An NR2F1-specific agonist suppresses metastasis by inducing cancer cell dormancy

We describe the discovery of an agonist of the nuclear receptor NR2F1 that specifically activates dormancy programs in malignant cells. The agonist led to a self-regulated increase in NR2F1 mRNA and protein and downstream transcription of a novel dormancy program. This program led to growth arrest of an HNSCC PDX line, human cell lines, and patient-derived organoids in 3D cultures and in vivo. This effect was lost when NR2F1 was knocked out by CRISPR-Cas9. RNA sequencing revealed that agonist treatment induces transcriptional changes associated with inhibition of cell cycle progression and mTOR signaling, metastasis suppression, and induction of a neural crest lineage program. In mice, agonist treatment resulted in inhibition of lung HNSCC metastasis, even after cessation of the treatment, where disseminated tumor cells displayed an NR2F1hi/p27hi/Ki-67lo/p-S6lo phenotype and remained in a dormant single-cell state. Our work provides proof of principle supporting the use of NR2F1 agonists to induce dormancy as a therapeutic strategy to prevent metastasis.

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A bulky glycocalyx fosters metastasis formation by promoting G1 cell cycle progression

eLife ◽

10.7554/elife.25752 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 27

Author(s):

Elliot C Woods ◽

FuiBoon Kai ◽

J Matthew Barnes ◽

Kayvon Pedram ◽

Michael W Pickup ◽

...

Keyword(s):

Cell Cycle ◽

Tumor Cells ◽

Cell Cycle Progression ◽

Disseminated Tumor Cells ◽

Metastatic Potential ◽

Cancer Cell Growth ◽

Cycle Progression ◽

Growth And Survival ◽

Syngeneic Mouse Model

Metastasis depends upon cancer cell growth and survival within the metastatic niche. Tumors which remodel their glycocalyces, by overexpressing bulky glycoproteins like mucins, exhibit a higher predisposition to metastasize, but the role of mucins in oncogenesis remains poorly understood. Here we report that a bulky glycocalyx promotes the expansion of disseminated tumor cells in vivo by fostering integrin adhesion assembly to permit G1 cell cycle progression. We engineered tumor cells to display glycocalyces of various thicknesses by coating them with synthetic mucin-mimetic glycopolymers. Cells adorned with longer glycopolymers showed increased metastatic potential, enhanced cell cycle progression, and greater levels of integrin-FAK mechanosignaling and Akt signaling in a syngeneic mouse model of metastasis. These effects were mirrored by expression of the ectodomain of cancer-associated mucin MUC1. These findings functionally link mucinous proteins with tumor aggression, and offer a new view of the cancer glycocalyx as a major driver of disease progression.

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MiR-142-3p Suppresses SOCS6 Expression and Promotes Cell Proliferation in Nasopharyngeal Carcinoma

Cellular Physiology and Biochemistry ◽

10.1159/000430147 ◽

2015 ◽

Vol 36 (5) ◽

pp. 1743-1752 ◽

Cited By ~ 20

Author(s):

Xiaoming Qi ◽

Jianqiang Li ◽

Changbo Zhou ◽

Chunlei Lv ◽

Min Tian

Keyword(s):

Cell Proliferation ◽

Nasopharyngeal Carcinoma ◽

Cell Cycle Progression ◽

Therapeutic Strategy ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Cycle Progression ◽

Direct Target

Background/Aims: An increasing number of studies show that microRNAs (miRNAs) play crucial roles in nasopharyngeal carcinoma (NPC) tumorigenesis. The aim of our study was to investigate the biological roles and mechanisms of miR-142-3p in NPC. Methods: miR-142-3p expression was examined in NPC specimens and nasopharyngitis biopsy samples by quantitative real-time PCR. The biological functions of miR-142-3p were studied using a series of in vitro and in vivo approaches. Results: miR-142-3p is over-expressed in NPC tissues and cell lines. Knockdown of miR-142-3p significantly inhibited cell proliferation and cell cycle progression in vitro, and suppressed tumor growth in a mouse model. Suppressor of cytokine signaling 6 (SOCS6) was identified as a direct target of miR-142-3p, and miR-142-3p down-regulated the expression of SOCS6 by directly binding to its 3′untranslated region (UTR). Knockdown of SOCS6 abrogated the effects of miR-142-3p down-regulation. Conclusion: These findings indicate that miR-142-3p regulates NPC development by down-regulating SOCS6 expression and suggest that modulation of miR-142-3p expression could be a therapeutic strategy for NPC.

