1
|
Holland AM, Jehoul R, Vranken J, Wohl SG, Boesmans W. MicroRNA regulation of enteric nervous system development and disease. Trends Neurosci 2025; 48:268-282. [PMID: 40089421 PMCID: PMC11981837 DOI: 10.1016/j.tins.2025.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 02/04/2025] [Accepted: 02/18/2025] [Indexed: 03/17/2025]
Abstract
The enteric nervous system (ENS), an elaborate network of neurons and glia woven through the gastrointestinal tract, is integral for digestive physiology and broader human health. Commensurate with its importance, ENS dysfunction is linked to a range of debilitating gastrointestinal disorders. MicroRNAs (miRNAs), with their pleiotropic roles in post-transcriptional gene regulation, serve as key developmental effectors within the ENS. Herein, we review the regulatory dynamics of miRNAs in ENS ontogeny, showcasing specific miRNAs implicated in both congenital and acquired enteric neuropathies, such as Hirschsprung's disease (HSCR), achalasia, intestinal neuronal dysplasia (IND), chronic intestinal pseudo-obstruction (CIPO), and slow transit constipation (STC). By delineating miRNA-mediated mechanisms in these diseases, we underscore their importance for ENS homeostasis and highlight their potential as therapeutic targets.
Collapse
Affiliation(s)
- Amy Marie Holland
- Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium; Department of Pathology, GROW - Research Institute for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Reindert Jehoul
- Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Jorunn Vranken
- Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Stefanie Gabriele Wohl
- Department of Biological and Vision Sciences, College of Optometry, The State University of New York, New York, NY, USA
| | - Werend Boesmans
- Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium; Department of Pathology, GROW - Research Institute for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, The Netherlands.
| |
Collapse
|
2
|
Kim H, Noristani HN, Zhai J, Manire M, Zhai J, Li S, Zhong J, Son YJ. Deleting PTEN, but not SOCS3 or myelin inhibitors, robustly boosts BRAF-elicited intraspinal regeneration of peripheral sensory axons. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.18.613685. [PMID: 39345461 PMCID: PMC11429726 DOI: 10.1101/2024.09.18.613685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Primary sensory axons fail to regenerate into the spinal cord following dorsal root injury leading to permanent sensory deficits. Re-entry is prevented at the dorsal root entry zone (DREZ), the CNS-PNS interface. Current approaches for promoting DR regeneration across the DREZ have had some success, but sustained, long-distance regeneration, particularly of large-diameter myelinated axons, still remains a formidable challenge. We have previously shown that induced expression of constitutively active B-RAF (kaBRAF) enhanced the regenerative competence of injured DRG neurons in adult mice. In this study, we investigated whether robust intraspinal regeneration can be achieved after a cervical DR injury by selective expression of kaBRAF alone or in combination with deletion of the myelin-associated inhibitors or neuron-intrinsic growth suppressors (PTEN or SOCS3). We found that kaBRAF promoted some axon regeneration across the DREZ but did not produce significant functional recovery by two months. Supplementary deletion of Nogo, MAG, and OMgp only modestly improved kaBRAF-induced regeneration. Deletion of PTEN or SOCS3 individually or in combination failed to promote any growth across the DREZ. In marked contrast, simultaneous deletion of PTEN, but not SOCS3, dramatically enhanced kaBRAF-mediated regeneration enabling many more axons to penetrate the DREZ and grow deep into the spinal cord. This study shows that dual activation of BRAF-MEK-ERK and PI3K-Akt-mTOR signaling is an effective strategy to stimulate robust intraspinal DR regeneration.
Collapse
|
3
|
Upreti A, Padula SL, Weaver JM, Wagner BD, Kneller AM, Petulla AL, Lachke SA, Robinson ML. A Transcriptomics Analysis of the Regulation of Lens Fiber Cell Differentiation in the Absence of FGFRs and PTEN. Cells 2024; 13:1222. [PMID: 39056803 PMCID: PMC11274593 DOI: 10.3390/cells13141222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 06/28/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
Adding 50% vitreous humor to the media surrounding lens explants induces fiber cell differentiation and a significant immune/inflammatory response. While Fgfr loss blocks differentiation in lens epithelial explants, this blockage is partially reversed by deleting Pten. To investigate the functions of the Fgfrs and Pten during lens fiber cell differentiation, we utilized a lens epithelial explant system and conducted RNA sequencing on vitreous humor-exposed explants lacking Fgfrs, or Pten or both Fgfrs and Pten. We found that Fgfr loss impairs both vitreous-induced differentiation and inflammation while the additional loss of Pten restores these responses. Furthermore, transcriptomic analysis suggested that PDGFR-signaling in FGFR-deficient explants is required to mediate the rescue of vitreous-induced fiber differentiation in explants lacking both Fgfrs and Pten. The blockage of β-crystallin induction in explants lacking both Fgfrs and Pten in the presence of a PDGFR inhibitor supports this hypothesis. Our findings demonstrate that a wide array of genes associated with fiber cell differentiation are downstream of FGFR-signaling and that the vitreous-induced immune responses also depend on FGFR-signaling. Our data also demonstrate that many of the vitreous-induced gene-expression changes in Fgfr-deficient explants are rescued in explants lacking both Fgfrs and Pten.
Collapse
Affiliation(s)
- Anil Upreti
- Cell, Molecular and Structural Biology Program, Miami University, Oxford, OH 45056, USA; (A.U.); (S.L.P.); (J.M.W.)
- Department of Biology and Center for Visual Sciences, Miami University, Oxford, OH 45056, USA; (B.D.W.); (A.M.K.); (A.L.P.)
| | - Stephanie L. Padula
- Cell, Molecular and Structural Biology Program, Miami University, Oxford, OH 45056, USA; (A.U.); (S.L.P.); (J.M.W.)
- Department of Biology and Center for Visual Sciences, Miami University, Oxford, OH 45056, USA; (B.D.W.); (A.M.K.); (A.L.P.)
| | - Jacob M. Weaver
- Cell, Molecular and Structural Biology Program, Miami University, Oxford, OH 45056, USA; (A.U.); (S.L.P.); (J.M.W.)
- Department of Biology and Center for Visual Sciences, Miami University, Oxford, OH 45056, USA; (B.D.W.); (A.M.K.); (A.L.P.)
| | - Brad D. Wagner
- Department of Biology and Center for Visual Sciences, Miami University, Oxford, OH 45056, USA; (B.D.W.); (A.M.K.); (A.L.P.)
| | - Allison M. Kneller
- Department of Biology and Center for Visual Sciences, Miami University, Oxford, OH 45056, USA; (B.D.W.); (A.M.K.); (A.L.P.)
| | - Anthony L. Petulla
- Department of Biology and Center for Visual Sciences, Miami University, Oxford, OH 45056, USA; (B.D.W.); (A.M.K.); (A.L.P.)
| | - Salil A. Lachke
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA;
- Center for Bioinformatics and Computational Biology, University of Delaware, Newark, DE 19716, USA
| | - Michael L. Robinson
- Cell, Molecular and Structural Biology Program, Miami University, Oxford, OH 45056, USA; (A.U.); (S.L.P.); (J.M.W.)
- Department of Biology and Center for Visual Sciences, Miami University, Oxford, OH 45056, USA; (B.D.W.); (A.M.K.); (A.L.P.)
| |
Collapse
|
4
|
Chesnokova LS, Mosher BS, Fulkerson HL, Nam HW, Shakya AK, Yurochko AD. Distinct early role of PTEN regulation during HCMV infection of monocytes. Proc Natl Acad Sci U S A 2024; 121:e2312290121. [PMID: 38483999 PMCID: PMC10962971 DOI: 10.1073/pnas.2312290121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 12/01/2023] [Indexed: 03/19/2024] Open
Abstract
Human cytomegalovirus (HCMV) infection of monocytes is essential for viral dissemination and persistence. We previously identified that HCMV entry/internalization and subsequent productive infection of this clinically relevant cell type is distinct when compared to other infected cells. We showed that internalization and productive infection required activation of epidermal growth factor receptor (EGFR) and integrin/c-Src, via binding of viral glycoprotein B to EGFR, and the pentamer complex to β1/β3 integrins. To understand how virus attachment drives entry, we compared infection of monocytes with viruses containing the pentamer vs. those without the pentamer and then used a phosphoproteomic screen to identify potential phosphorylated proteins that influence HCMV entry and trafficking. The screen revealed that the most prominent pentamer-biased phosphorylated protein was the lipid- and protein-phosphatase phosphatase and tensin homolog (PTEN). PTEN knockdown with siRNA or PTEN inhibition with a PTEN inhibitor decreased pentamer-mediated HCMV entry, without affecting trimer-mediated entry. Inhibition of PTEN activity affected lipid metabolism and interfered with the onset of the endocytic processes required for HCMV entry. PTEN inactivation was sufficient to rescue pentamer-null HCMV from lysosomal degradation. We next examined dephosphorylation of a PTEN substrate Rab7, a regulator of endosomal maturation. Inhibition of PTEN activity prevented dephosphorylation of Rab7. Phosphorylated Rab7, in turn, blocked early endosome to late endosome maturation and promoted nuclear localization of the virus and productive infection.
Collapse
Affiliation(s)
- Liudmila S. Chesnokova
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA71103
- Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA71103
| | - Bailey S. Mosher
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA71103
- Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA71103
| | - Heather L. Fulkerson
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA71103
- Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA71103
| | - Hyung W. Nam
- Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA71103
| | - Akhalesh K. Shakya
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA71103
| | - Andrew D. Yurochko
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA71103
- Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA71103
- Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA71103
- Feist-Weller Cancer Center, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA 71103, Shreveport, LA71103
- Center for Excellence in Arthritis and Rheumatology, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA71103
- Center of Excellence for Emerging Viral Threats, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA71103
| |
Collapse
|
5
|
Ertay A, Ewing RM, Wang Y. Synthetic lethal approaches to target cancers with loss of PTEN function. Genes Dis 2023; 10:2511-2527. [PMID: 37533462 PMCID: PMC7614861 DOI: 10.1016/j.gendis.2022.12.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 12/26/2022] [Accepted: 12/27/2022] [Indexed: 02/05/2023] Open
Abstract
Phosphatase and tensin homolog (PTEN) is a tumour suppressor gene and has a role in inhibiting the oncogenic AKT signalling pathway by dephosphorylating phosphatidylinositol 3,4,5-triphosphate (PIP3) into phosphatidylinositol 4,5-bisphosphate (PIP2). The function of PTEN is regulated by different mechanisms and inactive PTEN results in aggressive tumour phenotype and tumorigenesis. Identifying targeted therapies for inactive tumour suppressor genes such as PTEN has been challenging as it is difficult to restore the tumour suppressor functions. Therefore, focusing on the downstream signalling pathways to discover a targeted therapy for inactive tumour suppressor genes has highlighted the importance of synthetic lethality studies. This review focuses on the potential synthetic lethality genes discovered in PTEN-inactive cancer types. These discovered genes could be potential targeted therapies for PTEN-inactive cancer types and may improve the treatment response rates for aggressive types of cancer.
