Bivalent Genes Targeting of Glioma Heterogeneity and Plasticity

Gliomas account for most primary Central Nervous System (CNS) neoplasms, characterized by high aggressiveness and low survival rates. Despite the immense research efforts, there is a small improvement in glioma survival rates, mostly attributed to their heterogeneity and complex pathophysiology. Recent data indicate the delicate interplay of genetic and epigenetic mechanisms in regulating gene expression and cell differentiation, pointing towards the pivotal role of bivalent genes. Bivalency refers to a property of chromatin to acquire more than one histone marks during the cell cycle and rapidly transition gene expression from an active to a suppressed transcriptional state. Although first identified in embryonal stem cells, bivalent genes have now been associated with tumorigenesis and cancer progression. Emerging evidence indicates the implication of bivalent gene regulation in glioma heterogeneity and plasticity, mainly involving Homeobox genes, Wingless-Type MMTV Integration Site Family Members, Hedgehog protein, and Solute Carrier Family members. These genes control a wide variety of cellular functions, including cellular differentiation during early organism development, regulation of cell growth, invasion, migration, angiogenesis, therapy resistance, and apoptosis. In this review, we discuss the implication of bivalent genes in glioma pathogenesis and their potential therapeutic targeting options.

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Targeting Kca3.1 Channels in Cancer

Cellular Physiology and Biochemistry ◽

10.33594/000000374 ◽

2021 ◽

Vol 55 (S3) ◽

pp. 131-144

Keyword(s):

Cancer Patients ◽

Cancer Progression ◽

Therapy Resistance ◽

Inhibitor Binding ◽

Aggressive Cancer ◽

Imaging Probes ◽

Attractive Therapeutic Target ◽

Characteristic Features ◽

Dynamics Simulations

The Kca3.1 channels, previously designated as IK1 or SK4 channels and encoded by the KCNN4 gene, are activated by a rise of the intracellular Ca2+ concentration. These K+ channels are widely expressed in many organs and involved in many pathologies. In particular, Kca3.1 channels have been studied intensively in the context of cancer. They are not only a marker and a valid prognostic tool for cancer patients, but have an important share in driving cancer progression. Their function is required for many characteristic features of the aggressive cancer cell behavior such as migration, invasion and metastasis as well as proliferation and therapy resistance. In the context of cancer, another property of Kca3.1 is now emerging. These channels can be a target for novel small molecule-based imaging probes, as it has been validated in case of fluorescently labeled senicapoc-derivatives. The aim of this review is (i) to give an overview on the role of Kca3.1 channels in cancer progression and in shaping the cancer microenvironment, (ii) discuss the potential of using Kca3.1 targeting drugs for cancer imaging, (iii) and highlight the possibility of combining molecular dynamics simulations to image inhibitor binding to Kca3.1 channels in order to provide a deeper understanding of Kca3.1 channel pharmacology. Alltogether, Kca3.1 is an attractive therapeutic target so that senicapoc, originally developed for the treatment of sickle cell anemia, should be repurposed for the treatment of cancer patients.

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Increased Gene Expression of RUNX2 and SOX9 in Mesenchymal Circulating Progenitors Is Associated with Autophagy during Physical Activity

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/8426259 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 5

Author(s):

L. Dalle Carbonare ◽

M. Mottes ◽

S. Cheri ◽

M. Deiana ◽

F. Zamboni ◽

...

