TRP channel expression correlates with the epithelial–mesenchymal transition and high-risk endometrial carcinoma

AbstractTransient receptor potential (TRP) channels excel in cellular sensing as they allow rapid ion influx across the plasma membrane in response to a variety of extracellular cues. Recently, a distinct TRP mRNA expression signature was observed in stromal cells (ESC) and epithelial cells (EEC) of the endometrium, a tissue in which cell phenotypic plasticity is essential for normal functioning. However, it is unknown whether TRP channel mRNA expression is subject to the phenotypic switching that occurs during epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET), and whether TRP channel mRNA expression is associated with aggressive phenotypes in endometrial cancer (EC). Here, we induced EMT and MET in vitro using in primary EEC and ESC, respectively, and analyzed expression and functionality of TRP channels using RT-qPCR and intracellular Ca2+ imaging. The outcome of these experiments showed a strong association between TRPV2 and TRPC1 mRNA expression and the mesenchymal phenotype, whereas TRPM4 mRNA expression correlated with the epithelial phenotype. In line herewith, increased TRPV2 and TRPC1 mRNA expression levels were observed in both primary and metastatic EC biopsies and in primary EC cells with a high EMT status, indicating an association with an aggressive tumor phenotype. Remarkably, TRPV2 mRNA expression in primary EC biopsies was associated with tumor invasiveness and cancer stage. In contrast, increased TRPM4 mRNA expression was observed in EC biopsies with a low EMT status and less aggressive tumor phenotypes. Taken together, this dataset proved for the first time that TRP channel mRNA expression is strongly linked to cellular phenotypes of the endometrium, and that phenotypic transitions caused by either experimental manipulation or malignancy could alter this expression in a predictable manner. These results implicate that TRP channels are viable biomarkers to identify high-risk EC, and potential targets for EC treatment.

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TRP channel expression correlates with the epithelial-mesenchymal transition and high-risk endometrial carcinoma.

10.21203/rs.3.rs-787688/v1 ◽

2021 ◽

Author(s):

Charlotte Van den Eynde ◽

Katrien De Clercq ◽

Rieta Van Bree ◽

Daniela Annibali ◽

Frédéric Amant ◽

...

Keyword(s):

High Risk ◽

Transient Receptor Potential ◽

Trp Channels ◽

Epithelial Mesenchymal Transition ◽

Strong Association ◽

Trp Channel ◽

Phenotypic Switching ◽

Mesenchymal Transition ◽

Channel Expression ◽

Aggressive Tumor

Abstract Transient Receptor Potential (TRP) channels excel in cellular sensing as they allow rapid ion influx across the plasma membrane in response to a variety of extracellular cues. Recently, a distinct TRP expression signature was observed in stromal cells (ESC) and epithelial cells (EEC) of the endometrium, a tissue in which cell phenotypic plasticity is essential for normal functioning. However, it is unknown whether TRP channel expression is subject to the phenotypic switching that occurs during epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET), and whether TRP channel expression is associated with aggressive phenotypes in endometrial cancer (EC). Here, we induced EMT and MET in vitro using in primary EEC and ESC, respectively, and analyzed expression and functionality of TRP channels using RT-qPCR and intracellular Ca2+ imaging. The outcome of these experiments showed a strong association between TRPV2 and TRPC1 expression and the mesenchymal phenotype, whereas TRPM4 expression correlated with the epithelial phenotype. In line herewith, increased TRPV2 and TRPC1 expression levels were observed in both primary and metastatic EC biopsies and in primary EC cells with a high EMT status, indicating an association with an aggressive tumor phenotype. Remarkably, TRPV2 expression in primary EC biopsies was associated with tumor invasiveness and cancer stage. In contrast, increased TRPM4 expression was observed in EC biopsies with a low EMT status and less aggressive tumor phenotypes. Taken together, this dataset demonstrated for the first time that TRP channel expression is strongly linked to cellular phenotypes of the endometrium, and that phenotypic transitions caused by either experimental manipulation or malignancy could alter this expression in a predictable manner. These results implicate that TRP channels are viable biomarkers to identify high-risk EC, and potential targets for EC treatment.