Collapse
Affiliation(s)
- Ayse Ertay
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
| | - Rob M. Ewing
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
- Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
| | - Yihua Wang
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
- Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
| |
Collapse
|
6
|
Tomasin R, Rodrigues AM, Manucci AC, Bruni-Cardoso A. A molecular landscape of quiescence and proliferation highlights the role of Pten in mammary gland acinogenesis. J Cell Sci 2023; 136:jcs261178. [PMID: 37712332 DOI: 10.1242/jcs.261178] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 09/08/2023] [Indexed: 09/16/2023] Open
Abstract
Cell context is key for cell state. Using physiologically relevant models of laminin-rich extracellular matrix (lrECM) induction of mammary epithelial cell quiescence and differentiation, we provide a landscape of the key molecules for the proliferation-quiescence decision, identifying multiple layers of regulation at the mRNA and protein levels. Quiescence occurred despite activity of Fak (also known as PTK2), Src and phosphoinositide 3-kinases (PI3Ks), suggesting the existence of a disconnecting node between upstream and downstream proliferative signalling. Pten, a lipid and protein phosphatase, fulfils this role, because its inhibition increased proliferation and restored signalling via the Akt, mTORC1, mTORC2 and mitogen-activated protein kinase (MAPK) pathways. Pten and laminin levels were positively correlated in developing murine mammary epithelia, and Pten localized apicolaterally in luminal cells in ducts and near the nascent lumen in terminal end buds. Consistently, in three-dimensional acinogenesis models, Pten was required for triggering and sustaining quiescence, polarity and architecture. The multilayered regulatory circuitry that we uncovered provides an explanation for the robustness of quiescence within a growth-suppressive microenvironment, which could nonetheless be disrupted by perturbations in master regulators such as Pten.
Collapse
Affiliation(s)
- Rebeka Tomasin
- E-signal lab, Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, SP 05508-000, Brazil
| | - Ana Maria Rodrigues
- E-signal lab, Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, SP 05508-000, Brazil
| | - Antonio Carlos Manucci
- E-signal lab, Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, SP 05508-000, Brazil
| | - Alexandre Bruni-Cardoso
- E-signal lab, Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, SP 05508-000, Brazil
| |
Collapse
|
7
|
Kaufman-Szymczyk A, Kaczmarek W, Fabianowska-Majewska K, Lubecka-Gajewska K. Lunasin and Its Epigenetic Impact in Cancer Chemoprevention. Int J Mol Sci 2023; 24:ijms24119187. [PMID: 37298139 DOI: 10.3390/ijms24119187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/19/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023] Open
Abstract
Cancer diseases are a leading cause of death worldwide. Therefore, it is pivotal to search for bioactive dietary compounds that can avert tumor development. A diet rich in vegetables, including legumes, provides chemopreventive substances, which have the potential to prevent many diseases, including cancer. Lunasin is a soy-derived peptide whose anti-cancer activity has been studied for over 20 years. The results of the previous research have shown that lunasin inhibits histone acetylation, regulates the cell cycle, suppresses proliferation and induces apoptosis of cancer cells. Thus, lunasin seems to be a promising bioactive anti-cancer agent and a potent epigenetic modulator. The present review discusses studies of the underlying molecular mechanisms and new perspectives on lunasin application in epigenetic prevention and anti-cancer therapy.
Collapse
Affiliation(s)
- Agnieszka Kaufman-Szymczyk
- Department of Biomedical Chemistry, Faculty of Health Sciences, Medical University of Lodz, 92-215 Lodz, Poland
| | - Wiktoria Kaczmarek
- Department of Biomedical Chemistry, Faculty of Health Sciences, Medical University of Lodz, 92-215 Lodz, Poland
| | | | - Katarzyna Lubecka-Gajewska
- Department of Biomedical Chemistry, Faculty of Health Sciences, Medical University of Lodz, 92-215 Lodz, Poland
| |
Collapse
|
8
|
Hohmann T, Hohmann U, Dehghani F. MACC1-induced migration in tumors: Current state and perspective. Front Oncol 2023; 13:1165676. [PMID: 37051546 PMCID: PMC10084939 DOI: 10.3389/fonc.2023.1165676] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 03/14/2023] [Indexed: 03/29/2023] Open
Abstract
Malignant tumors are still a global, heavy health burden. Many tumor types cannot be treated curatively, underlining the need for new treatment targets. In recent years, metastasis associated in colon cancer 1 (MACC1) was identified as a promising biomarker and drug target, as it is promoting tumor migration, initiation, proliferation, and others in a multitude of solid cancers. Here, we will summarize the current knowledge about MACC1-induced tumor cell migration with a special focus on the cytoskeletal and adhesive systems. In addition, a brief overview of several in vitro models used for the analysis of cell migration is given. In this context, we will point to issues with the currently most prevalent models used to study MACC1-dependent migration. Lastly, open questions about MACC1-dependent effects on tumor cell migration will be addressed.
Collapse
|
9
|
Yoshioka S, Ikeda T, Fukuchi S, Kawai Y, Ohta K, Murakami H, Ogo N, Muraoka D, Takikawa O, Asai A. Identification and Characterization of a Novel Dual Inhibitor of
Indoleamine 2,3-dioxygenase 1 and Tryptophan 2,3-dioxygenase. Int J Tryptophan Res 2022; 15:11786469221138456. [PMCID: PMC9716449 DOI: 10.1177/11786469221138456] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 10/21/2022] [Indexed: 12/05/2022] Open
Abstract
Kynurenine (Kyn), a metabolite of tryptophan (Trp), is a key regulator of mammal
immune responses such as cancer immune tolerance. Indoleamine-2,3-dioxygenase
(IDO) and tryptophan-2,3-dioxygenase (TDO) are main enzymes regulating the first
and rate-limiting step of the Kyn pathway. To identify new small molecule
inhibitors of TDO, we selected A172 glioblastoma cell line constitutively
expressed TDO. Characterization of this cell line using kinase inhibitor library
resulted in identification of MEK/ERK pathway-dependent TDO expression. After
knowing the properties for TDO expression, we further proceeded to screen
chemical library for TDO inhibitors. We previously determined that
S-benzylisothiourea derivatives are enzymatic inhibitors of indoleamine
2,3-dioxygenase 1 (IDO1) and suggested that the isothiourea moiety could be an
important pharmacophore for binding to heme. Based on this premise, we screened
an in-house library composed of various isothiourea derivatives and identified a
bisisothiourea derivative, PVZB3001, as an inhibitor of TDO. Interestingly,
PVZB3001 also inhibited the enzymatic activity of IDO1 in both cell-based and
cell-free assays but did not inhibit other heme enzymes. Molecular docking
studies suggested the importance of isothiourea moieties at the ortho position
of the phenyl ring for the inhibition of catalytic activity. PVZB3001 showed
competitive inhibition against TDO, and this was supported by the docking
simulation. PVZB3001 recovered natural killer (NK) cell viability and functions
by inhibiting Kyn accumulation in conditioned medium of both IDO1- and
TDO-expressing cells. Furthermore, oral administration of IDO1-overexpressing
tumor-bearing mice with PVZB3001 significantly inhibited tumor growth. Thus, we
identified a novel selective dual inhibitor of IDO1 and TDO using the Kyn
production assay with a glioblastoma cell line. This inhibitor could be a useful
pharmacological tool for modulating the Kyn pathway in a variety of experimental
systems.
Collapse
Affiliation(s)
- Saeko Yoshioka
- Center for Drug Discovery, Graduate
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Tomonori Ikeda
- Center for Drug Discovery, Graduate
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Sogo Fukuchi
- Center for Drug Discovery, Graduate
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Yurika Kawai
- Center for Drug Discovery, Graduate
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Katsumi Ohta
- Center for Drug Discovery, Graduate
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Hisashi Murakami
- Center for Drug Discovery, Graduate
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Naohisa Ogo
- Center for Drug Discovery, Graduate
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Daisuke Muraoka
- Department of Oncology, Nagasaki
University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Osamu Takikawa
- National Institute for Longevity
Sciences, National Center for Geriatrics and Gerontology, Aichi, Japan
| | - Akira Asai
- Center for Drug Discovery, Graduate
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan,Akira Asai, Graduate School of
Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka
422-8526, Japan.
| |
Collapse
|
10
|
Wenta T, Schmidt A, Zhang Q, Devarajan R, Singh P, Yang X, Ahtikoski A, Vaarala M, Wei GH, Manninen A. Disassembly of α6β4-mediated hemidesmosomal adhesions promotes tumorigenesis in PTEN-negative prostate cancer by targeting plectin to focal adhesions. Oncogene 2022; 41:3804-3820. [PMID: 35773413 PMCID: PMC9307480 DOI: 10.1038/s41388-022-02389-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 06/14/2022] [Accepted: 06/15/2022] [Indexed: 11/09/2022]
Abstract
Loss of α6β4-dependent hemidesmosomal adhesions has been observed during prostate cancer progression. However, the significance and underlying mechanisms by which aberrant hemidesmosome assembly may modulate tumorigenesis remain elusive. Using an extensive CRISPR/Cas9-mediated genetic engineering approaches in different prostate cancer cell lines combined with in vivo tumorigenesis studies in mice, bone marrow-on-chip assays and bioinformatics, as well as histological analysis of prostate cancer patient cohorts, we demonstrated that simultaneous loss of PTEN and hemidesmosomal adhesions induced several tumorigenic properties including proliferation, migration, resistance to anoikis, apoptosis, and drug treatment in vitro, and increased metastatic capacity in vivo. These effects were plectin-depended and plectin was associated with actin-rich adhesions upon hemidesmosome disruption in PTEN-negative prostate cancer cells leading to activation of EGFR/PI3K/Akt- and FAK/Src-pathways. These results suggest that analysis of PTEN and hemidesmosomal proteins may have diagnostic value helping to stratify prostate cancer patients with high risk for development of aggressive disease and highlight actin-associated plectin as a potential therapeutic target specifically in PTEN/hemidesmosome dual-negative prostate cancer.
