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  1. Article ; Online: Modulation of immunosurveillance by tumor-intrinsic genomic alterations.

    Furman, Craig / Zhu, Ping / Korpal, Manav

    Immunotherapy

    2017  Volume 9, Issue 16, Page(s) 1305–1307

    MeSH term(s) Animals ; Antigens, Neoplasm/genetics ; Antigens, Neoplasm/metabolism ; Genome ; Humans ; Immunity ; Immunotherapy/methods ; Monitoring, Immunologic ; Mutation ; Neoplasms/immunology ; Neoplasms/therapy ; Tumor Escape
    Chemical Substances Antigens, Neoplasm
    Language English
    Publishing date 2017-11-29
    Publishing country England
    Document type Editorial
    ISSN 1750-7448
    ISSN (online) 1750-7448
    DOI 10.2217/imt-2017-0132
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  2. Article ; Online: Generating a Murine PTEN Null Cell Line to Discover the Key Role of p110β-PAK1 in Castration-Resistant Prostate Cancer Invasion.

    Wang, Haizhen / Zhou, Yu / Chu, Chen / Xiao, Jialing / Zheng, Shanshan / Korpal, Manav / Korn, Joshua M / Penaloza, Tiffany / Drake, Richard R / Gan, Wenjian / Gao, Xueliang

    Molecular cancer research : MCR

    2023  Volume 21, Issue 12, Page(s) 1317–1328

    Abstract: Although androgen deprivation treatment often effectively decreases prostate cancer, incurable metastatic castration-resistant prostate cancer (CRPC) eventually occurs. It is important to understand how CRPC metastasis progresses, which is not clearly ... ...

    Abstract Although androgen deprivation treatment often effectively decreases prostate cancer, incurable metastatic castration-resistant prostate cancer (CRPC) eventually occurs. It is important to understand how CRPC metastasis progresses, which is not clearly defined. The loss of PTEN, a phosphatase to dephosphorylate phosphatidylinositol 3,4,5-trisphosphate in the PI3K pathway, occurs in up to 70% to 80% of CRPC. We generated a mouse androgen-independent prostate cancer cell line (PKO) from PTEN null and Hi-Myc transgenic mice in C57BL/6 background. We confirmed that this PKO cell line has an activated PI3K pathway and can metastasize into the femur and tibia of immunodeficient nude and immunocompetent C57BL/6 mice. In vitro, we found that androgen deprivation significantly enhanced PKO cell migration/invasion via the p110β isoform-depended PAK1-MAPK activation. Inhibition of the p110β-PAK1 axis significantly decreased prostate cancer cell migration/invasion. Of note, our analysis using clinical samples showed that PAK1 is more activated in CRPC than in advanced prostate cancer; high PAK1/phosphorylated-PAK1 levels are associated with decreased survival rates in patients with CRPC. All the information suggests that this cell line reflects the characteristics of CRPC cells and can be applied to dissect the mechanism of CRPC initiation and progression. This study also shows that PAK1 is a potential target for CRPC treatment.
    Implications: This study uses a newly generated PTEN null prostate cancer cell line to define a critical functional role of p110β-PAK1 in CRPC migration/invasion. This study also shows that the p110β-PAK1 axis can potentially be a therapeutic target in CRPC metastasis.
    MeSH term(s) Animals ; Humans ; Male ; Mice ; Androgen Antagonists ; Androgens/therapeutic use ; Cell Line, Tumor ; Mice, Inbred C57BL ; Mice, Transgenic ; p21-Activated Kinases/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Prostatic Neoplasms, Castration-Resistant/metabolism ; PTEN Phosphohydrolase/genetics ; PTEN Phosphohydrolase/metabolism ; Receptors, Androgen/metabolism
    Chemical Substances Androgen Antagonists ; Androgens ; p21-Activated Kinases (EC 2.7.11.1) ; PAK1 protein, human (EC 2.7.11.1) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; PTEN Phosphohydrolase (EC 3.1.3.67) ; PTEN protein, human (EC 3.1.3.67) ; Receptors, Androgen ; Pik3ca protein, mouse (EC 2.7.1.137) ; Pten protein, mouse (EC 3.1.3.67) ; Pak1 protein, mouse (EC 2.7.11.1)
    Language English
    Publishing date 2023-08-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2098788-2
    ISSN 1557-3125 ; 1541-7786
    ISSN (online) 1557-3125
    ISSN 1541-7786
    DOI 10.1158/1541-7786.MCR-22-0808
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    Zs.A 5744: Show issues Location:
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  3. Article ; Online: Identification of 2-Sulfonyl/Sulfonamide Pyrimidines as Covalent Inhibitors of WRN Using a Multiplexed High-Throughput Screening Assay.