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TRP Channels as Sensors of Aldehyde and Oxidative Stress

Biomolecules ◽

10.3390/biom11101401 ◽

2021 ◽

Vol 11 (10) ◽

pp. 1401

Author(s):

Katharina E. M. Hellenthal ◽

Laura Brabenec ◽

Eric R. Gross ◽

Nana-Maria Wagner

Keyword(s):

Lipid Peroxidation ◽

Transient Receptor Potential ◽

Trp Channels ◽

Treatment Options ◽

Receptor Potential ◽

The Body ◽

Trp Channel ◽

Alcoholic Beverages ◽

Organ Injury ◽

Transient Receptor

The transient receptor potential (TRP) cation channel superfamily comprises more than 50 channels that play crucial roles in physiological processes. TRP channels are responsive to several exogenous and endogenous biomolecules, with aldehydes emerging as a TRP channel trigger contributing to a cellular cascade that can lead to disease pathophysiology. The body is not only exposed to exogenous aldehydes via tobacco products or alcoholic beverages, but also to endogenous aldehydes triggered by lipid peroxidation. In response to lipid peroxidation from inflammation or organ injury, polyunsaturated fatty acids undergo lipid peroxidation to aldehydes, such as 4-hydroxynonenal. Reactive aldehydes activate TRP channels via aldehyde-induced protein adducts, leading to the release of pro-inflammatory mediators driving the pathophysiology caused by cellular injury, including inflammatory pain and organ reperfusion injury. Recent studies have outlined how aldehyde dehydrogenase 2 protects against aldehyde toxicity through the clearance of toxic aldehydes, indicating that targeting the endogenous aldehyde metabolism may represent a novel treatment strategy. An addition approach can involve targeting specific TRP channel regions to limit the triggering of a cellular cascade induced by aldehydes. In this review, we provide a comprehensive summary of aldehydes, TRP channels, and their interactions, as well as their role in pathological conditions and the different therapeutical treatment options.

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Personalized approach to assessing mRNA expression of histidine-rich glycoprotein and immunohistochemical markers in diseases of the breast

Доклады Академии наук ◽

10.31857/s0869-56524845624-628 ◽

2019 ◽

Vol 484 (5) ◽

pp. 624-628 ◽

Cited By ~ 1

Author(s):

A. I. Autenshlyus ◽

A. V. Golovanova ◽

A. A. Studenikina ◽

I. I. Brusentsov ◽

A. V. Proskura ◽

...

Keyword(s):

Mrna Expression ◽

Epithelial Mesenchymal Transition ◽

Immunohistochemical Analysis ◽

Breast Diseases ◽

Biopsy Material ◽

Mesenchymal Transition ◽

Benign Breast Diseases ◽

Immunohistochemical Markers ◽

Atypical Cells ◽

Personalized Approach

Biopsy material of patients with malignant and benign breast diseases was examined. HRG mRNA expression was detected in 70% of cases in biopsy material obtained from patients with nonspecific invasive carcinoma and in 66.7% of cases in biopsy material of patients with benign breast diseases. Immunohistochemical analysis revealed expression of collagen II, the beta-1 integrin, and E-cadherin – markers of epithelial–mesenchymal transition. The use of RT-qPCR combined with immunohistochemical study made it possible to identify atypical cells, which can be regarded as precancerous changes, in individual patients.

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The Expression of Cold-Inducible RNA-Binding Protein mRNA in Sow Genital Tract Is Modulated by Natural Mating, But Not by Seminal Plasma

International Journal of Molecular Sciences ◽

10.3390/ijms21155333 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5333

Author(s):

Jaume Gardela ◽

Mateo Ruiz-Conca ◽

Cristina A. Martinez ◽

Dominic Wright ◽

Manel López-Béjar ◽

...

Keyword(s):

Ion Channels ◽

Mrna Expression ◽

Seminal Plasma ◽

Genital Tract ◽

Transient Receptor Potential ◽

Rna Binding ◽

Trp Channels ◽

Rna Binding Proteins ◽

Trp Ion Channels ◽

Natural Mating

The RNA-binding proteins (RBPs), some of them induced by transient receptor potential (TRP) ion channels, are crucial regulators of RNA function that can contribute to reproductive pathogenesis, including inflammation and immune dysfunction. This study aimed to reveal the influence of spermatozoa, seminal plasma, or natural mating on mRNA expression of RBPs and TRP ion channels in different segments of the internal genital tract of oestrous, preovulatory sows. Particularly, we focused on mRNA expression changes of the cold-inducible proteins (CIPs) and related TRP channels. Pre-ovulatory sows were naturally mated (NM) or cervically infused with semen (Semen-AI) or sperm-free seminal plasma either from the entire ejaculate (SP-TOTAL) or the sperm-rich fraction (SP-AI). Samples (cervix to infundibulum) were collected by laparotomy under general anaesthesia for transcriptomic analysis (GeneChip® Porcine Gene 1.0 ST Array) 24 h after treatments. The NM treatment induced most of the mRNA expression changes, compared to Semen-AI, SP-AI, and SP-TOTAL treatments including unique significative changes in CIRBP, RBM11, RBM15B, RBMS1, TRPC1, TRPC4, TRPC7, and TRPM8. The findings on the differential mRNA expression on RBPs and TRP ion channels, especially to CIPs and related TRP ion channels, suggest that spermatozoa and seminal plasma differentially modulated both protein families during the preovulatory phase, probably related to a still unknown early signalling mechanism in the sow reproductive tract.