Collapse
Affiliation(s)
- Tomasz Wenta
- Disease Networks Research Unit, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
| | - Anette Schmidt
- Disease Networks Research Unit, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
| | - Qin Zhang
- Disease Networks Research Unit, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
| | - Raman Devarajan
- Disease Networks Research Unit, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
| | | | - Xiayun Yang
- Disease Networks Research Unit, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
| | - Anne Ahtikoski
- Departments of Urology, Pathology and Radiology, and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Markku Vaarala
- Departments of Urology, Pathology and Radiology, and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Gong-Hong Wei
- Disease Networks Research Unit, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.,Fudan University Shanghai Cancer Center; Department of Biochemistry and Molecular Biology & Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Aki Manninen
- Disease Networks Research Unit, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
| |
Collapse
|
11
|
Delayed Therapeutic Administration of Melatonin Enhances Neuronal Survival Through AKT and MAPK Signaling Pathways Following Focal Brain Ischemia in Mice. J Mol Neurosci 2022; 72:994-1007. [PMID: 35307786 DOI: 10.1007/s12031-022-01995-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 03/01/2022] [Indexed: 10/18/2022]
Abstract
Melatonin has a role in the cell survival signaling pathways as a candidate for secondary stroke prevention. Therefore, in the present study, the coordination of ipsilateral and contralateral hemispheres to evaluate delayed post-acute effect of melatonin was examined on recovery of the cell survival and apoptosis after stroke. Melatonin was administered (4 mg/kg/day) intraperitoneally for 45 days, starting 3 days after 30 min of middle cerebral artery occlusion. The genes and proteins related to the cell survival and apoptosis were investigated by immunofluorescence, western blotting, and RT-PCR techniques after behavioral experiments. Melatonin produced delayed neurological recovery by improving motor coordination on grip strength and rotarod tests. This neurological recovery was also reflected by high level of NeuN positive cells and low level of TUNEL-positive cells suggesting enhanced neuronal survival and reduced apoptosis at the fifty-fifth day of stroke. The increase of NGF, Nrp1, c-jun; activation of AKT; and dephosphorylation of ERK and JNK at the fifty-fifth day showed that cell survival and apoptosis signaling molecules compete to contribute to the remodeling of brain. Furthermore, an increase in the CREB and Atf-1 expressions suggested the melatonin's strong reformative effect on neuronal regeneration. The contralateral hemisphere was more active at the latter stages of the molecular and functional regeneration which provides a further proof of principle about melatonin's action on the promotion of brain plasticity and recovery after stroke.
Collapse
|
12
|
Zhou X, Liu G, Xu M, Ying X, Li B, Cao F, Cheng S, Xiao B, Cheng M, Liang L, Jia M, Li W, Liu J, Li Z. Comprehensive analysis of PTEN-related ceRNA network revealing the key pathways WDFY3-AS2 - miR-21-5p/miR-221-3p/miR-222-3p - TIMP3 as potential biomarker in tumorigenesis and prognosis of kidney renal clear cell carcinoma. Mol Carcinog 2022; 61:508-523. [PMID: 35129856 DOI: 10.1002/mc.23396] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 01/06/2022] [Accepted: 01/17/2022] [Indexed: 11/10/2022]
Abstract
Kidney renal clear cell carcinoma (KIRC) is one of the most common malignancies, and there is still a lack of effective biomarkers for early detection and prognostic prediction. In here, we compared the characteristics of RNA sequencing data sets of KIRC samples based on the tumor suppressor gene phosphatase and tensin homolog (PTEN). The 1016 long noncoding RNAs, 48 microRNAs (miRNAs), and 2104 messenger RNAs associated with PTEN were identified and these genes were differentially expressed between tumor and paracancerous tissues. The most relevant pathway was found to be WDFY3-AS2 - miR-21-5p/miR-221-3p/miR-222-3p - TIMP3 according to the rules of competing endogenous RNA (ceRNA) regulation. WDFY3-AS2 and TIMP3 expression were positively correlated and reduced in KIRC samples, while miR-21-5p, miR-221-3p, and miR-222-3p were relatively highly expressed. The relatively low expression of WDFY3-AS2 and TIMP3 in KIRC were associated with poor prognosis in KIRC patients, while higher expression of miR-21-5p, miR-221-3p, and miR-222-3p predicted reduced survival (p < 0.05). Univariate and multivariate Cox regression analysis showed that lower expression of WDFY3-AS2 and TIMP3 was significantly related to tumor grade, tumor size, lymph node metastasis, distant metastasis, and TNM stage. The expression of TIMP3 in KIRC tissues was also verified by immunohistochemistry, and the results were consistent with our analytical data. In summary, this study constructed a new model with clinical predictive value and identified the WDFY3-AS2/TIMP3 pathway that was closely associated with the prognosis of KIRC, which could serve as a promising biomarker for the diagnosis and treatment of KIRC.
Collapse
Affiliation(s)
- Xishan Zhou
- Second Affiliated Hospital of Luohe Medical College, Luohe, Henan, China
| | - Guofeng Liu
- Second Affiliated Hospital of Luohe Medical College, Luohe, Henan, China
| | - Mo Xu
- Second Affiliated Hospital of Luohe Medical College, Luohe, Henan, China
| | - Xintao Ying
- Second Affiliated Hospital of Luohe Medical College, Luohe, Henan, China
| | - Bianfeng Li
- Second Affiliated Hospital of Luohe Medical College, Luohe, Henan, China
| | - Fengxi Cao
- Second Affiliated Hospital of Luohe Medical College, Luohe, Henan, China
| | - Shuqiang Cheng
- Second Affiliated Hospital of Luohe Medical College, Luohe, Henan, China
| | - Beibei Xiao
- Second Affiliated Hospital of Luohe Medical College, Luohe, Henan, China
| | - Miao Cheng
- Second Affiliated Hospital of Luohe Medical College, Luohe, Henan, China
| | - Liang Liang
- Second Affiliated Hospital of Luohe Medical College, Luohe, Henan, China
| | - Mingxi Jia
- National Engineering Research Center of Rice and Byproduct Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, Hunan, China.,College of Life Sciences and Chemistry, Hunan University of Technology, Zhuzhou, Hunan, China
| | - Wen Li
- National Engineering Research Center of Rice and Byproduct Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, Hunan, China.,College of Life Sciences and Chemistry, Hunan University of Technology, Zhuzhou, Hunan, China
| | - Jiheng Liu
- Department of Hematology and Oncology, The First Hospital of Changsha, Changsha, Hunan, China
| | - Zheng Li
- NHC Key Laboratory of Carcinogenesis, Cancer Research Institute and School of Basic Medical, Central South University, Changsha, Hunan, China
| |
Collapse
|
13
|
Synthesis and biological evaluation of novel isoxazole-piperazine hybrids as potential anti-cancer agents with inhibitory effect on liver cancer stem cells. Eur J Med Chem 2021; 221:113489. [PMID: 33951549 DOI: 10.1016/j.ejmech.2021.113489] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/15/2021] [Accepted: 04/16/2021] [Indexed: 02/07/2023]
Abstract
In our effort for the development of novel anticancer therapeutics, a series of isoxazole-piperazine analogues were prepared, and primarily screened for their antiproliferative potential against hepatocellular carcinoma (HCC; Huh7/Mahlavu) and breast (MCF-7) cancer cells. All compounds demonstrated potent to moderate cytotoxicity on all cell lines with IC50 values in the range of 0.09-11.7 μM. Further biological studies with 6a and 13d in HCC cells have shown that both compounds induced G1 or G2/M arrests resulting in apoptotic cell death. Subsequent analysis of proteins involved in cell cycle progression as well as proliferation of HCC cells revealed that 6a and 13d may affect cellular survival pathways differently depending on the mutation profiles of cells (p53 and PTEN), epidermal/mesenchymal characteristics, and activation of cell mechanisms through p53 dependent/independent pathways. Lastly, we have demonstrated the potential anti-stemness properties of these compounds in which the proportion of liver CSCs in Huh7 cells (CD133+/EpCAM+) were significantly reduced by 6a and 13d. Furthermore, both compounds caused a significant reduction in expression of stemness markers, NANOG or OCT4 proteins, in Mahlavu and Huh7 cells, as well as resulted in a decreased sphere formation capacity in Huh7 cells. Together, these novel isoxazole-piperazine derivatives may possess potential as leads for development of effective anti-cancer drugs against HCC cells with stem cell-like properties.
Collapse
|
14
|
EGFRvIII tumorigenicity requires PDGFRA co-signaling and reveals therapeutic vulnerabilities in glioblastoma. Oncogene 2021; 40:2682-2696. [PMID: 33707748 PMCID: PMC9159289 DOI: 10.1038/s41388-021-01721-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 02/15/2021] [Accepted: 02/18/2021] [Indexed: 01/31/2023]
Abstract
Focal amplification of epidermal growth factor receptor (EGFR) and its ligand-independent, constitutively active EGFRvIII mutant form are prominent oncogenic drivers in glioblastoma (GBM). The EGFRvIII gene rearrangement is considered to be an initiating event in the etiology of GBM, however, the mechanistic details of how EGFRvIII drives cellular transformation and tumor maintenance remain unclear. Here, we report that EGFRvIII demonstrates a reliance on PDGFRA co-stimulatory signaling during the tumorigenic process in a genetically engineered autochthonous GBM model. This dependency exposes liabilities that were leveraged using kinase inhibitors treatments in EGFRvIII-expressing GBM patient-derived xenografts (PDXs), where simultaneous pharmacological inhibition of EGFRvIII and PDGFRA kinase activities is necessary for anti-tumor efficacy. Our work establishes that EGFRvIII-positive tumors have unexplored vulnerabilities to targeted agents concomitant to the EGFR kinase inhibitor repertoire.
Collapse
|
15
|
Zhang Q, Liang H, Zhao X, Zheng L, Li Y, Gong J, Zhu Y, Jin Y, Yin Y. PTENε suppresses tumor metastasis through regulation of filopodia formation. EMBO J 2021; 40:e105806. [PMID: 33755220 PMCID: PMC8126949 DOI: 10.15252/embj.2020105806] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 01/03/2021] [Accepted: 02/01/2021] [Indexed: 01/16/2023] Open
Abstract
PTEN is one of the most frequently mutated genes in malignancies and acts as a powerful tumor suppressor. Tumorigenesis is involved in multiple and complex processes including initiation, invasion, and metastasis. The complexity of PTEN function is partially attributed to PTEN family members such as PTENα and PTENβ. Here, we report the identification of PTENε (also named as PTEN5), a novel N‐terminal‐extended PTEN isoform that suppresses tumor invasion and metastasis. We show that the translation of PTENε/PTEN5 is initiated from the CUG816 codon within the 5′UTR region of PTEN mRNA. PTENε/PTEN5 mainly localizes in the cell membrane and physically associates with and dephosphorylates VASP and ACTR2, which govern filopodia formation and cell motility. We found that endogenous depletion of PTENε/PTEN5 promotes filopodia formation and enhances the metastasis capacity of tumor cells. Overall, we identify a new isoform of PTEN with distinct subcellular localization and molecular function compared to the known members of the PTEN family. These findings advance our current understanding of the importance and diversity of PTEN functions.