    Parker, Mackenzie J / Lee, Hyelee / Yao, Shihua / Irwin, Sean / Hwang, Sunil / Belanger, Kylie / de Mare, Sofia Woo / Surgenor, Richard / Yan, Lu / Gee, Patricia / Morla, Shravan / Puyang, Xiaoling / Hsiao, Peng / Zeng, Hao / Zhu, Ping / Korpal, Manav / Dransfield, Paul / Bolduc, David M / Larsen, Nicholas A

    Biochemistry

    2023  Volume 62, Issue 14, Page(s) 2147–2160

    Abstract: Werner syndrome protein (WRN) is a multifunctional enzyme with helicase, ATPase, and exonuclease activities that are necessary for numerous DNA-related transactions in the human cell. Recent studies identified WRN as a synthetic lethal target in cancers ... ...

    Abstract Werner syndrome protein (WRN) is a multifunctional enzyme with helicase, ATPase, and exonuclease activities that are necessary for numerous DNA-related transactions in the human cell. Recent studies identified WRN as a synthetic lethal target in cancers characterized by genomic microsatellite instability resulting from defects in DNA mismatch repair pathways. WRN's helicase activity is essential for the viability of these high microsatellite instability (MSI-H) cancers and thus presents a therapeutic opportunity. To this end, we developed a multiplexed high-throughput screening assay that monitors exonuclease, ATPase, and helicase activities of full-length WRN. This screening campaign led to the discovery of 2-sulfonyl/sulfonamide pyrimidine derivatives as novel covalent inhibitors of WRN helicase activity. The compounds are specific for WRN versus other human RecQ family members and show competitive behavior with ATP. Examination of these novel chemical probes established the sulfonamide NH group as a key driver of compound potency. One of the leading compounds, H3B-960, showed consistent activities in a range of assays (IC
    MeSH term(s) Humans ; Werner Syndrome ; Exodeoxyribonucleases/genetics ; RecQ Helicases/genetics ; RecQ Helicases/metabolism ; High-Throughput Screening Assays ; Microsatellite Instability ; Werner Syndrome Helicase/metabolism ; Neoplasms
    Chemical Substances Exodeoxyribonucleases (EC 3.1.-) ; RecQ Helicases (EC 3.6.4.12) ; Werner Syndrome Helicase (EC 3.6.4.12) ; WRN protein, human (EC 3.6.4.12)
    Language English
    Publishing date 2023-07-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021/acs.biochem.2c00599
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    Zs.A 217: Show issues Location:
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  4. Article ; Online: Biochemical and structural basis for the pharmacological inhibition of nuclear hormone receptor PPARγ by inverse agonists.

    Irwin, Sean / Karr, Craig / Furman, Craig / Tsai, Jennifer / Gee, Patricia / Banka, Deepti / Wibowo, Ardian S / Dementiev, Alexey A / O'Shea, Morgan / Yang, Joyce / Lowe, Jason / Mitchell, Lorna / Ruppel, Sabine / Fekkes, Peter / Zhu, Ping / Korpal, Manav / Larsen, Nicholas A

    The Journal of biological chemistry

    2022  Volume 298, Issue 11, Page(s) 102539

    Abstract: Recent studies have reported that the peroxisome proliferator-activated receptor gamma (PPARγ) pathway is activated in approximately 40% of patients with muscle-invasive bladder cancer. This led us to investigate pharmacological repression of PPARγ as a ... ...