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Role of TRP Channels in Shaping the Gut Microbiome

Pathogens ◽

10.3390/pathogens9090753 ◽

2020 ◽

Vol 9 (9) ◽

pp. 753 ◽

Cited By ~ 1

Author(s):

Ravinder Nagpal ◽

Santosh Kumar Mishra ◽

Gagan Deep ◽

Hariom Yadav

Keyword(s):

Gut Microbiome ◽

Transient Receptor Potential ◽

Fatty Acid Biosynthesis ◽

Trp Channels ◽

Receptor Potential ◽

Trp Channel ◽

Double Knockout ◽

Therapeutic Modalities ◽

Trpv1 Channels ◽

Noxious Chemicals

Transient receptor potential (TRP) channel family proteins are sensors for pain, which sense a variety of thermal and noxious chemicals. Sensory neurons innervating the gut abundantly express TRPA1 and TRPV1 channels and are in close proximity of gut microbes. Emerging evidence indicates a bi-directional gut–brain cross-talk in several entero-neuronal pathologies; however, the direct evidence of TRP channels interacting with gut microbial populations is lacking. Herein, we examine whether and how the knockout (KO) of TRPA1 and TRPV1 channels individually or combined TRPA1/V1 double-knockout (dKO) impacts the gut microbiome in mice. We detect distinct microbiome clusters among the three KO mouse models versus wild-type (WT) mice. All three TRP-KO models have reduced microbial diversity, harbor higher abundance of Bacteroidetes, and a reduced proportion of Firmicutes. Specifically distinct arrays in the KO models are determined mainly by S24-7, Bacteroidaceae, Clostridiales, Prevotellaceae, Helicobacteriaceae, Rikenellaceae, and Ruminococcaceae. A1KO mice have lower Prevotella, Desulfovibrio, Bacteroides, Helicobacter and higher Rikenellaceae and Tenericutes; V1KO mice demonstrate higher Ruminococcaceae, Lachnospiraceae, Ruminococcus, Desulfovibrio and Mucispirillum; and A1V1dKO mice exhibit higher Bacteroidetes, Bacteroides and S24-7 and lower Firmicutes, Ruminococcaceae, Oscillospira, Lactobacillus and Sutterella abundance. Furthermore, the abundance of taxa involved in biosynthesis of lipids and primary and secondary bile acids is higher while that of fatty acid biosynthesis-associated taxa is lower in all KO groups. To our knowledge, this is the first study demonstrating distinct gut microbiome signatures in TRPA1, V1 and dKO models and should facilitate prospective studies exploring novel diagnostic/ therapeutic modalities regarding the pathophysiology of TRP channel proteins.

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The nonselective cation channel TRPV4 inhibits angiotensin II receptors

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.014325 ◽

2020 ◽

Vol 295 (29) ◽

pp. 9986-9997

Author(s):

Nicholas W. Zaccor ◽

Charlotte J. Sumner ◽

Solomon H. Snyder

Keyword(s):