Collapse
Affiliation(s)
- Qiaoling Zhang
- Department of Pathology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, China
| | - Hui Liang
- Department of Pathology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, China
| | - Xuyang Zhao
- Department of Pathology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, China
| | - Lin Zheng
- Department of Pathology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, China
| | - Yunqiao Li
- Department of Pathology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, China
| | - Jingjing Gong
- Department of Pathology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, China
| | - Yizhang Zhu
- Department of Pathology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, China
| | - Yan Jin
- Department of Pathology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, China
| | - Yuxin Yin
- Department of Pathology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, China.,Institute of Precision Medicine, Peking University Shenzhen Hospital, Shenzhen, China
| |
Collapse
|
16
|
Abstract
In over two decades since the discovery of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), nearly 18,000 publications have attempted to elucidate its functions and roles in normal physiology and disease. The frequent disruption of PTEN in cancer cells was a strong indication that it had critical roles in tumour suppression. Germline PTEN mutations have been identified in patients with heterogeneous tumour syndromic diseases, known as PTEN hamartoma tumour syndrome (PHTS), and in some individuals with autism spectrum disorders (ASD). Today we know that by limiting oncogenic signalling through the phosphoinositide 3-kinase (PI3K) pathway, PTEN governs a number of processes including survival, proliferation, energy metabolism, and cellular architecture. Some of the most exciting recent advances in the understanding of PTEN biology and signalling have revisited its unappreciated roles as a protein phosphatase, identified non-enzymatic scaffold functions, and unravelled its nuclear function. These discoveries are certain to provide a new perspective on its full tumour suppressor potential, and knowledge from this work will lead to new anti-cancer strategies that exploit PTEN biology. In this review, we will highlight some outstanding questions and some of the very latest advances in the understanding of the tumour suppressor PTEN.
Collapse
Affiliation(s)
- Jonathan Tak-Sum Chow
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
| | - Leonardo Salmena
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| |
Collapse
|
17
|
Fiuji H, Nassiri M. Gene expression profiling of chromosome 10 in PTEN-knockout (−/−) human neural and mesenchymal stem cells: A system biology study. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|
18
|
Lens fiber cell differentiation occurs independently of fibroblast growth factor receptor signaling in the absence of Pten. Dev Biol 2020; 467:1-13. [PMID: 32858001 DOI: 10.1016/j.ydbio.2020.07.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 07/30/2020] [Accepted: 07/31/2020] [Indexed: 11/21/2022]
Abstract
Fibroblast growth factor receptor (FGFR) signaling patterns multiple tissues in both vertebrates and invertebrates, largely through the activation of intracellular kinases. Recent studies have demonstrated that the phosphatase, PTEN negatively regulates FGFR signaling, such that the loss of PTEN can compensate for reduced FGFR signaling to rescue aspects of normal development. In the developing mouse lens, FGFR signaling promotes cell survival and fiber cell differentiation, and the loss of Pten largely compensates for the loss of Fgfr2 during lens development. To explore this regulatory relationship further, we focused on the phenotypic consequences of Pten loss on lens development and fiber cell differentiation in the absence of all FGFR signaling, both in vivo and in lens epithelial explants. Pten deletion partially rescues primary fiber cell elongation and γ-crystallin accumulation in FGFR-deficient lenses in vivo but fails to rescue cell survival or proliferation. However, in lens epithelial explants, where cells survive without FGFR signaling, Pten deletion rescues vitreous humor-induced lens fiber cell differentiation in the combined absence of Fgfr1, Fgfr2 and Fgfr3. This represents the first evidence that vitreous-initiated signaling cascades, independent of FGFR signaling, can drive mammalian lens fiber cell differentiation, when freed from repression by PTEN.
Collapse
|
19
|
Azzi A. SHIP2 inhibition alters redox-induced PI3K/AKT and MAP kinase pathways via PTEN over-activation in cervical cancer cells. FEBS Open Bio 2020; 10:2191-2205. [PMID: 32881386 PMCID: PMC7530381 DOI: 10.1002/2211-5463.12967] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 08/09/2020] [Accepted: 08/26/2020] [Indexed: 12/27/2022] Open
Abstract
Phosphatidylinositol (3,4,5)‐trisphosphate (PI(3,4,5)P3) is required for protein kinase B (AKT) activation. The level of PI(3,4,5)P3 is constantly regulated through balanced synthesis by phosphoinositide 3‐kinase (PI3K) and degradation by phosphoinositide phosphatases phosphatase and tensin homologue (PTEN) and SH2‐domain containing phosphatidylinositol‐3,4,5‐trisphosphate 5‐phosphatase 2 (SHIP2), known as negative regulators of AKT. Here, I show that SHIP2 inhibition in cervical cancer cell lines alters H2O2‐mediated AKT and mitogen‐activated protein kinase/extracellular signal‐regulated kinase pathway activation. In addition, SHIP2 inhibition enhances reactive oxygen species generation. Interestingly, I found that SHIP2 inhibition and H2O2 treatment enhance lipid and protein phosphatase activity of PTEN. Pharmacological targeting or RNA interference(RNAi) mediated knockdown of PTEN rescues extracellular signal‐regulated kinase and AKT activation. Using a series of pharmacological and biochemical approaches, I provide evidence that crosstalk between SHIP2 and PTEN occurs upon an increase in oxidative stress to modulate the activity of mitogen‐activated protein kinase and phosphoinositide 3/ATK pathways.
Collapse
Affiliation(s)
- Abdelhalim Azzi
- GIGA-Molecular Biology of Disease, GIGA-B34, University of Liège, Belgium
| |
Collapse
|
20
|
Amin R, Tripathi K, Sanderson RD. Nuclear Heparanase Regulates Chromatin Remodeling, Gene Expression and PTEN Tumor Suppressor Function. Cells 2020; 9:cells9092038. [PMID: 32899927 PMCID: PMC7564302 DOI: 10.3390/cells9092038] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 09/02/2020] [Accepted: 09/04/2020] [Indexed: 02/08/2023] Open
Abstract
Heparanase (HPSE) is an endoglycosidase that cleaves heparan sulfate and has been shown in various cancers to promote metastasis, angiogenesis, osteolysis, and chemoresistance. Although heparanase is thought to act predominantly extracellularly or within the cytoplasm, it is also present in the nucleus, where it may function in regulating gene transcription. Using myeloma cell lines, we report here that heparanase enhances chromatin accessibility and confirm a previous report that it also upregulates the acetylation of histones. Employing the Multiple Myeloma Research Foundation CoMMpass database, we demonstrate that patients expressing high levels of heparanase display elevated expression of proteins involved in chromatin remodeling and several oncogenic factors compared to patients expressing low levels of heparanase. These signatures were consistent with the known function of heparanase in driving tumor progression. Chromatin opening and downstream target genes were abrogated by inhibition of heparanase. Enhanced levels of heparanase in myeloma cells led to a dramatic increase in phosphorylation of PTEN, an event known to stabilize PTEN, leading to its inactivity and loss of tumor suppressor function. Collectively, this study demonstrates that heparanase promotes chromatin opening and transcriptional activity, some of which likely is through its impact on diminishing PTEN tumor suppressor activity.
Collapse
|
21
|
Kim K, Kim HH, Lee CH, Kim S, Cheon GJ, Kang KW, Chung JK, Youn H. Therapeutic efficacy of modified anti-miR21 in metastatic prostate cancer. Biochem Biophys Res Commun 2020; 529:707-713. [PMID: 32736696 DOI: 10.1016/j.bbrc.2020.05.215] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023]
Abstract
Despite improved therapeutic efficacy of the locked nucleic acid (LNA)- and peptide nucleic acid (PNA)-modified antisense microRNAs (anti-miRs), their wider application in clinical practice is still not thoroughly investigated. This study aimed to investigate the stability and therapeutic efficacy of the modified LNA- and PNA-type anti-miRs in a murine prostate cancer model under various treatment conditions. After verifying the anti-cancer potential of anti-miR21 by targeting tumor suppressor PTEN, the potential of the modified LNA- and PNA-type anti-miR21s was compared in vitro and in vivo. We found that PNA-type anti-miR21 showed better stability and therapeutic efficacy in the xenografted mouse tumor model than the LNA-type anti-miR21. Furthermore, PNA-type anti-miR21 treatment showed reduced tumor metastasis. This study may serve as a ground for exploring diverse choices in therapeutic oligonucleotide modification techniques to improve cancer treatment.
Collapse
Affiliation(s)
- Kyungmin Kim
- Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyun Hee Kim
- Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Chul-Hee Lee
- Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Seunghoo Kim
- Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Gi Jeong Cheon
- Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Keon Wook Kang
- Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - June-Key Chung
- Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Nuclear Medicine, National Cancer Center, Goyang, Republic of Korea
| | - Hyewon Youn
- Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Cancer Imaging Center, Seoul National University Hospital, Seoul, Republic of Korea.
| |
Collapse
|
22
|
Posttranslational Regulation and Conformational Plasticity of PTEN. Cold Spring Harb Perspect Med 2020; 10:cshperspect.a036095. [PMID: 31932468 DOI: 10.1101/cshperspect.a036095] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor that is frequently down-modulated in human cancer. PTEN inhibits the phosphatidylinositol 3-phosphate kinase (PI3K)/AKT pathway through its lipid phosphatase activity. Multiple PI3K/AKT-independent actions of PTEN, protein-phosphatase activities and functions within the nucleus have also been described. PTEN, therefore, regulates many cellular processes including cell proliferation, survival, genomic integrity, polarity, migration, and invasion. Even a modest decrease in the functional dose of PTEN may promote cancer development. Understanding the molecular and cellular mechanisms that regulate PTEN protein levels and function, and how these may go awry in cancer contexts, is, therefore, key to fully understanding the role of PTEN in tumorigenesis. Here, we discuss current knowledge on posttranslational control and conformational plasticity of PTEN, as well as therapeutic possibilities toward reestablishment of PTEN tumor-suppressor activity in cancer.
Collapse
|
23
|
Skelton PD, Stan RV, Luikart BW. The Role of PTEN in Neurodevelopment. MOLECULAR NEUROPSYCHIATRY 2020; 5:60-71. [PMID: 32399470 PMCID: PMC7206585 DOI: 10.1159/000504782] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 11/13/2019] [Indexed: 12/11/2022]
Abstract
PTEN is a lipid and protein phosphatase that regulates cell growth and survival. Mutations to PTEN are highly penetrant for autism spectrum disorder (ASD). Here, we briefly review the evidence linking PTEN mutations to ASD and the mouse models that have been used to study the role of PTEN in neurodevelopment. We then focus on the cellular phenotypes associated with PTEN loss in neurons, highlighting the role PTEN plays in neuronal proliferation, migration, survival, morphology, and plasticity.