    Abstract Recent studies have reported that the peroxisome proliferator-activated receptor gamma (PPARγ) pathway is activated in approximately 40% of patients with muscle-invasive bladder cancer. This led us to investigate pharmacological repression of PPARγ as a possible intervention strategy. Here, we characterize PPARγ antagonists and inverse agonists and find that the former behave as silent ligands, whereas inverse agonists (T0070907 and SR10221) repress downstream PPARγ target genes leading to growth inhibition in bladder cancer cell lines. To understand the mechanism, we determined the ternary crystal structure of PPARγ bound to T0070907 and the corepressor (co-R) peptide NCOR1. The structure shows that the AF-2 helix 12 (H12) rearranges to bind inside the ligand-binding domain, where it forms stabilizing interactions with the compound. This dramatic movement in H12 unveils a large interface for co-R binding. In contrast, the crystal structure of PPARγ bound to a SR10221 analog shows more subtle structural differences, where the compound binds and pushes H12 away from the ligand-binding domain to allow co-R binding. Interestingly, we found that both classes of compound promote recruitment of co-R proteins in biochemical assays but with distinct conformational changes in H12. We validate our structural models using both site-directed mutagenesis and chemical probes. Our findings offer new mechanistic insights into pharmacological modulation of PPARγ signaling.
    MeSH term(s) Humans ; PPAR gamma/metabolism ; Ligands ; Urinary Bladder Neoplasms ; Benzamides/pharmacology
    Chemical Substances PPAR gamma ; T 0070907 ; Ligands ; Benzamides
    Language English
    Publishing date 2022-09-28
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2022.102539
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  5. Article ; Online: Estrogen Receptor Covalent Antagonists: The Best Is Yet to Come.

    Furman, Craig / Hao, Ming-Hong / Prajapati, Sudeep / Reynolds, Dominic / Rimkunas, Victoria / Zheng, Guo Z / Zhu, Ping / Korpal, Manav

    Cancer research

    2019  Volume 79, Issue 8, Page(s) 1740–1745

    Abstract: The development of tamoxifen and subsequent estrogen receptor alpha (ERα) antagonists represents a tremendous therapeutic breakthrough in the treatment of breast cancer. Despite the ability of ERα antagonists to increase survival rates, resistance to ... ...

    Abstract The development of tamoxifen and subsequent estrogen receptor alpha (ERα) antagonists represents a tremendous therapeutic breakthrough in the treatment of breast cancer. Despite the ability of ERα antagonists to increase survival rates, resistance to these therapies is an all-too-common occurrence. The majority of resistant tumors, including those with hotspot mutations in the ligand-binding domain of ERα, remain dependent on ERα signaling, indicating that either a more potent or novel class of antagonist could have clinical benefit. With this thought in mind, we developed a novel ERα antagonist that exhibits enhanced potency due to its ability to covalently target a unique cysteine in ER. This review describes the design of this antagonist, H3B-5942, and discusses opportunities for future improvements, which could reduce the risk of escape mutations to this therapeutic modality.
    MeSH term(s) Animals ; Breast Neoplasms/drug therapy ; Drug Resistance, Neoplasm/drug effects ; Estrogen Receptor Antagonists/therapeutic use ; Female ; Humans ; Indazoles/therapeutic use ; Receptors, Estrogen/antagonists & inhibitors
    Chemical Substances Estrogen Receptor Antagonists ; H3B-5942 ; Indazoles ; Receptors, Estrogen
    Language English
    Publishing date 2019-04-05
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-18-3634
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  6. Article ; Online: Targeting the transforming growth factor-beta signalling pathway in metastatic cancer.

    Korpal, Manav / Kang, Yibin

    European journal of cancer (Oxford, England : 1990)

    2010  Volume 46, Issue 7, Page(s) 1232–1240

    Abstract: Transforming growth factor (TGF)-beta signalling plays a dichotomous role in tumour progression, acting as a tumour suppressor early and as a pro-metastatic pathway in late-stages. There is accumulating evidence that advanced-stage tumours produce ... ...