Angiotensin Ii ◽

G Protein ◽

Transient Receptor Potential ◽

Trp Channels ◽

Receptor Potential ◽

Trp Channel ◽

Luciferase Assay ◽

Transient Receptor Potential Vanilloid ◽

Dependent Manner ◽

Transient Receptor

G-protein–coupled receptors (GPCRs) are a ubiquitously expressed family of receptor proteins that regulate many physiological functions and other proteins. They act through two dissociable signaling pathways: the exchange of GDP to GTP by linked G-proteins and the recruitment of β-arrestins. GPCRs modulate several members of the transient receptor potential (TRP) channel family of nonselective cation channels. How TRP channels reciprocally regulate GPCR signaling is less well-explored. Here, using an array of biochemical approaches, including immunoprecipitation and fluorescence, calcium imaging, phosphate radiolabeling, and a β-arrestin–dependent luciferase assay, we characterize a GPCR–TRP channel pair, angiotensin II receptor type 1 (AT1R), and transient receptor potential vanilloid 4 (TRPV4), in primary murine choroid plexus epithelial cells and immortalized cell lines. We found that AT1R and TRPV4 are binding partners and that activation of AT1R by angiotensin II (ANGII) elicits β-arrestin–dependent inhibition and internalization of TRPV4. Activating TRPV4 with endogenous and synthetic agonists inhibited angiotensin II–mediated G-protein–associated second messenger accumulation, AT1R receptor phosphorylation, and β-arrestin recruitment. We also noted that TRPV4 inhibits AT1R phosphorylation by activating the calcium-activated phosphatase calcineurin in a Ca2+/calmodulin–dependent manner, preventing β-arrestin recruitment and receptor internalization. These findings suggest that when TRP channels and GPCRs are co-expressed in the same tissues, many of these channels can inhibit GPCR desensitization.

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Coordinated regulation of Rel expression by MAP3K4, CBP, and HDAC6 controls phenotypic switching

Communications Biology ◽

10.1038/s42003-020-01200-z ◽

2020 ◽

Vol 3 (1) ◽

Author(s):

Noha Ahmed Mohammed Shendy ◽

Deepthi Raghu ◽

Sujoy Roy ◽

Charles Hamilton Perry ◽

Adiba Safi ◽

...

Keyword(s):

Gene Expression ◽

Feedback Loop ◽

Normal Development ◽

Epithelial Mesenchymal Transition ◽

Phenotypic Switching ◽

Mesenchymal Transition ◽

Developmental Program ◽

Disease States ◽

Trophoblast Stem ◽

Mesenchymal Epithelial Transition

AbstractCoordinated gene expression is required for phenotypic switching between epithelial and mesenchymal phenotypes during normal development and in disease states. Trophoblast stem (TS) cells undergo epithelial-mesenchymal transition (EMT) during implantation and placentation. Mechanisms coordinating gene expression during these processes are poorly understood. We have previously demonstrated that MAP3K4-regulated chromatin modifiers CBP and HDAC6 each regulate thousands of genes during EMT in TS cells. Here we show that CBP and HDAC6 coordinate expression of only 183 genes predicted to be critical regulators of phenotypic switching. The highest-ranking co-regulated gene is the NF-κB family member Rel. Although NF-κB is primarily regulated post-transcriptionally, CBP and HDAC6 control Rel transcript levels by binding Rel regulatory regions and controlling histone acetylation. REL re-expression in mesenchymal-like TS cells induces a mesenchymal-epithelial transition. Importantly, REL forms a feedback loop, blocking HDAC6 expression and nuclear localization. Together, our work defines a developmental program coordinating phenotypic switching.

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BMI1,ALDH1A1, andCD133Transcripts Connect Epithelial-Mesenchymal Transition to Cancer Stem Cells in Lung Carcinoma

Stem Cells International ◽

10.1155/2016/9714315 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 20

Author(s):

Ana Koren ◽

Matija Rijavec ◽

Izidor Kern ◽

Eva Sodja ◽

Peter Korosec ◽

...

Keyword(s):

Lung Cancer ◽

Mrna Expression ◽

Whole Blood ◽

Epithelial Mesenchymal Transition ◽

Immunohistochemical Analysis ◽

Underlying Mechanism ◽

Primary Tumors ◽

Mesenchymal Transition ◽

Cellular Models ◽

Nsclc Patients

Epithelial-mesenchymal transition (EMT) is the underlying mechanism of tumor invasion and metastasis. Evidences from lung cancer cellular models show EMT can trigger conversion to a cancer stem cell (CSC) phenotype. In this study, we assessed mRNA expression levels of EMT-inducing transcription factors (BMI1,TWIST1), CSC (CD133,ALDH1A1), and epithelial (EpCAM) markers in primary tumor and whole blood samples obtained from 57 patients with operable non-small-cell lung cancer (NSCLC) as well as in circulating tumor cells (CTCs) of 13 patients with metastatic disease; then possible associations between marker expressions were evaluated. In primary tumors as well as in whole blood, correlations betweenBMI1andALDH1A1and betweenBMI1andCD133mRNA expressions were identified. No correlations betweenTWIST1and CSC markers were observed.BMI1mRNA expression in tumors positively correlated withBMI1mRNA expression in blood. The immunohistochemical analysis confirmed coexpression of BMI1 and CSC markers in tumors. Gene expression profiling in CTCs revealed upregulated expression of EMT/CSC markers in CTCs. Our results suggest CSCs are present in both, tumor tissue and blood of NSCLC patients, whereas Bmi1 may play an important role in initiation and maintenance of CSCs and might be involved in the blood-borne dissemination of NSCLC.