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A Bulky Glycocalyx Fosters Metastasis Formation by Promoting G1 Cell Cycle Progression

10.1101/156893 ◽

2017 ◽

Author(s):

Elliot C. Woods ◽

J. Matthew Barnes ◽

Michael W. Pickup ◽

Kayvon Pedram ◽

FuiBoon Kai ◽

...

Keyword(s):

Cell Cycle ◽

Tumor Cells ◽

Cell Cycle Progression ◽

Disseminated Tumor Cells ◽

Metastatic Potential ◽

Cancer Cell Growth ◽

Cycle Progression ◽

Growth And Survival ◽

Syngeneic Mouse Model

AbstractMetastasis depends upon cancer cell growth and survival within the metastatic niche. Tumors which remodel their glycocalyces, by overexpressing bulky glycoproteins like mucins, exhibit a higher predisposition to metastasize, but the role of mucins in oncogenesis remains poorly understood. Here we report that a bulky glycocalyx promotes the expansion of disseminated tumor cells in vivo by fostering integrin adhesion assembly to permit G1 cell cycle progression. We engineered tumor cells to display glycocalyces of various thicknesses by coating them with synthetic mucin-mimetic glycopolymers. Cells adorned with longer glycopolymers showed increased metastatic potential, enhanced cell cycle progression, and greater levels of integrin-FAK mechanosignaling and Akt signaling in a syngeneic mouse model of metastasis. These effects were mirrored by expression of the ectodomain of cancer-associated mucin MUC1. These findings functionally link mucinous proteins with tumor aggression, and offer a new view of the cancer glycocalyx as a major driver of disease progression.

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To Divide or Not to Divide? How Deuterium Affects Growth and Division of Chlamydomonas reinhardtii

Biomolecules ◽

10.3390/biom11060861 ◽

2021 ◽

Vol 11 (6) ◽

pp. 861

Author(s):

Veronika Kselíková ◽

Vilém Zachleder ◽

Kateřina Bišová

Keyword(s):

Cell Cycle ◽

Chlamydomonas Reinhardtii ◽

Cell Cycle Progression ◽

Model Organism ◽

Cycle Progression ◽

Synchronous Cultures ◽

Multiple Fission ◽

First Choice ◽

High Doses

Extensive in vivo replacement of hydrogen by deuterium, a stable isotope of hydrogen, induces a distinct stress response, reduces cell growth and impairs cell division in various organisms. Microalgae, including Chlamydomonas reinhardtii, a well-established model organism in cell cycle studies, are no exception. Chlamydomonas reinhardtii, a green unicellular alga of the Chlorophyceae class, divides by multiple fission, grows autotrophically and can be synchronized by alternating light/dark regimes; this makes it a model of first choice to discriminate the effect of deuterium on growth and/or division. Here, we investigate the effects of high doses of deuterium on cell cycle progression in C. reinhardtii. Synchronous cultures of C. reinhardtii were cultivated in growth medium containing 70 or 90% D2O. We characterize specific deuterium-induced shifts in attainment of commitment points during growth and/or division of C. reinhardtii, contradicting the role of the “sizer” in regulating the cell cycle. Consequently, impaired cell cycle progression in deuterated cultures causes (over)accumulation of starch and lipids, suggesting a promising potential for microalgae to produce deuterated organic compounds.

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Analysis of Cell Cycle and Replication of Mouse Macrophages afterIn VivoandIn VitroCryptococcus neoformans Infection Using Laser Scanning Cytometry

Infection and Immunity ◽

10.1128/iai.06332-11 ◽

2012 ◽

Vol 80 (4) ◽

pp. 1467-1478 ◽

Cited By ~ 12

Author(s):

Carolina Coelho ◽

Lydia Tesfa ◽

Jinghang Zhang ◽

Johanna Rivera ◽

Teresa Gonçalves ◽

...