    Abstract Transforming growth factor (TGF)-beta signalling plays a dichotomous role in tumour progression, acting as a tumour suppressor early and as a pro-metastatic pathway in late-stages. There is accumulating evidence that advanced-stage tumours produce excessive levels of TGF-beta, which acts to promote tumour growth, invasion and colonisation of secondary organs. In light of the pro-metastasis function, many strategies are currently being explored to antagonise the TGF-beta pathway as a treatment for metastatic cancers. Strategies such as using large molecule ligand traps, reducing the translational efficiency of TGF-beta ligands using antisense technology, and antagonising TGF-beta receptor I/II kinase function using small molecule inhibitors are the most prominent methods being explored today. Administration of anti-TGF-beta therapies alone, or in combination with immunosuppressive or cytotoxic therapies, has yielded promising results in the preclinical and clinical settings. Despite these successes, the temporal- and context-dependent roles of TGF-beta signalling in cancer has made it challenging to define patient subgroups that are most likely to respond, and the therapeutic regimens that will be most effective in the clinic. Novel mouse models and diagnostic tools are being developed today to circumvent these issues, which may potentially expedite anti-TGF-beta drug development and clinical application.
    MeSH term(s) Animals ; Antibodies, Monoclonal/therapeutic use ; Antineoplastic Agents/pharmacology ; Antisense Elements (Genetics)/therapeutic use ; Cell Transformation, Neoplastic/metabolism ; Combined Modality Therapy ; Disease Progression ; Humans ; Mice ; Neoplasm Metastasis/drug therapy ; Neoplasm Metastasis/physiopathology ; Neoplasm Proteins/immunology ; Neoplasm Proteins/physiology ; Signal Transduction/drug effects ; Transforming Growth Factor beta/antagonists & inhibitors ; Transforming Growth Factor beta/immunology ; Transforming Growth Factor beta/physiology
    Chemical Substances Antibodies, Monoclonal ; Antineoplastic Agents ; Antisense Elements (Genetics) ; Neoplasm Proteins ; Transforming Growth Factor beta
    Language English
    Publishing date 2010-05
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 82061-1
    ISSN 1879-0852 ; 0277-5379 ; 0959-8049 ; 0964-1947
    ISSN (online) 1879-0852
    ISSN 0277-5379 ; 0959-8049 ; 0964-1947
    DOI 10.1016/j.ejca.2010.02.040
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    Zs.A 456: Show issues Location:
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  7. Article ; Online: The emerging role of miR-200 family of microRNAs in epithelial-mesenchymal transition and cancer metastasis.

    Korpal, Manav / Kang, Yibin

    RNA biology

    2009  Volume 5, Issue 3, Page(s) 115–119

    Abstract: MicroRNAs (miRNAs) play essential roles in many physiological and pathological processes, including tumor development, by regulating the expression of a plethora of mRNAs. Although the importance of miRNAs in tumorigenesis is well established, only ... ...

    Abstract MicroRNAs (miRNAs) play essential roles in many physiological and pathological processes, including tumor development, by regulating the expression of a plethora of mRNAs. Although the importance of miRNAs in tumorigenesis is well established, only recently have reports elucidated miRNAs as promoters or suppressors of metastasis. The miR-200 family has been shown to inhibit the initiating step of metastasis, epithelial-mesenchymal transition (EMT), by maintaining the epithelial phenotype through direct targeting of transcriptional repressors of E-cadherin, ZEB1 and ZEB2. These findings shed light into a miRNA-mediated regulatory pathway that influences EMT in a developmentally and pathologically relevant setting.
    MeSH term(s) Animals ; Epithelium/pathology ; Humans ; Mesoderm/pathology ; MicroRNAs/metabolism ; Neoplasm Metastasis/genetics ; Neoplasms/genetics ; Neoplasms/pathology ; Transcription Factors/metabolism
    Chemical Substances MicroRNAs ; Transcription Factors
    Language English
    Publishing date 2009-02-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
    ISSN 1555-8584
    ISSN (online) 1555-8584
    DOI 10.4161/rna.5.3.6558
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  8. Article ; Online: Blocking PI3K p110β Attenuates Development of PTEN-Deficient Castration-Resistant Prostate Cancer.

