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Article ; Online: Deletion of AMPK minimizes graft-versus-host disease through an early impact on effector donor T cells.

Monlish, Darlene A / Beezhold, Kevin J / Chiaranunt, Pailin / Paz, Katelyn / Moore, Nathan J / Dobbs, Andrea K / Brown, Rebecca A / Ozolek, John A / Blazar, Bruce R / Byersdorfer, Craig A

JCI insight

2021 Volume 6, Issue 14

Abstract: Allogeneic hematopoietic stem cell transplantation is a viable treatment for multiple hematologic diseases, but its application is often limited by graft-versus-host disease (GVHD), where donor T cells attack host tissues in the skin, liver, and ... ...

Abstract	Allogeneic hematopoietic stem cell transplantation is a viable treatment for multiple hematologic diseases, but its application is often limited by graft-versus-host disease (GVHD), where donor T cells attack host tissues in the skin, liver, and gastrointestinal tract. Here, we examined the role of the cellular energy sensor AMP kinase (AMPK) in alloreactive T cells during GVHD development. Early posttransplant, AMPK activity increased more than 15-fold in allogeneic T cells, and transplantation of T cells deficient in both AMPKα1 and AMPKα2 decreased GVHD severity in multiple disease models. Importantly, a lack of AMPK lessened GVHD without compromising antileukemia responses or impairing lymphopenia-driven immune reconstitution. Mechanistically, absence of AMPK decreased both CD4+ and CD8+ effector T cell numbers as early as day 3 posttransplant, while simultaneously increasing regulatory T cell (Treg) percentages. Improvements in GVHD resulted from cell-intrinsic perturbations in conventional effector T cells as depletion of donor Tregs had minimal impact on AMPK-related improvements. Together, these results highlight a specific role for AMPK in allogeneic effector T cells early posttransplant and suggest that AMPK inhibition may be an innovative approach to mitigate GVHD while preserving graft-versus-leukemia responses and maintaining robust immune reconstitution.
MeSH term(s)	AMP-Activated Protein Kinases/deficiency ; AMP-Activated Protein Kinases/genetics ; Animals ; Bone Marrow Transplantation/adverse effects ; Disease Models, Animal ; Female ; Graft vs Host Disease/blood ; Graft vs Host Disease/immunology ; Graft vs Host Disease/pathology ; Hematopoietic Stem Cell Transplantation/adverse effects ; Humans ; Male ; Mice ; Mice, Knockout ; Severity of Illness Index ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; Transplantation, Homologous/adverse effects
Chemical Substances	AMPK alpha1 subunit, mouse (EC 2.7.11.1) ; AMPK alpha2 subunit, mouse (EC 2.7.11.1) ; AMP-Activated Protein Kinases (EC 2.7.11.31)
Language	English
Publishing date	2021-07-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.143811
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Article ; Online: Deletion of AMPK minimizes graft-versus-host disease through an early impact on effector donor T cells

Darlene A. Monlish / Kevin J. Beezhold / Pailin Chiaranunt / Katelyn Paz / Nathan J. Moore / Andrea K. Dobbs / Rebecca A. Brown / John A. Ozolek / Bruce R. Blazar / Craig A. Byersdorfer

JCI Insight, Vol 6, Iss

2021 Volume 14

Abstract	Allogeneic hematopoietic stem cell transplantation is a viable treatment for multiple hematologic diseases, but its application is often limited by graft-versus-host disease (GVHD), where donor T cells attack host tissues in the skin, liver, and gastrointestinal tract. Here, we examined the role of the cellular energy sensor AMP kinase (AMPK) in alloreactive T cells during GVHD development. Early posttransplant, AMPK activity increased more than 15-fold in allogeneic T cells, and transplantation of T cells deficient in both AMPKα1 and AMPKα2 decreased GVHD severity in multiple disease models. Importantly, a lack of AMPK lessened GVHD without compromising antileukemia responses or impairing lymphopenia-driven immune reconstitution. Mechanistically, absence of AMPK decreased both CD4+ and CD8+ effector T cell numbers as early as day 3 posttransplant, while simultaneously increasing regulatory T cell (Treg) percentages. Improvements in GVHD resulted from cell-intrinsic perturbations in conventional effector T cells as depletion of donor Tregs had minimal impact on AMPK-related improvements. Together, these results highlight a specific role for AMPK in allogeneic effector T cells early posttransplant and suggest that AMPK inhibition may be an innovative approach to mitigate GVHD while preserving graft-versus-leukemia responses and maintaining robust immune reconstitution.
Keywords	Metabolism ; Transplantation ; Medicine ; R
Language	English
Publishing date	2021-07-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
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Article ; Online: Microprocessor of microRNAs: regulation and potential for therapeutic intervention.