Keyword(s):

Cell Cycle ◽

Cell Division ◽

Cytotoxic Effect ◽

Laser Scanning ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Content Type ◽

Cycle Arrest ◽

Laser Scanning Cytometry

ABSTRACTWe investigated the outcome of the interaction ofCryptococcus neoformanswith murine macrophages using laser scanning cytometry (LSC). Previous results in our lab had shown that phagocytosis ofC. neoformanspromoted cell cycle progression. LSC allowed us to simultaneously measure the phagocytic index, macrophage DNA content, and 5-ethynyl-2′-deoxyuridine (EdU) incorporation such that it was possible to study host cell division as a function of phagocytosis. LSC proved to be a robust, reliable, and high-throughput method for quantifying phagocytosis. Phagocytosis ofC. neoformanspromoted cell cycle progression, but infected macrophages were significantly less likely to complete mitosis. Hence, we report a new cytotoxic effect associated with intracellularC. neoformansresidence that manifested itself in impaired cell cycle completion as a consequence of a block in the G2/M stage of the mitotic cell cycle. Cell cycle arrest was not due to increased cell membrane permeability or DNA damage. We investigated alveolar macrophage replicationin vivoand demonstrated that these cells are capable of low levels of cell division in the presence or absence ofC. neoformansinfection. In summary, we simultaneously studied phagocytosis, the cell cycle state of the host cell and pathogen-mediated cytotoxicity, and our results demonstrate a new cytotoxic effect ofC. neoformansinfection on murine macrophages: fungus-induced cell cycle arrest. Finally, we provide evidence for alveolar macrophage proliferationin vivo.

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SCL-mediated regulation of the cell-cycle regulator p21 is critical for murine megakaryopoiesis

Blood ◽

10.1182/blood-2011-01-328765 ◽

2011 ◽

Vol 118 (3) ◽

pp. 723-735 ◽

Cited By ~ 28

Author(s):

Hedia Chagraoui ◽

Mira Kassouf ◽

Sreemoti Banerjee ◽

Nicolas Goardon ◽

Kevin Clark ◽

...

Keyword(s):

Cell Cycle ◽

Transcriptional Control ◽

Cell Cycle Progression ◽

Cellular Proliferation ◽

Loss Of Function ◽

Cycle Progression ◽

Cell Cycle Regulator ◽

Nuclear Changes ◽

Cytoplasmic Maturation

Abstract Megakaryopoiesis is a complex process that involves major cellular and nuclear changes and relies on controlled coordination of cellular proliferation and differentiation. These mechanisms are orchestrated in part by transcriptional regulators. The key hematopoietic transcription factor stem cell leukemia (SCL)/TAL1 is required in early hematopoietic progenitors for specification of the megakaryocytic lineage. These early functions have, so far, prevented full investigation of its role in megakaryocyte development in loss-of-function studies. Here, we report that SCL critically controls terminal megakaryocyte maturation. In vivo deletion of Scl specifically in the megakaryocytic lineage affects all key attributes of megakaryocyte progenitors (MkPs), namely, proliferation, ploidization, cytoplasmic maturation, and platelet release. Genome-wide expression analysis reveals increased expression of the cell-cycle regulator p21 in Scl-deleted MkPs. Importantly, p21 knockdown-mediated rescue of Scl-mutant MkPs shows full restoration of cell-cycle progression and partial rescue of the nuclear and cytoplasmic maturation defects. Therefore, SCL-mediated transcriptional control of p21 is essential for terminal maturation of MkPs. Our study provides a mechanistic link between a major hematopoietic transcriptional regulator, cell-cycle progression, and megakaryocytic differentiation.

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Regulation of Raf-1-dependent signaling during early Xenopus development.