Collapse
Affiliation(s)
- Patrick D. Skelton
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Radu V. Stan
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Bryan W. Luikart
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| |
Collapse
|
24
|
Choi JS. Cisplatin Suppresses Proliferation of Ovarian Cancer Cells through Inhibition Akt and Modulation MAPK Pathways. KOREAN JOURNAL OF CLINICAL LABORATORY SCIENCE 2020. [DOI: 10.15324/kjcls.2020.52.1.62] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Affiliation(s)
- Jae-Sun Choi
- Department of Biomedical Laboratory Science, Far East University, Eumseong, Korea
| |
Collapse
|
25
|
Lee J, Lee J, Sim W, Kim JH. Differential Dependency of Human Pancreatic Cancer Cells on Targeting PTEN via PLK 1 Expression. Cancers (Basel) 2020; 12:cancers12020277. [PMID: 31979216 PMCID: PMC7072440 DOI: 10.3390/cancers12020277] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 01/21/2020] [Indexed: 02/07/2023] Open
Abstract
Even though the tumour suppressive role of PTEN is well-known, its prognostic implications are ambiguous. The objective of this study was to further explore the function of PTEN expression in human pancreatic cancer. The expression of PTEN has been dominant in various human cancers including pancreatic cancer when compared with their matched normal tissues. The pancreatic cancer cells have been divided into PTEN blockade-susceptible and PTEN blockade-impassible groups dependent on targeting PTEN by altering intracellular signaling. The expression of PTEN has led to varying clinical outcomes of pancreatic cancer based on GEO Series (GSE) data analysis and Liptak’s z analysis. Differential dependency to PTEN blockade has been ascertained based on the expression of polo-like kinase1 PLK1 in pancreatic cancer cells. The prognostic value of PTEN also depends on PLK1 expression in pancreatic cancer. Collectively, the present study provides a rationale for targeting PTEN as a promising therapeutic strategy dependent on PLK1 expressions using a companion biomarker discovery platform.
Collapse
Affiliation(s)
- Jungwhoi Lee
- Department of Applied Life Science, SARI, Jeju National University, Jeju-do 63243, Korea
- Correspondence: (J.L.); (J.-H.K.); Tel.: +82-64-729-8556 (J.L.); Fax: +82-64-756-3351 (J.L.)
| | - Jungsul Lee
- Department of Bio and Brain Engineering, KAIST, Daejeon 34141, Korea; (J.L.); (W.S.)
| | - Woogwang Sim
- Department of Bio and Brain Engineering, KAIST, Daejeon 34141, Korea; (J.L.); (W.S.)
| | - Jae-Hoon Kim
- Department of Applied Life Science, SARI, Jeju National University, Jeju-do 63243, Korea
- Subtropical/tropical Organism Gene Bank, Jeju National University, Jeju-do 63243, Korea
- Correspondence: (J.L.); (J.-H.K.); Tel.: +82-64-729-8556 (J.L.); Fax: +82-64-756-3351 (J.L.)
| |
Collapse
|
26
|
Wang ZF, Li J, Ma C, Huang C, Li ZQ. Telmisartan ameliorates Aβ oligomer-induced inflammation via PPARγ/PTEN pathway in BV2 microglial cells. Biochem Pharmacol 2020; 171:113674. [PMID: 31634455 DOI: 10.1016/j.bcp.2019.113674] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 10/16/2019] [Indexed: 12/18/2022]
|
27
|
Padula SL, Anand D, Hoang TV, Chaffee BR, Liu L, Liang C, Lachke SA, Robinson ML. High-throughput transcriptome analysis reveals that the loss of Pten activates a novel NKX6-1/RASGRP1 regulatory module to rescue microphthalmia caused by Fgfr2-deficient lenses. Hum Genet 2019; 138:1391-1407. [PMID: 31691004 DOI: 10.1007/s00439-019-02084-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 10/28/2019] [Indexed: 01/17/2023]
Abstract
FGFR signaling is critical to development and disease pathogenesis, initiating phosphorylation-driven signaling cascades, notably the RAS-RAF-MEK-ERK and PI3 K-AKT cascades. PTEN antagonizes FGFR signaling by reducing AKT and ERK activation. Mouse lenses lacking FGFR2 exhibit microphakia and reduced ERK and AKT phosphorylation, widespread apoptosis, and defective lens fiber cell differentiation. In contrast, simultaneous deletion of both Fgfr2 and Pten restores ERK and AKT activation levels as well as lens size, cell survival and aspects of fiber cell differentiation; however, the molecular basis of this "rescue" remains undefined. We performed transcriptomic analysis by RNA sequencing of mouse lenses with conditional deletion of Fgfr2, Pten or both Fgfr2 and Pten, which reveal new molecular mechanisms that uncover how FGFR2 and PTEN signaling interact during development. The FGFR2-deficient lens transcriptome demonstrates overall loss of fiber cell identity with deregulated expression of 1448 genes. We find that ~ 60% of deregulated genes return to normal expression levels in lenses lacking both Fgfr2 and Pten. Further, application of customized filtering parameters to these RNA-seq data sets identified 68 high-priority candidate genes. Bioinformatics analyses showed that the cis-binding motif of a high-priority homeodomain transcription factor, NKX6-1, was present in the putative promoters of ~ 78% of these candidates. Finally, biochemical reporter assays demonstrate that NKX6-1 activated the expression of the high-priority candidate Rasgrp1, a RAS-activating protein. Together, these data define a novel regulatory module in which NKX6-1 directly activates Rasgrp1 expression to restore the balance of ERK and AKT activation, thus providing new insights into alternate regulation of FGFR downstream events.
Collapse
Affiliation(s)
| | - Deepti Anand
- Department of Biological Sciences, University of Delaware, Newark, DE, USA
| | - Thanh V Hoang
- Department of Biology, Miami University, Oxford, OH, 45056, USA.,Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Blake R Chaffee
- Department of Biology, Miami University, Oxford, OH, 45056, USA
| | - Lin Liu
- Department of Biology, Miami University, Oxford, OH, 45056, USA
| | - Chun Liang
- Department of Biology, Miami University, Oxford, OH, 45056, USA
| | - Salil A Lachke
- Department of Biological Sciences, University of Delaware, Newark, DE, USA.,Center for Bioinformatics and Computational Biology, University of Delaware, Newark, DE, USA
| | | |
Collapse
|
28
|
Smith IN, Thacker S, Seyfi M, Cheng F, Eng C. Conformational Dynamics and Allosteric Regulation Landscapes of Germline PTEN Mutations Associated with Autism Compared to Those Associated with Cancer. Am J Hum Genet 2019; 104:861-878. [PMID: 31006514 PMCID: PMC6506791 DOI: 10.1016/j.ajhg.2019.03.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Accepted: 03/08/2019] [Indexed: 01/07/2023] Open
Abstract
Individuals with germline PTEN tumor-suppressor variants have PTEN hamartoma tumor syndrome (PHTS). Clinically, PHTS has variable presentations; there are distinct subsets of PHTS-affected individuals, such as those diagnosed with autism spectrum disorder (ASD) or cancer. It remains unclear why mutations in one gene can lead to such seemingly disparate phenotypes. Therefore, we sought to determine whether it is possible to predict a given PHTS-affected individual's a priori risk of ASD, cancer, or the co-occurrence of both phenotypes. By integrating network proximity analysis performed on the human interactome, molecular simulations, and residue-interaction networks, we demonstrate the role of conformational dynamics in the structural communication and long-range allosteric regulation of germline PTEN variants associated with ASD or cancer. We show that the PTEN interactome shares significant overlap with the ASD and cancer interactomes, providing network-based evidence that PTEN is a crucial player in the biology of both disorders. Importantly, this finding suggests that a germline PTEN variant might perturb the ASD or cancer networks differently, thus favoring one disease outcome at any one time. Furthermore, protein-dynamic structural-network analysis reveals small-world structural communication mediated by highly conserved functional residues and potential allosteric regulation of PTEN. We identified a salient structural-communication pathway that extends across the inter-domain interface for cancer-only mutations. In contrast, the structural-communication pathway is predominantly restricted to the phosphatase domain for ASD-only mutations. Our integrative approach supports the prediction and potential modulation of the relevant conformational states that influence structural communication and long-range perturbations associated with mutational effects that lead to PTEN-ASD or PTEN-cancer phenotypes.
Collapse
Affiliation(s)
- Iris Nira Smith
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Stetson Thacker
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA
| | - Marilyn Seyfi
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Feixiong Cheng
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Charis Eng
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
| |
Collapse
|
29
|
Zhang X, Gao X, Hu J, Xie Y, Zuo Y, Xu H, Zhu S. ADAR1p150 Forms a Complex with Dicer to Promote miRNA-222 Activity and Regulate PTEN Expression in CVB3-Induced Viral Myocarditis. Int J Mol Sci 2019; 20:ijms20020407. [PMID: 30669342 PMCID: PMC6359435 DOI: 10.3390/ijms20020407] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Revised: 01/02/2019] [Accepted: 01/04/2019] [Indexed: 02/06/2023] Open
Abstract
Adenosine deaminases acting on RNA (ADAR) are enzymes that regulate RNA metabolism through post-transcriptional mechanisms. ADAR1 is involved in a variety of pathological conditions including inflammation, cancer, and the host defense against viral infections. However, the role of ADAR1p150 in vascular disease remains unclear. In this study, we examined the expression of ADAR1p150 and its role in viral myocarditis (VMC) in a mouse model. VMC mouse cardiomyocytes showed significantly higher expression of ADAR1p150 compared to the control samples. Coimmunoprecipitation verified that ADAR1p150 forms a complex with Dicer in VMC. miRNA-222, which is involved in many cardiac diseases, is highly expressed in cardiomyocytes in VMC. In addition, the expression of miRNA-222 was promoted by ADAR1p150/Dicer. Among the target genes of miRNA-222, the expression of phosphatase-and-tensin (PTEN) protein was significantly reduced in VMC. By using a bioinformatics tool, we found a potential binding site of miRNA-222 on the PTEN gene’s 3′-UTR, suggesting that miRNA-222 might play a regulatory role. In cultured cells, miR-222 suppressed PTEN expression. Our findings suggest that ADAR1p150 plays a key role in complexing with Dicer and promoting the expression of miRNA-222, the latter of which suppresses the expression of the target gene PTEN during VMC. Our work reveals a previously unknown role of ADAR1p150 in gene expression in VMC.