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Arterial smooth muscle cell PKD2 (TRPP1) channels regulate systemic blood pressure

eLife ◽

10.7554/elife.42628 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 9

Author(s):

Simon Bulley ◽

Carlos Fernández-Peña ◽

Raquibul Hasan ◽

M Dennis Leo ◽

Padmapriya Muralidharan ◽

...

Keyword(s):

Blood Pressure ◽

Smooth Muscle ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Transient Receptor Potential ◽

Trp Channels ◽

Systemic Blood Pressure ◽

Trp Channel ◽

Systemic Blood ◽

Arterial Smooth Muscle

Systemic blood pressure is determined, in part, by arterial smooth muscle cells (myocytes). Several Transient Receptor Potential (TRP) channels are proposed to be expressed in arterial myocytes, but it is unclear if these proteins control physiological blood pressure and contribute to hypertension in vivo. We generated the first inducible, smooth muscle-specific knockout mice for a TRP channel, namely for PKD2 (TRPP1), to investigate arterial myocyte and blood pressure regulation by this protein. Using this model, we show that intravascular pressure and α1-adrenoceptors activate PKD2 channels in arterial myocytes of different systemic organs. PKD2 channel activation in arterial myocytes leads to an inward Na+ current, membrane depolarization and vasoconstriction. Inducible, smooth muscle cell-specific PKD2 knockout lowers both physiological blood pressure and hypertension and prevents pathological arterial remodeling during hypertension. Thus, arterial myocyte PKD2 controls systemic blood pressure and targeting this TRP channel reduces high blood pressure.

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Rapamycin Attenuates Aldosterone-Induced Tubulointerstitial Inflammation and Fibrosis

Cellular Physiology and Biochemistry ◽

10.1159/000369680 ◽

2015 ◽

Vol 35 (1) ◽

pp. 116-125 ◽

Cited By ~ 28

Author(s):

Bin Wang ◽

Wei Ding ◽

Minmin Zhang ◽

Hongmei Li ◽

Yong Gu

Keyword(s):

Mrna Expression ◽

Epithelial Mesenchymal Transition ◽

Kidney Diseases ◽

Immunofluorescent Staining ◽

Sprague Dawley ◽

Mesenchymal Transition ◽

Tnf Α ◽

Tubulointerstitial Inflammation

Background/Aim: Aldosterone (Aldo), a mediator of kidney fibrosis, is implicated in the pathogenesis of chronic kidney diseases (CKD). The aim of this study was to evaluate the regulatory role of rapamycin (Rap) in Aldo-induced tubulointerstitial inflammation and fibrosis. Methods: Uninephrectomized, Sprague-Dawley rats were given 1% NaCl (salt) to drink and were randomized to receive treatment for 28 days as follows: vehicle infusion (control), 0.75 μg/h Aldo subcutaneous infusion, or Aldo infusion plus 1 mg/kg/day of Rap by intraperitoneal injection. The effect of Rap on Aldo-induced fibrosis and renal inflammation was investigated using Masson's technique, immunohistochemistry, and western blotting. The effects of Rap on the Aldo-induced epithelial-mesenchymal transition (EMT) process and on TNF-α mRNA expression and secretion in cultured HK-2 cells were investigated by immunofluorescent staining, western blot, qRT-PCR and ELISA. Results: An in vivo study indicated that signaling by the mammalian target of Rap (mTOR) was activated in rats in the Aldo group compared to controls, as indicated by up-regulated expression of p-mTOR and p-S6K. In addition, the inflammatory response increased, as evidenced by increases in inflammatory markers (MCP-1, ICAM-1, F4/80), and the accumulation of extracellular matrix (ECM), as indicated by increased collagen I and fibronectin expression and pro-fibrogenic gene (PAI-1 and TGF-β1) expression. These changes were attenuated by Rap treatment. An in vitro study showed that Rap significantly suppressed the Aldo-induced EMT process and TNF-α mRNA expression and secretion in cultured HK-2 cells. Conclusions: Rap can ameliorate tubulointerstitial inflammation and fibrosis by blocking mTOR signaling. Tubular cells may be a major cell type involved in this physiologic process.

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