STIM1, ORAI1, and KDM2B in circulating tumor cells (CTCs) isolated from prostate cancer patients.

Previous publications have shown that STIM1, ORAI1, and KDM2B, are implicated in Ca signaling and are highly expressed in various cancer subtypes including prostate cancer. They play multiple roles in cancer cell migration, invasion, and metastasis. In the current study we investigated the expression of the above biomarkers in circulating tumor cells from patients with metastatic prostate cancer.

Role of KDM2B epigenetic factor in regulating calcium signaling in prostate cancer cells.

KDM2B, a histone lysine demethylase, is expressed in a plethora of cancers. Earlier studies from our group, have showcased that overexpression of KDM2B in the human prostate cancer cell line DU-145 is associated with cell adhesion, actin reorganization, and improved cancer cell migration. In addition, we have previously examined changes of cytosolic Ca, regulated by the pore-forming proteins ORAI and the Ca sensing stromal interaction molecules (STIM), via store-operated Ca entry (SOCE) in wild-type DU-145.

Chorein sensitive microtubule organization in tumor cells.

Background: The purpose of this study is to analyzed the involvement of chorein in microtubules organization of three types of malignant; rhabdomyosarcoma tumor cells (ZF), rhabdomyosarcoma cells (RH30), and rhabdomyosarcoma cells (RD). ZF are expressing high chorein levels. Previous studies revealed that chorein protein silencing in ZF tumor cells persuaded apoptotic response followed by cell death.

Detyrosinated α-Tubulin, Vimentin and PD-L1 in Circulating Tumor Cells (CTCs) Isolated from Non-Small Cell Lung Cancer (NSCLC) Patients.

Upregulation of Vimentin (VIM), alpha-Tubulin (TUB) and Detyrosinated tubulin (GLU) in circulating tumor cells (CTCs) derived from breast cancer patients is related to poor prognosis. In the current study we evaluated for the first time, these cytoskeletal proteins in sixty Non-Small Cell Lung Cancer (NSCLC) patients' CTCs (33 treatment-naïve and 27 pre-treated). Samples were isolated using the ISET platform and stained with a pancytokeratin (CK)/CD45/TUB, CK/GLU/VIM and CK/programmed death ligand 1 (PD-L1) combination of antibodies.

Bismuth oxide nanoparticles induce oxidative stress and apoptosis in human breast cancer cells.

Metal nanomaterials such as bismuth oxide nanoparticles (BiONPs) have been extensively used in cosmetics, dental materials, pulp capping, and biomedical imaging. There is little knowledge about the health risk of BiONPs in humans, which warrants a thorough toxicity investigation of BiONPs at the cellular level. In this experiment, we investigated the cytotoxic effect of BiONPs on human breast cancer (MCF-7) cells over 24 and 48 h.

Efficient proliferation and mitosis of glioblastoma cells infected with human cytomegalovirus is mediated by RhoA GTPase.

Human cytomegalovirus (HCMV) is a prevalent viral pathogen, which can cause severe clinical consequences in neonates, immunocompromised individuals, patients with AIDS, and organ and stem cell transplant recipients. HCMV inhibits the host cell cycle progress while the immediate‑early protein 1 (IE1) tethers to condensed chromatin in mitotic cells. The present study investigated the effect of HCMV on the cell cycle in human glioblastoma cells, as well as the role of RhoA GTPase during mitosis in the same context.

CXCR4 and JUNB double-positive disseminated tumor cells are detected frequently in breast cancer patients at primary diagnosis.

Background: The chemokine receptor CXCR4 and the transcription factor JUNB, expressed on a variety of tumor cells, seem to play an important role in the metastatic process. Since disseminated tumor cells (DTCs) in the bone marrow (BM) have been associated with worse outcomes, we evaluated the expression of CXCR4 and JUNB in DTCs of primary, nonmetastatic breast cancer (BC) patients before the onset of any systemic treatment.

Methods: Bilateral BM (10 ml) aspirations of 39 hormone receptor (HR)-positive, HER2-negative BC patients were assessed for the presence of DTCs using the following combination of antibodies: pan-cytokeratin (A45-B/B3)/CXCR4/JUNB.

Identification of Structural Elements of the Lysine Specific Demethylase 2B CxxC Domain Associated with Replicative Senescence Bypass in Primary Mouse Cells.