Collapse
Affiliation(s)
- Xincai Zhang
- Institute of Forensic Medicine, Soochow University, Suzhou 215021, China.
| | - Xiangting Gao
- Department of Pathology, School of Medicine, Shihezi University, Shihezi 215021, China.
| | - Jun Hu
- Institute of Forensic Medicine, Soochow University, Suzhou 215021, China.
| | - Yuxin Xie
- Institute of Forensic Medicine, Soochow University, Suzhou 215021, China.
| | - Yuanyi Zuo
- Institute of Forensic Medicine, Soochow University, Suzhou 215021, China.
| | - Hongfei Xu
- Institute of Forensic Medicine, Soochow University, Suzhou 215021, China.
| | - Shaohua Zhu
- Institute of Forensic Medicine, Soochow University, Suzhou 215021, China.
| |
Collapse
|
30
|
Elibol B, Beker M, Sahbaz CD, Kilic U, Jakubowska-Doğru E. Prenatal ethanol intoxication and maternal intubation stress alter cell survival and apoptosis in the postnatal development of rat hippocampus. Acta Neurobiol Exp (Wars) 2019. [DOI: 10.21307/ane-2019-012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
|
31
|
Novel Clofarabine-Based Combinations with Polyphenols Epigenetically Reactivate Retinoic Acid Receptor Beta, Inhibit Cell Growth, and Induce Apoptosis of Breast Cancer Cells. Int J Mol Sci 2018; 19:ijms19123970. [PMID: 30544666 PMCID: PMC6321577 DOI: 10.3390/ijms19123970] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 12/06/2018] [Accepted: 12/08/2018] [Indexed: 12/25/2022] Open
Abstract
An epigenetic component, especially aberrant DNA methylation pattern, has been shown to be frequently involved in sporadic breast cancer development. A growing body of literature demonstrates that combination of agents, i.e. nucleoside analogues with dietary phytochemicals, may provide enhanced therapeutic effects in epigenetic reprogramming of cancer cells. Clofarabine (2-chloro-2′-fluoro-2′-deoxyarabinosyladenine, ClF), a second-generation 2′-deoxyadenosine analogue, has numerous anti-cancer effects, including potential capacity to regulate epigenetic processes. Our present study is the first to investigate the combinatorial effects of ClF (used at IC50 concentration) with epigallocatechin-3-gallate (EGCG, tea catechin) or genistein (soy phytoestrogen), at physiological concentrations, on breast cancer cell growth, apoptosis, and epigenetic regulation of retinoic acid receptor beta (RARB) transcriptional activity. In MCF7 and MDA-MB-231 cells, RARB promoter methylation and expression of RARB, modifiers of DNA methylation reaction (DNMT1, CDKN1A, TP53), and potential regulator of RARB transcription, PTEN, were estimated using methylation-sensitive restriction analysis (MSRA) and quantitative real-time polymerase chain reaction (qPCR), respectively. The combinatorial exposures synergistically or additively inhibited the growth and induced apoptosis of breast cancer cells, followed by RARB hypomethylation with concomitant multiple increase in RARB, PTEN, and CDKN1A transcript levels. Taken together, our results demonstrate the ability of ClF-based combinations with polyphenols to promote cancer cell death and reactivate DNA methylation-silenced tumor suppressor genes in breast cancer cells with different invasive potential.
Collapse
|
32
|
Que WC, Qiu HQ, Cheng Y, Liu MB, Wu CY. PTEN in kidney cancer: A review and meta-analysis. Clin Chim Acta 2018; 480:92-98. [DOI: 10.1016/j.cca.2018.01.031] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 01/17/2018] [Accepted: 01/19/2018] [Indexed: 01/11/2023]
|
33
|
Arora N, Gavya S L, Ghosh SS. Multi-facet implications of PEGylated lysozyme stabilized-silver nanoclusters loaded recombinant PTEN cargo in cancer theranostics. Biotechnol Bioeng 2018; 115:1116-1127. [PMID: 29384195 DOI: 10.1002/bit.26553] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 01/14/2018] [Accepted: 01/22/2018] [Indexed: 12/17/2022]
Abstract
Amalgamation of delivery and tracking of therapeutically relevant moieties on a single platform is made possible by the application of metal nanoclusters, an innovative class of luminescent nanomaterials. Metal nanoclusters, possessing molecule-like attributes, display extraordinary size and shape tunable properties befitting theranostic applications. Herein, we report successful assembly of therapeutically significant phosphatase protein PTEN and fluorescent lysozyme-stabilized silver nanoclusters to accomplish delivery and tracking of the protein. Down-regulation of PTEN perturbs the cellular networking leading to copious pathological conditions. The integration of purified recombinant PTEN with silver nanoclusters was evaluated by fluorescence spectroscopy study. A key feature of this study is the use of polyethylene glycol coating that allows fabrication of the assembly into spherical nanocomposites as characterized by transmission electron microscope along with retention of both optical functionality of the cluster and biological activity of the protein. Prior to cellular application, the functional integrity of PTEN in the composite was determined in vitro, by enzymatic assay employing para-nitrophenylphosphate as substrate. Cellular internalization of the cargo was studied by confocal microscopy and flow cytometry analysis. The efficacy of the payload on modulation of cellular signaling was assessed on cell lines that expressed PTEN differentially. PTEN null U-87 MG and PTEN expressing MCF7 cell lines displayed successful alteration of AKT and FAK signaling proteins culminating in cell cycle arrest and reduced wound healing capacity. A dose dependent reduction in cell proliferation of MCF7 cells was achieved. For U-87 MG, treatment with the payload resulted in chemosensitization toward anti-cancer drug erlotinib. Thus, PEG coated GST-PTEN loaded silver nanoclusters serves as a comprehensive system encompassing cellular imaging and protein delivery with potential biomedical implications.
Collapse
Affiliation(s)
- Neha Arora
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Lalitha Gavya S
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Siddhartha S Ghosh
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India.,Center for Nanotechnology, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| |
Collapse
|
34
|
Targeting PTEN in Colorectal Cancers. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1110:55-73. [DOI: 10.1007/978-3-030-02771-1_5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
|
35
|
Bailón E, Aguilera-Montilla N, Gutiérrez-González A, Ugarte-Berzal E, Van den Steen PE, Opdenakker G, García-Marco JA, García-Pardo A. A catalytically inactive gelatinase B/MMP-9 mutant impairs homing of chronic lymphocytic leukemia cells by altering migration regulatory pathways. Biochem Biophys Res Commun 2018; 495:124-130. [DOI: 10.1016/j.bbrc.2017.10.129] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 10/25/2017] [Indexed: 11/30/2022]
|
36
|
Byrne RM, Tsikitis VL. Colorectal polyposis and inherited colorectal cancer syndromes. Ann Gastroenterol 2017; 31:24-34. [PMID: 29333064 PMCID: PMC5759610 DOI: 10.20524/aog.2017.0218] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 10/30/2017] [Indexed: 12/30/2022] Open
Abstract
The majority of colorectal cancer (CRC) cases are sporadic, with hereditary factors contributing to approximately 35% of CRC cases. Less than 5% of CRC is associated with a known genetic syndrome. Although adenomatous polyposis syndromes, hamartomatous polyposis syndromes, and those previously classified as non-polyposis CRC syndromes are quite rare, it is important for clinicians to know the characteristics of each syndrome and to understand the differences in cancer risks between the different conditions. This information is very important when treatment and surveillance plans are formulated for each individual patient.
Collapse
Affiliation(s)
- Raphael M Byrne
- Department of Surgery, Division of GI and General Surgery, Oregon Health & Science University, Portland, OR, USA
| | - Vassiliki Liana Tsikitis
- Department of Surgery, Division of GI and General Surgery, Oregon Health & Science University, Portland, OR, USA
| |
Collapse
|
37
|
Comprehensive genomic analysis of Oesophageal Squamous Cell Carcinoma reveals clinical relevance. Sci Rep 2017; 7:15324. [PMID: 29127303 PMCID: PMC5681595 DOI: 10.1038/s41598-017-14909-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 10/18/2017] [Indexed: 12/27/2022] Open
Abstract
Oesophageal carcinoma is the fourth leading cause of cancer-related death in China, and more than 90% of these tumours are oesophageal squamous cell carcinoma (ESCC). Although several ESCC genomic sequencing studies have identified mutated somatic genes, the number of samples in each study was relatively small, and the molecular basis of ESCC has not been fully elucidated. Here, we performed an integrated analysis of 490 tumours by combining the genomic data from 7 previous ESCC projects. We identified 18 significantly mutated genes (SMGs). PTEN, DCDC1 and CUL3 were first reported as SMGs in ESCC. Notably, the AJUBA mutations and mutational signature4 were significantly correlated with a poorer survival in patients with ESCC. Hierarchical clustering analysis of the copy number alteration (CNA) of cancer gene census (CGC) genes in ESCC patients revealed three subtypes, and subtype3 exhibited more CNAs and marked for worse prognosis compared with subtype2. Moreover, database annotation suggested that two significantly differential CNA genes (PIK3CA and FBXW7) between subtype3 and subtype2 may serve as therapeutic drug targets. This study has extended our knowledge of the genetic basis of ESCC and shed some light into the clinical relevance, which would help improve the therapy and prognosis of ESCC patients.
Collapse
|
38
|
Godena VK, Ning K. Phosphatase and tensin homologue: a therapeutic target for SMA. Signal Transduct Target Ther 2017; 2:17038. [PMID: 29263925 PMCID: PMC5661640 DOI: 10.1038/sigtrans.2017.38] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Revised: 05/09/2017] [Accepted: 06/01/2017] [Indexed: 01/15/2023] Open
Abstract
Spinal muscular atrophy (SMA) is one of the most common juvenile neurodegenerative diseases, which can be associated with child mortality. SMA is caused by a mutation of ubiquitously expressed gene, Survival Motor Neuron1 (SMN1), leading to reduced SMN protein and the motor neuron death. The disease is incurable and the only therapeutic strategy to follow is to improve the expression of SMN protein levels in motor neurons. Significant numbers of motor neurons in SMA mice and SMA cultures are caspase positive with condensed nuclei, suggesting that these cells are prone to a process of cell death called apoptosis. Searching for other potential molecules or signaling pathways that are neuroprotective for central nervous system (CNS) insults is essential for widening the scope of developmental medicine. PTEN, a Phosphatase and Tensin homologue, is a tumor suppressor, which is widely expressed in CNS. PTEN depletion activates anti-apoptotic factors and it is evident that the pathway plays an important protective role in many neurodegenerative disorders. It functions as a negative regulator of PIP3/AKT pathway and thereby modulates its downstream cellular functions through lipid phosphatase activity. Moreover, previous reports from our group demonstrated that, PTEN depletion using viral vector delivery system in SMN delta7 mice reduces disease pathology, with significant rescue on survival rate and the body weight of the SMA mice. Thus knockdown/depletion/mutation of PTEN and manipulation of PTEN medicated Akt/PKB signaling pathway may represent an important therapeutic strategy to promote motor neuron survival in SMA.