Keyword(s):

Gene Expression ◽

Physical Activity ◽

Physical Exercise ◽

Cellular Functions ◽

Enhanced Expression ◽

Chondrocytic Differentiation ◽

Marathon Performance ◽

Array Analyses

Lack of physical exercise is considered an important risk factor for chronic diseases. On the contrary, physical exercise reduces the morbidity rates of obesity, diabetes, bone disease, and hypertension. In order to gain novel molecular and cellular clues, we analyzed the effects of physical exercise on differentiation of mesenchymal circulating progenitor cells (M-CPCs) obtained from runners. We also investigated autophagy and telomerase-related gene expression to evaluate the involvement of specific cellular functions in the differentiation process. We performed cellular and molecular analyses in M-CPCs, obtained by a depletion method, of 22 subjects before (PRE RUN) and after (POST RUN) a half marathon performance. In order to prove our findings, we performed also in vitro analyses by testing the effects of runners’ sera on a human bone marrow-derived mesenchymal stem (hBM-MSC) cell line. PCR array analyses of PRE RUN versus POST RUN M-CPC total RNAs put in evidence several genes which appeared to be modulated by physical activity. Our results showed that physical exercise promotes differentiation. Osteogenesis-related genes as RUNX2, MSX1, and SPP1 appeared to be upregulated after the run; data showed also increased levels of BMP2 and BMP6 expressions. SOX9, COL2A1, and COMP gene enhanced expression suggested the induction of chondrocytic differentiation as well. The expression of telomerase-associated genes and of two autophagy-related genes, ATG3 and ULK1, was also affected and correlated positively with MSC differentiation. These data highlight an attractive cellular scenario, outlining the role of autophagic response to physical exercise and suggesting new insights into the benefits of physical exercise in counteracting chronic degenerative conditions.

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Differing Roles of Hyaluronan Molecular Weight on Cancer Cell Behavior and Chemotherapy Resistance

Cancers ◽

10.3390/cancers10120482 ◽

2018 ◽

Vol 10 (12) ◽

pp. 482 ◽

Cited By ~ 17

Author(s):

Zoe Price ◽

Noor Lokman ◽

Carmela Ricciardelli

Keyword(s):

Molecular Weight ◽

Tyrosine Kinase ◽

Cancer Cell ◽

Cancer Progression ◽

Receptor Tyrosine Kinase ◽

Intracellular Signaling ◽

Therapy Resistance ◽

Cell Behavior ◽

Mesenchymal Transition

Hyaluronan (HA), a glycosaminoglycan located in the extracellular matrix, is important in embryo development, inflammation, wound healing and cancer. There is an extensive body of research demonstrating the role of HA in all stages of cancer, from initiation to relapse and therapy resistance. HA interacts with multiple cell surface receptors, including CD44, receptor for hyaluronan mediated motility (RHAMM) and intracellular signaling pathways, including receptor tyrosine kinase pathways, to promote the survival and proliferation of cancer cells. Additionally, HA promotes the formation of cancer stem cell (CSC) populations, which are hypothesized to be responsible for the initiation of tumors and therapy resistance. Recent studies have identified that the molecular weight of HA plays differing roles on both normal and cancer cell behavior. This review explores the role of HA in cancer progression and therapy resistance and how its molecular weight is important in regulating CSC populations, epithelial to mesenchymal transition (EMT), ATP binding cassette (ABC) transporter expression and receptor tyrosine kinase pathways.

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The Role of miR-210 in the Biological System: A Current Overview

Human Heredity ◽

10.1159/000509280 ◽

2019 ◽

Vol 84 (6) ◽

pp. 233-239

Author(s):

Xu Hui ◽

Hisham Al-Ward ◽

Fahmi Shaher ◽

Chun-Yang Liu ◽

Ning Liu

Keyword(s):

Gene Expression ◽

Regulation Of Gene Expression ◽

Low Oxygen ◽

Cellular Functions ◽

Regulate Gene Expression ◽

System A ◽

Non Coding Rnas ◽

Post Transcriptional Regulation ◽

A Current

Background: MicroRNAs (miRNAs) represent a group of non-coding RNAs measuring 19–23 nucleotides in length and are recognized as powerful molecules that regulate gene expression in eukaryotic cells. miRNAs stimulate the post-transcriptional regulation of gene expression via direct or indirect mechanisms. Summary: miR-210 is highly upregulated in cells under hypoxia, thereby revealing its significance to cell endurance. Induction of this mRNA expression is an important feature of the cellular low-oxygen response and the most consistent and vigorous target of HIF. Key Message: miR-210 is involved in many cellular functions under the effect of HIF-1α, including the cell cycle, DNA repair, immunity and inflammation, angiogenesis, metabolism, and macrophage regulation. It also plays an important regulatory role in T-cell differentiation and stimulation.