Molecular and Cellular Biology ◽

10.1128/mcb.15.12.6686 ◽

1995 ◽

Vol 15 (12) ◽

pp. 6686-6693 ◽

Cited By ~ 21

Author(s):

A M MacNicol ◽

A J Muslin ◽

E L Howard ◽

A Kikuchi ◽

M C MacNicol ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Mapk Pathway ◽

Mapk Signaling ◽

Embryonic Cell ◽

Cycle Progression ◽

Mapk Activity ◽

Cytostatic Factor ◽

Differentiation And Proliferation

The Raf-1 gene product is activated in response to cellular stimulation by a variety of growth factors and hormones. Raf-1 activity has been implicated in both cellular differentiation and proliferation. We have examined the regulation of the Raf-1/MEK/MAP kinase (MAPK) pathway during embryonic development in the frog Xenopus laevis. We report that Raf-1, MEK, and MAPK activities are turned off following fertilization and remain undetectable up until blastula stages (stage 8), some 4 h later. Tight regulation of the Raf-1/MEK/MAPK pathway following fertilization is crucial for embryonic cell cycle progression. Inappropriate reactivation of MAPK activity by microinjection of oncogenic Raf-1 RNA results in metaphase cell cycle arrest and, consequently, embryonic lethality. Our findings demonstrate an absolute requirement, in vivo, for inactivation of the MAPK signaling pathway to allow normal cell cycle progression during the period of synchronous cell divisions which occur following fertilization. Further, we show that cytostatic factor effects are mediated through MEK and MAPK.

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Roquin1 Suppresses Breast Cancer Growth by Inducing Cell Cycle Arrest via Selectively Destabilizing Cell Cycle–Promoting Gene mRNAs

10.21203/rs.3.rs-53499/v1 ◽

2020 ◽

Author(s):

Wenbao Lu ◽

Meicen Zhou ◽

Bing Wang ◽

Xueting Liu ◽

Bingwei Li

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Proliferation ◽

Cell Cycle Arrest ◽

Breast Cancer Cell ◽

Breast Tumor ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Cycle Arrest

Abstract Background: Dysregulation of cell cycle progression is one of the common features of human cancer cells, however, its mechanism remains unclear. This study aims to clarify the role and the underlying mechanisms of Roquin1 in cell cycle arrest induction in breast cancer.Methods: Public cancer databases were analyzed to identify the expression pattern of Roquin1 in human breast cancers and the significant association with patient survival. Quantitative real-time PCR and western blots were performed to detect the expression of Roquin1 in breast cancer samples and cell lines. Cell counting, MTT assay, flow cytometry, and in vivo study were conducted to investigate the effects of Roquin1 on cell proliferation, cell cycle progression and tumor progression. RNA-sequencing was applied to identify the differential genes and pathways regulated by Roquin1. RNA immunoprecipitation assay, luciferase reporter assay, mRNA half-life detection, RNA affinity binding assay, and RIP-ChIP were used to explore the molecular mechanisms of Roquin1.Results: We showed that Roquin1 expression in breast cancer tissues and cell lines was inhibited, and the reduction in Roquin1 expression was associated with poor overall survival and relapse free survival of patients with breast cancer. Roquin1 overexpression inhibited breast cancer cell proliferation and induced G1/S cell cycle arrest without causing significant apoptosis. In contrast, knockdown of Roquin1 promoted breast cancer cell growth and cycle progression. Moreover, in vivo induction of Roquin1 by adenovirus significantly suppressed breast tumor growth and metastasis. Mechanistically, Roquin1 selectively destabilizing cell cycle–promoting genes, including Cyclin D1, Cyclin E1, cyclin dependent kinase 6 (CDK6) and minichromosome maintenance 2 (MCM2) through targeting the stem–loop structure in the 3’untranslated region (3’UTR) of mRNAs via its ROQ domain, leading to the downregulation of cell cycle–promoting mRNAs.Conclusions: Our findings demonstrated that Roquin1 was a novel breast tumor suppressor and could induce G1/S cell cycle arrest by selectively downregulating the expression of cell cycle–promoting genes, which might as a potential molecular target for breast cancer treatment.

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