Lysine specific demethylase 2B, KDM2B, regulates genes that participate in cellular development, morphogenesis, differentiation and metabolism as a component of the polycomb repressive complex 1 (PRC1). The CxxC finger of KDM2B is responsible for the DNA binding capacity of this epigenetic regulator, acting as a sampling mechanism across chromatin for gene repression OBJECTIVES: The molecular determinants of the CxxC-DNA interaction remain largely unknown, revealing a significant knowledge gap to be explored. Our goal was to elucidate the key residues of the CxxC domain that contribute to its function as well as to further elaborate on the significance of this domain in the KDM2B role METHODS: By using electrophoresis mobility swift assay, we identified structural elements of CxxC domain that participate in the DNA recognition.

The histone demethylase KDM2B activates FAK and PI3K that control tumor cell motility.

Recent studies revealed that the histone demethylase KDM2B regulates the epithelial markers E-Cadherin and ZO-1, the RhoA/B/C-small-GTPases and actin cytoskeleton organization, in DU-145 prostate- and HCT-116 colon-tumor cells. Here we addressed the role of KDM2B in the activation of Focal Adhesion Kinase (FAK)-signaling and its involvement in regulating tumor cell motility. We used RT-PCR for gene transcriptional analysis, Western blotting for the assessment of protein expression and activity and wound-healing assay for the study of cell migration.

Induction of interleukin-11 mediated by RhoA GTPase during human cytomegalovirus lytic infection.

Human cytomegalovirus (HCMV) is a ubiquitous pathogen which periodically reactivates, causing severe clinical consequences in immunosuppressed patients, organ and stem cell transplant recipients or newborn babies with congenital infections. HCMV infection stimulates the expression of several proinflammatory cytokines, which may contribute to the pathogenesis of the infection. Rho GTPases mediate cytokine expression while increasing evidence implicates them in important aspects of HCMV life cycle.

The prognostic value of JUNB-positive CTCs in metastatic breast cancer: from bioinformatics to phenotypic characterization.

Background: Circulating tumor cells (CTCs) are important for metastatic dissemination of cancer. They can provide useful information, regarding biological features and tumor heterogeneity; however, their detection and characterization are difficult due to their limited number in the bloodstream and their mesenchymal characteristics. Therefore, new biomarkers are needed to address these questions.

Serum- and glucocorticoid-inducible kinase 1 and the response to cell stress.

Expression of the serum- and glucocorticoid-inducible kinase 1 (SGK1) is up-regulated by several types of cell stress, such as ischemia, radiation and hyperosmotic shock. The SGK1 protein is activated by a signaling cascade involving phosphatidylinositide-3-kinase (PI3K), 3-phosphoinositide-dependent kinase 1 (PDK1) and mammalian target of rapamycin (mTOR). SGK1 up-regulates Na/K-ATPase, a variety of carriers including Na-,K-,2Cl- cotransporter (NKCC), NaCl cotransporter (NCC), Na/H exchangers, diverse amino acid transporters and several glucose carriers such as Na-coupled glucose transporter SGLT1.

Regulation of fibroblast growth factor 23 (FGF23) in health and disease.

Fibroblast growth factor 23 (FGF23) is mainly produced in the bone and, upon secretion, forms a complex with a FGF receptor and coreceptor αKlotho. FGF23 can exert several endocrine functions, such as inhibiting renal phosphate reabsorption and 1,25-dihydroxyvitamin D3 production. Moreover, it has paracrine activities on several cell types, including neutrophils and hepatocytes.

Upregulation of Orai1 and STIM1 expression as well as store-operated Ca entry in ovary carcinoma cells by placental growth factor.

Placental growth factor (PlGF) is produced by tumor cells and stimulates tumor growth and metastasis in part by upregulation of hypoxia inducible factor HIF1α. Orchestration of tumor cell proliferation and migration involves oscillations of cytosolic Ca activity ([Ca]). The [Ca] oscillations could be accomplished by triggering of intracellular Ca release followed by store-operated Ca-entry (SOCE).

Phosphate Homeostasis, Inflammation and the Regulation of FGF-23.

Fibroblast growth factor 23 (FGF23) is released primarily from osteoblasts/osteocytes in bone. In cooperation with the transmembrane protein Klotho, FGF23 is a powerful inhibitor of 1α 25OH Vitamin D Hydroxylase (Cyp27b1) and thus of the formation of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). As 1,25(OH)2D3 up-regulates intestinal calcium and phosphate absorption, the downregulation of 1,25(OH)2D3 synthesis counteracts phosphate excess and tissue calcification.