    Gao, Xueliang / Wang, Yubao / Ribeiro, Caroline F / Manokaran, Cherubin / Chang, Hyeyoun / Von, Thanh / Rodrigues, Silvia / Cizmecioglu, Onur / Jia, Shidong / Korpal, Manav / Korn, Joshua M / Wang, Zhigang / Schmit, Fabienne / Jiang, Lan / Pagliarini, Raymond / Yang, Yi / Sethi, Isha / Signoretti, Sabina / Yuan, Guo-Cheng /
    Loda, Massimo / Zhao, Jean J / Roberts, Thomas M

    Molecular cancer research : MCR

    2022  Volume 20, Issue 5, Page(s) 673–685

    Abstract: A common outcome of androgen deprivation in prostate cancer therapy is disease relapse and progression to castration-resistant prostate cancer (CRPC) via multiple mechanisms. To gain insight into the recent clinical findings that highlighted genomic ... ...

    Abstract A common outcome of androgen deprivation in prostate cancer therapy is disease relapse and progression to castration-resistant prostate cancer (CRPC) via multiple mechanisms. To gain insight into the recent clinical findings that highlighted genomic alterations leading to hyperactivation of PI3K, we examined the roles of the commonly expressed p110 catalytic isoforms of PI3K in a murine model of Pten-null invasive CRPC. While blocking p110α had negligible effects in the development of Pten-null invasive CRPC, either genetic or pharmacologic perturbation of p110β dramatically slowed CRPC initiation and progression. Once fully established, CRPC tumors became partially resistant to p110β inhibition, indicating the acquisition of new dependencies. Driven by our genomic analyses highlighting potential roles for the p110β/RAC/PAK1 and β-catenin pathways in CRPC, we found that combining p110β with RAC/PAK1 or tankyrase inhibitors significantly reduced the growth of murine and human CRPC organoids in vitro and in vivo. Because p110β activity is dispensable for most physiologic processes, our studies support novel therapeutic strategies both for preventing disease progression into CRPC and for treating CRPC.
    Implications: This work establishes p110β as a promising target for preventing the progression of primary PTEN-deficient prostate tumors to CRPC, and for treating established CRPC in combination with RAC/PAK1 or tankyrase inhibitors.
    MeSH term(s) Androgen Antagonists ; Animals ; Humans ; Male ; Mice ; PTEN Phosphohydrolase/genetics ; Phosphatidylinositol 3-Kinases ; Prostate ; Prostatic Neoplasms, Castration-Resistant/drug therapy ; Prostatic Neoplasms, Castration-Resistant/genetics ; Tankyrases
    Chemical Substances Androgen Antagonists ; Tankyrases (EC 2.4.2.30) ; PTEN Phosphohydrolase (EC 3.1.3.67) ; PTEN protein, human (EC 3.1.3.67)
    Language English
    Publishing date 2022-02-01
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2098788-2
    ISSN 1557-3125 ; 1541-7786
    ISSN (online) 1557-3125
    ISSN 1541-7786
    DOI 10.1158/1541-7786.MCR-21-0322
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  9. Article ; Online: Nonclinical pharmacokinetics and in vitro metabolism of H3B-6545, a novel selective ERα covalent antagonist (SERCA).

    Rioux, Nathalie / Smith, Sherri / Korpal, Manav / O'Shea, Morgan / Prajapati, Sudeep / Zheng, Guo Zhu / Warmuth, Markus / Smith, Peter G

    Cancer chemotherapy and pharmacology

    2018  Volume 83, Issue 1, Page(s) 151–160

    Abstract: Purpose: H3B-6545, a novel selective estrogen receptor (ER)α covalent antagonist (SERCA) which inactivates both wild-type and mutant ERα, is in clinical development for the treatment of metastatic breast cancer. Preclinical studies were conducted to ... ...