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SGK1 in Human Cancer: Emerging Roles and Mechanisms

Frontiers in Oncology ◽

10.3389/fonc.2020.608722 ◽

2021 ◽

Vol 10 ◽

Author(s):

Yiwen Sang ◽

Piaoping Kong ◽

Shizhen Zhang ◽

Lingyu Zhang ◽

Ying Cao ◽

...

Keyword(s):

Cancer Progression ◽

Kinase Activity ◽

Human Cancer ◽

Therapy Resistance ◽

Cancer Cell Proliferation ◽

Serine Threonine Kinase ◽

Aberrant Expression ◽

Threonine Kinase ◽

Cancer Types

Serum and glucocorticoid-induced protein kinase 1 (SGK1) is a member of the “AGC” subfamily of protein kinases, which shares structural and functional similarities with the AKT family of kinases and displays serine/threonine kinase activity. Aberrant expression of SGK1 has profound cellular consequences and is closely correlated with human cancer. SGK1 is considered a canonical factor affecting the expression and signal transduction of multiple genes involved in the genesis and development of many human cancers. Abnormal expression of SGK1 has been found in tissue and may hopefully become a useful indicator of cancer progression. In addition, SGK1 acts as a prognostic factor for cancer patient survival. This review systematically summarizes and discusses the role of SGK1 as a diagnostic and prognostic biomarker of diverse cancer types; focuses on its essential roles and functions in tumorigenesis, cancer cell proliferation, apoptosis, invasion, metastasis, autophagy, metabolism, and therapy resistance and in the tumor microenvironment; and finally summarizes the current understanding of the regulatory mechanisms of SGK1 at the molecular level. Taken together, this evidence highlights the crucial role of SGK1 in tumorigenesis and cancer progression, revealing why it has emerged as a potential target for cancer therapy.

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Nucleoporin TPR is an integral component of the TREX-2 mRNA export pathway

Nature Communications ◽

10.1038/s41467-020-18266-2 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 3

Author(s):

Vasilisa Aksenova ◽

Alexandra Smith ◽

Hangnoh Lee ◽

Prasanna Bhat ◽

Caroline Esnault ◽

...

Keyword(s):

Gene Expression ◽

Mrna Export ◽

Mrna Turnover ◽

Nuclear Pore ◽

Nuclear Pore Complexes ◽

Nucleocytoplasmic Trafficking ◽

Cellular Functions ◽

Pore Complexes ◽

Slow Turnover

Abstract Nuclear pore complexes (NPCs) are important for cellular functions beyond nucleocytoplasmic trafficking, including genome organization and gene expression. This multi-faceted nature and the slow turnover of NPC components complicates investigations of how individual nucleoporins act in these diverse processes. To address this question, we apply an Auxin-Induced Degron (AID) system to distinguish roles of basket nucleoporins NUP153, NUP50 and TPR. Acute depletion of TPR causes rapid and pronounced changes in transcriptomic profiles. These changes are dissimilar to shifts observed after loss of NUP153 or NUP50, but closely related to changes caused by depletion of mRNA export receptor NXF1 or the GANP subunit of the TRanscription-EXport-2 (TREX-2) mRNA export complex. Moreover, TPR depletion disrupts association of TREX-2 subunits (GANP, PCID2, ENY2) to NPCs and results in abnormal RNA transcription and export. Our findings demonstrate a unique and pivotal role of TPR in gene expression through TREX-2- and/or NXF1-dependent mRNA turnover.

