TRPC Channels and Their Splice Variants are Essential for Promoting Human Ovarian Cancer Cell Proliferation and Tumorigenesis

Zeng, Bo; Yuan, Cunzhong; Yang, Xinggang; Atkin, Stephen L.; Xu, Shusheng

doi:10.2174/15680096130109

Cited by 17 publications

(23 citation statements)

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“…In contrast, activation of TRPC4‐containing channels in ovarian carcinoma cells enhances their proliferation (Zeng et al . ), and it has been suggested that the opposite effects of TRPC4 activation in different cancer cell lines may reflect the fact that different levels of intracellular Ca 2+ rises may cause different effects in cells (Gaunt et al . ).…”

Section: Discussionmentioning

confidence: 99%

Functional expression of calcium‐permeable canonical transient receptor potential 4‐containing channels promotes migration of medulloblastoma cells

Wei

Huang

Lin

et al. 2017

The Journal of Physiology

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Key points 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. AbstractAberrant 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.

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Section: Discussionmentioning

confidence: 99%

Functional expression of calcium‐permeable canonical transient receptor potential 4‐containing channels promotes migration of medulloblastoma cells

Wei

Huang

Lin

et al. 2017

The Journal of Physiology

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“…A variety of IC signal transduction cascades can be differentially transduced by multiple PAC1 splice variants with altered EC or IC protein domains (Figure 4) (Arimura, 1998; Dickson and Finlayson, 2009; Vaudry et al, 2009; Furness et al, 2012). The most studied pathways include coupling of PAC1 to Gs and Gq proteins and activation of AC and phospholipase Cβ PLCβ) which result in the respective stimulation of production of cAMP and/or IP3 (Milligan and Kostenis, 2006; Couvineau and Laburthe, 2012) (Figures 3 and 4). In addition, PAC1 was shown to regulate the level of IC Ca 2+ in either G-protein dependent or independent manners.…”

Section: Alternative Pac1 Splicing Alters Intracellular Signal Transdmentioning

confidence: 99%

Alternative Splicing of the Pituitary Adenylate Cyclase-Activating Polypeptide Receptor PAC1: Mechanisms of Fine Tuning of Brain Activity

Blechman¹,

Levkowitz²

2013

Front. Endocrinol.

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Alternative splicing of the precursor mRNA encoding for the neuropeptide receptor PAC1/ADCYAP1R1 generates multiple protein products that exhibit pleiotropic activities. Recent studies in mammals and zebrafish have implicated some of these splice isoforms in control of both cellular and body homeostasis. Here, we review the regulation of PAC1 splice variants and their underlying signal transduction and physiological processes in the nervous system.

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“…Therefore, genes and pathways on the HPG axis are related to both AAM and ovarian cancer. It has been reported that KiSS1 , GNRHR , and DUSP6 on the HPG axis are involved in the development of ovarian cancer . Onset of puberty needs the activation of the GnRH secretory system.…”

Section: Discussionmentioning

confidence: 99%

Age at menarche and epithelial ovarian cancer risk: A meta‐analysis and Mendelian randomization study

et al. 2019

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Age at menarche (AAM) was found to be associated with ovarian cancer risk in previous observational studies. However, the causality of this association remains unclear. Here, after systematic meta‐analyses, we performed two‐sample Mendelian randomization (MR) analyses to evaluate the causal effect of AAM in epithelial ovarian cancer (EOC) etiology. We performed meta‐analyses including 11 410 cases and 1 163 117 noncases to quantitatively evaluate the association between AAM and ovarian cancer risk. In MR analyses, we used 25 single nucleotide polymorphisms (SNPs) associated with AAM for Chinese and 390 SNPs for Europeans as instrumental variables. MR estimates were calculated using inverse‐variance weighted methods from 1044 cases and 1172 controls in a Chinese genome‐wide association study and validated by the Ovarian Cancer Association Consortium and Consortium of Investigators of Modifiers of BRCA1/2 studies with 29 396 cases and 68 502 controls of European ancestry. In meta‐analyses, we observed an inverse association (odds ratio [OR] = 0.96, 95% confidence interval [CI] = 0.93 to 1.00, P = 0.036) between per year older AAM and ovarian cancer risk in case–control studies, but no association was observed in cohort studies. In MR analyses, the OR of EOC risk per year increase in AAM was 0.81 (95% CI = 0.67 to 0.97, P = 0.026) in Chinese and 0.94 (95% CI = 0.90 to 0.98, P = 0.003) in Europeans, respectively. Our study supports a causal association between AAM and EOC risk.

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TRPC Channels and Their Splice Variants are Essential for Promoting Human Ovarian Cancer Cell Proliferation and Tumorigenesis

Cited by 17 publications

References 0 publications

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

Alternative Splicing of the Pituitary Adenylate Cyclase-Activating Polypeptide Receptor PAC1: Mechanisms of Fine Tuning of Brain Activity

Age at menarche and epithelial ovarian cancer risk: A meta‐analysis and Mendelian randomization study

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