblastoma cells not arising from granule precursor cells show neither prominent rises in [Ca2+]i nor enhanced motility in response to TRPC4 activation unless they overexpressTRPC4. Our results suggest that OGR1 enhances expression of TRPC4‐containing channels that contribute to enhanced invasion and metastasis of granule precursor‐derived human medulloblastoma.