Collapse
Affiliation(s)
- Vinay K Godena
- Department of Neuroscience, Sheffield Institute of Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK
| | - Ke Ning
- Department of Neuroscience, Sheffield Institute of Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK
| |
Collapse
|
39
|
Targeting cancer cell integrins using gold nanorods in photothermal therapy inhibits migration through affecting cytoskeletal proteins. Proc Natl Acad Sci U S A 2017; 114:E5655-E5663. [PMID: 28652358 DOI: 10.1073/pnas.1703151114] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Metastasis is responsible for most cancer-related deaths, but the current clinical treatments are not effective. Recently, gold nanoparticles (AuNPs) were discovered to inhibit cancer cell migration and prevent metastasis. Rationally designed AuNPs could greatly benefit their antimigration property, but the molecular mechanisms need to be explored. Cytoskeletons are cell structural proteins that closely relate to migration, and surface receptor integrins play critical roles in controlling the organization of cytoskeletons. Herein, we developed a strategy to inhibit cancer cell migration by targeting integrins, using Arg-Gly-Asp (RGD) peptide-functionalized gold nanorods. To enhance the effect, AuNRs were further activated with 808-nm near-infrared (NIR) light to generate heat for photothermal therapy (PPTT), where the temperature was adjusted not to affect the cell viability/proliferation. Our results demonstrate changes in cell morphology, observed as cytoskeleton protrusions-i.e., lamellipodia and filopodia-were reduced after treatment. The Western blot analysis indicates the downstream effectors of integrin were attracted toward the antimigration direction. Proteomics results indicated broad perturbations in four signaling pathways, Rho GTPases, actin, microtubule, and kinases-related pathways, which are the downstream regulators of integrins. Due to the dominant role of integrins in controlling cytoskeleton, focal adhesion, actomyosin contraction, and actin and microtubule assembly have been disrupted by targeting integrins. PPTT further enhanced the remodeling of cytoskeletal proteins and decreased migration. In summary, the ability of targeting AuNRs to cancer cell integrins and the introduction of PPTT stimulated broad regulation on the cytoskeleton, which provides the evidence for a potential medical application for controlling cancer metastasis.
Collapse
|
40
|
Augello G, Puleio R, Emma MR, Cusimano A, Loria GR, McCubrey JA, Montalto G, Cervello M. A PTEN inhibitor displays preclinical activity against hepatocarcinoma cells. Cell Cycle 2016; 15:573-83. [PMID: 26794644 DOI: 10.1080/15384101.2016.1138183] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Phosphatase and tensin homolog (PTEN) gene is considered a tumor suppressor gene. However, PTEN mutations rarely occur in hepatocellular carcinoma (HCC), whereas heterozygosity of PTEN, resulting in reduced PTEN expression, has been observed in 32-44% of HCC patients. In the present study, we investigated the effects of the small molecule PTEN inhibitor VO-OHpic in HCC cells. VO-OHpic inhibited cell viability, cell proliferation and colony formation, and induced senescence-associated β-galactosidase activity in Hep3B (low PTEN expression) and to a lesser extent in PLC/PRF/5 (high PTEN expression) cells, but not in PTEN-negative SNU475 cells. VO-OHpic synergistically inhibited cell viability when combined with PI3K/mTOR and RAF/MEK/ERK pathway inhibitors, but only in Hep3B cells, and significantly inhibited tumor growth in nude mice bearing xenografts of Hep3B cells. Therefore, we demonstrated for the first time that VO-OHpic inhibited cell growth and induced senescence in HCC cells with low PTEN expression, and that the combination of VO-OHpic with PI3K/mTOR and RAF/MEK/ERK inhibitors resulted in a more effective tumor cell kill. Our findings, hence, provide proof-of-principle evidence that pharmacological inhibition of PTEN may represent a promising approach for HCC therapy in a subclass of patients with a low PTEN expression.
Collapse
Affiliation(s)
- Giuseppa Augello
- a Institute of Biomedicine and Molecular Immunology "Alberto Monroy,", National Research Council (CNR) , Palermo , Italy
| | - Roberto Puleio
- b Istituto Zooprofilattico Sperimentale della Sicilia "A Mirri,", Area Diagnostica Specialistica, Laboratorio di Istopatologia ed Immunoistochimica , Palermo , Italy
| | - Maria Rita Emma
- a Institute of Biomedicine and Molecular Immunology "Alberto Monroy,", National Research Council (CNR) , Palermo , Italy
| | - Antonella Cusimano
- a Institute of Biomedicine and Molecular Immunology "Alberto Monroy,", National Research Council (CNR) , Palermo , Italy
| | - Guido R Loria
- b Istituto Zooprofilattico Sperimentale della Sicilia "A Mirri,", Area Diagnostica Specialistica, Laboratorio di Istopatologia ed Immunoistochimica , Palermo , Italy
| | - James A McCubrey
- c Department of Microbiology and Immunology , Brody School of Medicine at East Carolina University , Greenville , NC , USA
| | - Giuseppe Montalto
- a Institute of Biomedicine and Molecular Immunology "Alberto Monroy,", National Research Council (CNR) , Palermo , Italy.,d Biomedical Department of Internal Medicine and Specialties (DiBiMIS), University of Palermo , Palermo , Italy
| | - Melchiorre Cervello
- a Institute of Biomedicine and Molecular Immunology "Alberto Monroy,", National Research Council (CNR) , Palermo , Italy
| |
Collapse
|
41
|
MiR-200a acts as an oncogene in colorectal carcinoma by targeting PTEN. Exp Mol Pathol 2016; 101:308-313. [DOI: 10.1016/j.yexmp.2016.10.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 09/22/2016] [Accepted: 10/24/2016] [Indexed: 12/13/2022]
|
42
|
Pioglitazone induces cell growth arrest and activates mitochondrial apoptosis in human uterine leiomyosarcoma cells by a peroxisome proliferator-activated receptor γ-independent mechanism. Naunyn Schmiedebergs Arch Pharmacol 2016; 390:37-48. [PMID: 27664035 DOI: 10.1007/s00210-016-1291-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2016] [Accepted: 08/19/2016] [Indexed: 12/13/2022]
Abstract
The peroxisome proliferator-activated receptor γ (PPARγ) agonists, thiazolidinediones, including pioglitazone (PIO) exhibit anti-tumour activities in cancer cells. The present study investigates the effects of PIO on cell proliferation and apoptosis in SK-UT-1 cells, a human uterine leiomyosarcoma cell line, and human uterine smooth muscle cells (HUtSMC). The proliferation and viability of SK-UT-1 cells treated with vehicle or PIO were assessed by cell counting and WST-1 assay. The activity of MEK/ERK and p38 MAPK signalling pathways and the expression of p53, the cyclin-dependent kinase inhibitor, p21, Bax, Bad and Bim proteins and cleaved caspase-3 were analysed by Western blotting. Quiescent SK-UT-1 cells intensively proliferate and display high levels of phosphorylated, activated MEK1/2, ERK1/2 and p38 MAPK. PIO (10 or 25 μM) induced time- and dose-dependently cell-growth arrest, reduced the cell numbers and effectively suppressed the over-activated MEK/ERK and p38 MAPK signalling pathways as evidenced by the abolished levels of phosphorylated MEK1/2, ERK1/2 and p38 MAPK. PIO activated the intrinsic apoptotic pathway, i.e. up-regulated the p53, p21, Bax and Bad proteins and cleaved caspase-3. PIO also reduced cell numbers of highly proliferative SK-UT-1 cells cultured in growth medium. The anti-proliferative and pro-apoptotic actions of PIO were not PPARγ dependent and exclusive for SK-UT-1 cells as PIO did not interfere with the proliferation of HUtSMC. The pronounced anti-tumorigenic effects of PIO in SK-UT-1 cells address an important issue about the relevance of the PPARγ agonist in the treatment of the human uterine leiomyosarcoma.
Collapse
|
43
|
Yang Z, Xie C, Xu W, Liu G, Cao X, Li W, Chen J, Zhu Y, Luo S, Luo Z, Lu N. Phosphorylation and inactivation of PTEN at residues Ser380/Thr382/383 induced by Helicobacter pylori promotes gastric epithelial cell survival through PI3K/Akt pathway. Oncotarget 2016; 6:31916-26. [PMID: 26376616 PMCID: PMC4741650 DOI: 10.18632/oncotarget.5577] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 08/19/2015] [Indexed: 02/07/2023] Open
Abstract
Phosphorylation of PTEN at residues Ser380/Thr382/383 leads to loss of phosphatase activity and tumor suppressor function. Here, we found that phosphorylation of PTEN at residues Ser380/Thr382/383 was increased with gastric carcinogenesis, and more importantly, Helicobacter pylori was a trigger of this modification in chronic non-atrophic gastritis. H. pylori could phosphorylate and inactivate PTEN in vivo and in vitro, resulting in survival of gastric epithelial cells. Furthermore, stable expression of dominant-negative mutant PTEN or inhibition of Akt prevented the enhanced survival induced by H. pylori. These results indicate that PTEN phosphorylation at residues Ser380/Thr382/383 is a novel mechanism of PTEN inactivation in gastric carcinogenesis, and H. pylori triggers this modification, resulting in activation of the PI3K/Akt pathway and promotion of cell survival.
Collapse
Affiliation(s)
- Zhen Yang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Chuan Xie
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Wenting Xu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Gongmeizi Liu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Ximei Cao
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Wei Li
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jiang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Yin Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Shiwen Luo
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.,Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zhijun Luo
- The Medical College of Nanchang University, Nanchang, Jiangxi, China.,Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA
| | - Nonghua Lu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| |
Collapse
|
44
|
Lubecka-Pietruszewska K, Kaufman-Szymczyk A, Stefanska B, Cebula-Obrzut B, Smolewski P, Fabianowska-Majewska K. Sulforaphane Alone and in Combination with Clofarabine Epigenetically Regulates the Expression of DNA Methylation-Silenced Tumour Suppressor Genes in Human Breast Cancer Cells. JOURNAL OF NUTRIGENETICS AND NUTRIGENOMICS 2016; 8:91-101. [PMID: 26372775 DOI: 10.1159/000439111] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 07/29/2015] [Indexed: 11/19/2022]
Abstract
BACKGROUND/AIM Sporadic breast cancer is frequently associated with aberrant DNA methylation patterns that are reversible and responsive to environmental factors, including diet. In the present study, we investigated the effects of sulforaphane (SFN), a phytochemical from cruciferous vegetables, on the methylation and expression of PTEN and RARbeta2 tumour suppressor genes as well as on the expression of regulators of DNA methylation reaction, DNMT1 , p53 , and p21 , in MCF-7 and MDA-MB-231 human breast cancer cells with different invasive potential. We also evaluate the role of SFN epigenetic effects in support of therapy with clofarabine (ClF) that was recently shown to modulate the epigenome as well. METHODS Promoter methylation and gene expression were estimated using methylation-sensitive restriction analysis and real-time PCR, respectively. RESULTS In both MCF-7 and MDA-MB-231 cells, SFN at IC 50 (22 and 46 μ M , respectively) and a physiologically relevant 10 μ M concentration lead to hypomethylation of PTEN and RARbeta2 promoters with concomitant gene upregulation. The combination of SFN and ClF enhances these effects, resulting in an increase in cell growth arrest and apoptosis at a non-invasive breast cancer stage. CONCLUSIONS Our findings provide evidence that SFN activates DNA methylation-silenced tumour suppressor genes in breast cancer cells and may contribute to SFN-mediated support of therapy with an anti-cancer drug, ClF, increasing its applications in solid tumours.