    Abstract Purpose: H3B-6545, a novel selective estrogen receptor (ER)α covalent antagonist (SERCA) which inactivates both wild-type and mutant ERα, is in clinical development for the treatment of metastatic breast cancer. Preclinical studies were conducted to characterize the pharmacokinetics and metabolism of H3B-6545 in rat and monkeys.
    Methods: The clearance and metabolic profiles of H3B-6545 were studied using rat, monkey and human hepatocytes, and reaction phenotyping was done using recombinant human cytochrome P450 enzymes. Blood stability, protein binding, and permeability were also determined in vitro. Pharmacokinetics of H3B-6545 was assessed after both intravenous and oral dosing. A nonclinical PBPK model was developed to assess in vitro-in vivo correlation of clearance.
    Results: H3B-6545 had a terminal elimination half-life of 2.4 h in rats and 4.0 h in monkeys and showed low to moderate bioavailability, in line with the in vitro permeability assessment. Plasma protein binding was similar across species, at 99.5-99.8%. Nine metabolites of H3B-6545 were identified in hepatocyte incubations, none of which were unique to humans. Formation of glutathione-related conjugate of H3B-6545 was minimal in vitro. H3B-6545, a CYP3A substrate, is expected to be mostly cleared via hepatic phase 1 metabolism. Hepatocyte clearance values were used to adequately model the time-concentration profiles in rat and monkey.
    Conclusions: We report on the absorption and metabolic fate and disposition of H3B-6545 in rats and dogs and illustrate that in vitro-in vivo correlation of clearance is possible for targeted covalent inhibitors, provided reactivity is not a predominant mechanism of clearance.
    MeSH term(s) Animals ; Biological Availability ; Cells, Cultured ; Cytochrome P-450 Enzyme Inhibitors/pharmacokinetics ; Cytochrome P-450 Enzyme Inhibitors/pharmacology ; Cytochrome P-450 Enzyme System/drug effects ; Dogs ; Drug Evaluation, Preclinical ; Estrogen Receptor Antagonists/pharmacokinetics ; Estrogen Receptor Antagonists/pharmacology ; Estrogen Receptor alpha/antagonists & inhibitors ; Female ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Humans ; In Vitro Techniques ; Indazoles/pharmacokinetics ; Indazoles/pharmacology ; Macaca fascicularis ; Metabolic Clearance Rate ; Microsomes, Liver/drug effects ; Microsomes, Liver/metabolism ; Protein Binding ; Pyridines/pharmacokinetics ; Pyridines/pharmacology ; Rats, Sprague-Dawley ; Species Specificity ; Tissue Distribution
    Chemical Substances Cytochrome P-450 Enzyme Inhibitors ; Estrogen Receptor Antagonists ; Estrogen Receptor alpha ; H3B-6545 ; Indazoles ; Pyridines ; Cytochrome P-450 Enzyme System (9035-51-2)
    Language English
    Publishing date 2018-11-01
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 6820-2
    ISSN 1432-0843 ; 0344-5704 ; 0943-9404
    ISSN (online) 1432-0843
    ISSN 0344-5704 ; 0943-9404
    DOI 10.1007/s00280-018-3716-3
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  10. Article: The emerging role of miR-200 family of MicroRNAs in epithelial-mesenchymal transition and cancer metastasis

    Korpal, Manav / Kang, Yibin

    RNA biology. 2008 July 1, v. 5, no. 3

    2008  

    Abstract: MicroRNAs (miRNAs) play essential roles in many physiological and pathological processes, including tumor development, by regulating the expression of a plethora of mRNAs. Although the importance of miRNAs in tumorigenesis is well established, only ... ...

    Abstract MicroRNAs (miRNAs) play essential roles in many physiological and pathological processes, including tumor development, by regulating the expression of a plethora of mRNAs. Although the importance of miRNAs in tumorigenesis is well established, only recently have reports elucidated miRNAs as promoters or suppressors of metastasis. The miR-200 family has been shown to inhibit the initiating step of metastasis, epithelial-mesenchymal transition (EMT), by maintaining the epithelial phenotype through direct targeting of transcriptional repressors of E-cadherin, ZEB1 and ZEB2. These findings shed light into a miRNA-mediated regulatory pathway that influences EMT in a developmentally and pathologically relevant setting.
    Keywords cadherins ; carcinogenesis ; epithelium ; messenger RNA ; metastasis ; microRNA ; neoplasms ; phenotype ; repressor proteins
    Language English
    Dates of publication 2008-0701
    Size p. 115-119.
    Publishing place Taylor & Francis
    Document type Article
    ISSN 1555-8584
    DOI 10.4161/rna.5.3.6558
    Database NAL-Catalogue (AGRICOLA)

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