To die or not to die SGK1-sensitive ORAI/STIM in cell survival.

The pore forming Ca release activated Ca channel (CRAC) isoforms ORAI1-3 and their regulators STIM1,2 accomplish store operated Ca entry (SOCE). Activation of SOCE may lead to cytosolic Ca oscillations, which in turn support cell proliferation and cell survival. ORAI/STIM and thus SOCE are upregulated by the serum and glucocorticoid inducible kinase SGK1, a kinase under powerful genomic regulation and activated by phosphorylation via the phosphoinositol-3-phosphate pathway.

The Epigenetic Factor KDM2B Regulates EMT and Small GTPases in Colon Tumor Cells.

Background/aims: The epigenetic factor KDM2B is a histone demethylase expressed in various tumors. Recently, we have shown that KDM2B regulates actin cytoskeleton organization, small Rho GTPases signaling, cell-cell adhesion and migration of prostate tumor cells. In the present study, we addressed its role in regulating EMT and small GTPases expression in colon tumor cells.

Modulation of TGFβ/Smad signaling by the small GTPase RhoB.

We have shown previously that the small GTPases RhoA and RhoB play important roles in early TGFβ-induced actin cytoskeleton reorganization and that RhoB is transcriptionally activated by TGFβ and its signaling effectors, the Smad proteins. However, this long-term impact of RhoB gene upregulation by TGFβ on cellular functions is not known. We now show that increased levels of RhoB, but not of RhoA, inhibit the TGFβ/Smad-mediated transcriptional induction of the cell cycle inhibitor p21 gene as well as of a generic Smad-responsive promoter suggesting that RhoB could be part of an auto-inhibitory loop in TGFβ signaling by inhibiting the genomic responses to TGFβ.

Transcriptional and post-transcriptional regulation of the genes encoding the small GTPases RhoA, RhoB, and RhoC: implications for the pathogenesis of human diseases.

Rho GTPases are highly conserved proteins that play critical roles in many cellular processes including actin dynamics, vesicular trafficking, gene transcription, cell-cycle progression, and cell adhesion. The main mode of regulation of Rho GTPases is through guanine nucleotide binding (cycling between an active GTP-bound form and an inactive GDP-bound form), but transcriptional, post-transcriptional, and post-translational modes of Rho regulation have also been described. In the present review, we summarize recent progress on the mechanisms that control the expression of the three members of the Rho-like subfamily (RhoA, RhoB, and RhoC) at the level of gene transcription as well as their post-transcriptional regulation by microRNAs.

Evaluation of PD-L1/PD-1 on circulating tumor cells in patients with advanced non-small cell lung cancer.

Background: Circulating tumor cells (CTCs) could escape from the immune system through the programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) axis leading to the development of metastasis. The current study investigated the expression of PD-1/PD-L1 on CTCs isolated from non-small cell lung cancer (NSCLC) patients treated with chemotherapy.

Patients And Methods: CTCs were isolated from 30 chemo-naïve stage IV NSCLC patients before and after front-line chemotherapy using the ISET filtration platform.

Neurons, Erythrocytes and Beyond -The Diverse Functions of Chorein.

Chorea-acanthocytosis (ChAc), a neurodegenerative disease, results from loss-of-function-mutations of the chorein-encoding gene VPS13A. Affected patients suffer from a progressive movement disorder including chorea, parkinsonism, dystonia, tongue protrusion, dysarthria, dysphagia, tongue and lip biting, gait impairment, progressive distal muscle wasting, weakness, epileptic seizures, cognitive impairment, and behavioral changes. Those pathologies may be paralleled by erythrocyte acanthocytosis.

Lithium Sensitivity of Store Operated Ca2+ Entry and Survival of Fibroblasts Isolated from Chorea-Acanthocytosis Patients.

Background: The widely expressed protein chorein fosters activation of the phosphoinositide 3 kinase (PI3K) pathway thus supporting cell survival. Loss of function mutations of the chorein encoding gene VPS13A (vacuolar protein sorting-associated protein 13A) causes chorea-acanthocytosis (ChAc), a neurodegenerative disorder paralleled by deformations of erythrocytes. In mice, genetic knockout of chorein leads to enhanced neuronal apoptosis.