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Gene Expression Alterations during Development of Castration-Resistant Prostate Cancer Are Detected in Circulating Tumor Cells

Cancers ◽

10.3390/cancers12010039 ◽

2019 ◽

Vol 12 (1) ◽

pp. 39 ◽

Cited By ~ 2

Author(s):

Andreas Josefsson ◽

Karin Larsson ◽

Eva Freyhult ◽

Jan-Erik Damber ◽

Karin Welén

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Progression ◽

Expression Patterns ◽

Therapy Resistance ◽

Castration Resistant Prostate Cancer ◽

Cancer Specific Survival ◽

Castration Resistant

Development of castration-resistant prostate cancer (CRPC) is associated with alterations in gene expression involved in steroidogenesis and androgen signaling. This study investigates whether gene expression changes related to CRPC development can be identified in circulating tumor cells (CTCs). Gene expression in paired CTC samples from 29 patients, before androgen deprivation therapy (ADT) and at CRPC relapse, was compared using a panel including 47 genes related to prostate cancer progression on a qPCR platform. Fourteen genes displayed significantly changed gene expression in CTCs at CRPC relapse compared to before start of ADT. The genes with increased expression at CRPC relapse were related to steroidogenesis, AR-signaling, and anti-apoptosis. In contrast, expression of prostate markers was downregulated at CRPC. We also show that midkine (MDK) expression in CTCs from metastatic hormone-sensitive prostate cancer (mHSPC) was associated to short cancer-specific survival (CSS). In conclusion, this study shows that gene expression patterns in CTCs reflect the development of CRPC, and that MDK expression levels in CTCs are prognostic for cancer-specific survival in mHSPC. This study emphasizes the role of CTCs in exploring mechanisms of therapy resistance, as well as a promising biomarker for prognostic and treatment-predictive purposes in advanced mHSPC.

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RhoGDIα-dependent balance between RhoA and RhoC is a key regulator of cancer cell tumorigenesis

Molecular Biology of the Cell ◽

10.1091/mbc.e11-01-0020 ◽

2011 ◽

Vol 22 (17) ◽

pp. 3263-3275 ◽

Cited By ~ 23

Author(s):

T. T. Giang Ho ◽

Audrey Stultiens ◽

Johanne Dubail ◽

Charles M. Lapière ◽

Betty V. Nusgens ◽

...

Keyword(s):

Tumor Growth ◽

Cancer Progression ◽

Dynamic Balance ◽

Cellular Functions ◽

Expression Of Genes ◽

Genes Encoding ◽

Interfering Rna

RhoGTPases are key signaling molecules regulating main cellular functions such as migration, proliferation, survival, and gene expression through interactions with various effectors. Within the RhoA-related subclass, RhoA and RhoC contribute to several steps of tumor growth, and the regulation of their expression affects cancer progression. Our aim is to investigate their respective contributions to the acquisition of an invasive phenotype by using models of reduced or forced expression. The silencing of RhoC, but not of RhoA, increased the expression of genes encoding tumor suppressors, such as nonsteroidal anti-inflammatory drug–activated gene 1 (NAG-1), and decreased migration and the anchorage-independent growth in vitro. In vivo, RhoC small interfering RNA (siRhoC) impaired tumor growth. Of interest, the simultaneous knockdown of RhoC and NAG-1 repressed most of the siRhoC-related effects, demonstrating the central role of NAG-1. In addition of being induced by RhoC silencing, NAG-1 was also largely up-regulated in cells overexpressing RhoA. The silencing of RhoGDP dissociation inhibitor α (RhoGDIα) and the overexpression of a RhoA mutant unable to bind RhoGDIα suggested that the effect of RhoC silencing is indirect and results from the up-regulation of the RhoA level through competition for RhoGDIα. This study demonstrates the dynamic balance inside the RhoGTPase network and illustrates its biological relevance in cancer progression.

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