Collapse
|
45
|
Li J, Zhang J, Tang M, Xin J, Xu Y, Volk A, Hao C, Hu C, Sun J, Wei W, Cao Q, Breslin P, Zhang J. Hematopoietic Stem Cell Activity Is Regulated by Pten Phosphorylation Through a Niche-Dependent Mechanism. Stem Cells 2016; 34:2130-44. [PMID: 27096933 DOI: 10.1002/stem.2382] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Revised: 03/19/2016] [Accepted: 03/26/2016] [Indexed: 12/21/2022]
Abstract
The phosphorylated form of Pten (p-Pten) is highly expressed in >70% of acute myeloid leukemia samples. However, the role of p-Pten in normal and abnormal hematopoiesis has not been studied. We found that Pten protein levels are comparable among long-term (LT) hematopoietic stem cells (HSCs), short-term (ST) HSCs, and multipotent progenitors (MPPs); however, the levels of p-Pten are elevated during the HSC-to-MPP transition. To study whether p-Pten is involved in regulating self-renewal and differentiation in HSCs, we compared the effects of overexpression of p-Pten and nonphosphorylated Pten (non-p-Pten) on the hematopoietic reconstitutive capacity (HRC) of HSCs. We found that overexpression of non-p-Pten enhances the LT-HRC of HSCs, whereas overexpression of p-Pten promotes myeloid differentiation and compromises the LT-HRC of HSCs. Such phosphorylation-regulated Pten functioning is mediated by repressing the cell:cell contact-induced activation of Fak/p38 signaling independent of Pten's lipid phosphatase activity because both p-Pten and non-p-Pten have comparable activity in repressing PI3K/Akt signaling. Our studies suggest that, in addition to repressing PI3K/Akt/mTor signaling, non-p-Pten maintains HSCs in bone marrow niches via a cell-contact inhibitory mechanism by inhibiting Fak/p38 signaling-mediated proliferation and differentiation. In contrast, p-Pten promotes the proliferation and differentiation of HSCs by enhancing the cell contact-dependent activation of Src/Fak/p38 signaling. Stem Cells 2016;34:2130-2144.
Collapse
Affiliation(s)
- Jing Li
- Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China.,Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA
| | - Jun Zhang
- Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China.,Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA
| | - Minghui Tang
- Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA
| | - Junping Xin
- Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA
| | - Yan Xu
- Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China
| | - Andrew Volk
- Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA
| | - Caiqin Hao
- Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China
| | - Chenglong Hu
- Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China
| | - Jiewen Sun
- Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China
| | - Wei Wei
- Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA
| | - Quichan Cao
- Department of Public Health Sciences, Loyola University Chicago, Chicago, Illinois, USA
| | - Peter Breslin
- Department of Biology, Loyola University Chicago, Chicago, Illinois, USA.,Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA.,Department of Molecular and Cellular Physiology, Loyola University Chicago, Chicago, Illinois, USA
| | - Jiwang Zhang
- Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA.,Department of Pathology, Loyola University Medical Center, Maywood, Illinois, USA
| |
Collapse
|
46
|
Identification of key regulators of pancreatic cancer progression through multidimensional systems-level analysis. Genome Med 2016; 8:38. [PMID: 27137215 PMCID: PMC4853852 DOI: 10.1186/s13073-016-0282-3] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 02/19/2016] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Pancreatic cancer is an aggressive cancer with dismal prognosis, urgently necessitating better biomarkers to improve therapeutic options and early diagnosis. Traditional approaches of biomarker detection that consider only one aspect of the biological continuum like gene expression alone are limited in their scope and lack robustness in identifying the key regulators of the disease. We have adopted a multidimensional approach involving the cross-talk between the omics spaces to identify key regulators of disease progression. METHODS Multidimensional domain-specific disease signatures were obtained using rank-based meta-analysis of individual omics profiles (mRNA, miRNA, DNA methylation) related to pancreatic ductal adenocarcinoma (PDAC). These domain-specific PDAC signatures were integrated to identify genes that were affected across multiple dimensions of omics space in PDAC (genes under multiple regulatory controls, GMCs). To further pin down the regulators of PDAC pathophysiology, a systems-level network was generated from knowledge-based interaction information applied to the above identified GMCs. Key regulators were identified from the GMC network based on network statistics and their functional importance was validated using gene set enrichment analysis and survival analysis. RESULTS Rank-based meta-analysis identified 5391 genes, 109 miRNAs and 2081 methylation-sites significantly differentially expressed in PDAC (false discovery rate ≤ 0.05). Bimodal integration of meta-analysis signatures revealed 1150 and 715 genes regulated by miRNAs and methylation, respectively. Further analysis identified 189 altered genes that are commonly regulated by miRNA and methylation, hence considered GMCs. Systems-level analysis of the scale-free GMCs network identified eight potential key regulator hubs, namely E2F3, HMGA2, RASA1, IRS1, NUAK1, ACTN1, SKI and DLL1, associated with important pathways driving cancer progression. Survival analysis on individual key regulators revealed that higher expression of IRS1 and DLL1 and lower expression of HMGA2, ACTN1 and SKI were associated with better survival probabilities. CONCLUSIONS It is evident from the results that our hierarchical systems-level multidimensional analysis approach has been successful in isolating the converging regulatory modules and associated key regulatory molecules that are potential biomarkers for pancreatic cancer progression.
Collapse
|
47
|
Fan W, Huang J, Xiao H, Liang Z. MicroRNA-22 is downregulated in clear cell renal cell carcinoma, and inhibits cell growth, migration and invasion by targeting PTEN. Mol Med Rep 2016; 13:4800-6. [PMID: 27082730 DOI: 10.3892/mmr.2016.5101] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Accepted: 03/03/2016] [Indexed: 11/06/2022] Open
Abstract
MicroRNA (miR)-22 has previously been reported to be frequently downregulated in certain types of cancer. The present study examined the expression and effects of miR-22 in renal cell carcinoma (RCC). The results indicated that miR‑22 was downregulated in tumor tissue from patients with RCC. In addition, lower miR‑22 expression levels were associated with histological grade, tumor stage and lymph node metas-tasis. Following transfection of RCC cells with miR‑22, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, cell migration, cell invasion and luciferase assays, and western blotting were conducted. The results demonstrated that miR‑22 was able to inhibit cell proliferation, migration and invasion in 786‑O and A498 cells. Furthermore, the results indicated that miR‑22 may directly target phosphatase and tensin homolog (PTEN) in RCC. In conclusion, the present study suggested that the miR-22/PTEN axis may be considered a novel therapeutic target in RCC. These findings may be beneficial for the development of an effective therapy against RCC.
Collapse
Affiliation(s)
- Wenxing Fan
- Department of Nephrology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Jie Huang
- Department of Nephrology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Hua Xiao
- Department of Nephrology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Zhang Liang
- Department of Science and Technology, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| |
Collapse
|
48
|
Abstract
Loss of the tumor suppressor gene PTEN is implicated in breast cancer progression and resistance to targeted therapies, and is thought to promote tumorigenesis by activating PI3K signaling. In a transgenic model of breast cancer, Pten suppression using a tetracycline-regulatable short hairpin (sh)RNA cooperates with human epidermal growth factor receptor 2 (HER2/neu), leading to aggressive and metastatic disease with elevated signaling through PI3K and, surprisingly, the mitogen-activated protein kinase (MAPK) pathway. Restoring Pten function is sufficient to down-regulate both PI3K and MAPK signaling and triggers dramatic tumor regression. Pharmacologic inhibition of MAPK signaling produces similar effects to Pten restoration, suggesting that the MAPK pathway contributes to the maintenance of advanced breast cancers harboring Pten loss.
Collapse
|
49
|
Abstract
Starting from the discovery of "inhibitory chromosomes" by Theodor Boveri to the finding by Henry Harris that fusing a normal cell to a cancer cell reduced tumorigenic potential, the notion of tumor suppression was recognized well before any tumor-suppressor genes were discovered. Although not the first to be revealed, PTEN has been demonstrated to be one of the most frequently altered tumor suppressors in cancer. This introductory chapter provides a historical perspective on our current understanding of PTEN including some of the seminal discoveries in the tumor suppressor field, the events leading to PTEN's discovery, and an introduction to some of the most important researchers and their studies which have shed light on PTEN biology and function as we know it today.
Collapse
Affiliation(s)
- Leonardo Salmena
- Department of Pharmacology and Toxicology, University of Toronto, Princess Margaret Cancer Centre, Room 4211, Medical Sciences Building, 1 King's College Circle, Toronto, ON, Canada, M5S 1A8.
| |
Collapse
|
50
|
Kaufman-Szymczyk A, Majewski G, Lubecka-Pietruszewska K, Fabianowska-Majewska K. The Role of Sulforaphane in Epigenetic Mechanisms, Including Interdependence between Histone Modification and DNA Methylation. Int J Mol Sci 2015; 16:29732-43. [PMID: 26703571 PMCID: PMC4691138 DOI: 10.3390/ijms161226195] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Revised: 12/03/2015] [Accepted: 12/04/2015] [Indexed: 12/21/2022] Open
Abstract
Carcinogenesis as well as cancer progression result from genetic and epigenetic changes of the genome that leads to dysregulation of transcriptional activity of genes. Epigenetic mechanisms in cancer cells comprise (i) post-translation histone modification (i.e., deacetylation and methylation); (ii) DNA global hypomethylation; (iii) promoter hypermethylation of tumour suppressor genes and genes important for cell cycle regulation, cell differentiation and apoptosis; and (iv) posttranscriptional regulation of gene expression by noncoding microRNA. These epigenetic aberrations can be readily reversible and responsive to both synthetic agents and natural components of diet. A source of one of such diet components are cruciferous vegetables, which contain high levels of a number of glucosinolates and deliver, after enzymatic hydrolysis, sulforaphane and other bioactive isothiocyanates, that are involved in effective up-regulation of transcriptional activity of certain genes and also in restoration of active chromatin structure. Thus a consumption of cruciferous vegetables, treated as a source of isothiocyanates, seems to be potentially useful as an effective cancer preventive factor or as a source of nutrients improving efficacy of standard chemotherapies. In this review an attempt is made to elucidate the role of sulforaphane in regulation of gene promoter activity through a direct down-regulation of histone deacetylase activity and alteration of gene promoter methylation in indirect ways, but the sulforaphane influence on non-coding micro-RNA will not be a subject of this review.
Collapse
Affiliation(s)
- Agnieszka Kaufman-Szymczyk
- Department of Biomedical Chemistry, Faculty of Health Sciences, Medical University of Lodz, 6/8 Mazowiecka St., 92-215 Lodz, Poland.
| | - Grzegorz Majewski
- Faculty of Public Health, University of Social Sciences in Lodz, 9 Sienkiewicza St., 90-113 Lodz, Poland.
| | - Katarzyna Lubecka-Pietruszewska
- Department of Biomedical Chemistry, Faculty of Health Sciences, Medical University of Lodz, 6/8 Mazowiecka St., 92-215 Lodz, Poland.
| | - Krystyna Fabianowska-Majewska
- Department of Biomedical Chemistry, Faculty of Health Sciences, Medical University of Lodz, 6/8 Mazowiecka St., 92-215 Lodz, Poland.
| |
Collapse
|