Beezhold, Kevin J / Castranova, Vince / Chen, Fei

Molecular cancer

2010 Volume 9, Page(s) 134

Abstract: MicroRNAs (miRNAs) are a class of small, noncoding RNAs critically involved in a wide spectrum of normal and pathological processes of cells or tissues by fine-tuning the signals important for stem cell development, cell differentiation, cell cycle ... ...

Abstract	MicroRNAs (miRNAs) are a class of small, noncoding RNAs critically involved in a wide spectrum of normal and pathological processes of cells or tissues by fine-tuning the signals important for stem cell development, cell differentiation, cell cycle regulation, apoptosis, and transformation. Considerable progress has been made in the past few years in understanding the transcription, biogenesis and functional regulation of miRNAs. Numerous studies have implicated altered expression of miRNAs in human cancers, suggesting that aberrant expression of miRNAs is one of the hallmarks for carcinogenesis. In this review, we briefly discuss most recent discoveries on the regulation of miRNAs at the level of microprocessor-mediated biogenesis of miRNAs.
MeSH term(s)	Animals ; Gene Expression Regulation ; Humans ; MicroRNAs/physiology ; Neoplasms/genetics
Chemical Substances	MicroRNAs
Language	English
Publishing date	2010-06-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ISSN	1476-4598
ISSN (online)	1476-4598
DOI	10.1186/1476-4598-9-134
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Article ; Online: Microprocessor of microRNAs

Chen Fei / Castranova Vince / Beezhold Kevin J

Molecular Cancer, Vol 9, Iss 1, p

regulation and potential for therapeutic intervention

2010 Volume 134

Abstract: Abstract MicroRNAs (miRNAs) are a class of small, noncoding RNAs critically involved in a wide spectrum of normal and pathological processes of cells or tissues by fine-tuning the signals important for stem cell development, cell differentiation, cell ... ...

Abstract	Abstract MicroRNAs (miRNAs) are a class of small, noncoding RNAs critically involved in a wide spectrum of normal and pathological processes of cells or tissues by fine-tuning the signals important for stem cell development, cell differentiation, cell cycle regulation, apoptosis, and transformation. Considerable progress has been made in the past few years in understanding the transcription, biogenesis and functional regulation of miRNAs. Numerous studies have implicated altered expression of miRNAs in human cancers, suggesting that aberrant expression of miRNAs is one of the hallmarks for carcinogenesis. In this review, we briefly discuss most recent discoveries on the regulation of miRNAs at the level of microprocessor-mediated biogenesis of miRNAs.
Keywords	Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Oncology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	500
Language	English
Publishing date	2010-06-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
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Article ; Online: Expression kinetics of miRNA involved in dermal toluene 2,4-diisocyanate sensitization.

Anderson, Stacey E / Beezhold, Kevin / Lukomska, Ewa / Richardson, Jodi / Long, Carrie / Anderson, Katie / Franko, Jennifer / Meade, B Jean / Beezhold, Donald H

Journal of immunotoxicology

2013 Volume 11, Issue 3, Page(s) 250–259

Abstract: Allergic disease is an important occupational health concern, with work-related asthma and allergic contact dermatitis being the most frequently diagnosed occupational illnesses. Diisocyanates, particularly toluene 2,4-diisocyanate (TDI), have been the ... ...

Abstract	Allergic disease is an important occupational health concern, with work-related asthma and allergic contact dermatitis being the most frequently diagnosed occupational illnesses. Diisocyanates, particularly toluene 2,4-diisocyanate (TDI), have been the leading cause of occupational asthma for many years. Understanding the mechanisms behind allergic disease is critical for treatment and prevention. Recently, the study of post-transcriptional regulation by microRNAs (miRNA) has shed light on mechanisms of allergic disease. The present studies report the expression of miRNA during the sensitization phase of an allergic response to TDI in a murine model. Female BALB/c mice were dermally exposed to TDI (0.1-15% [v/v]) or vehicle. RNA was isolated from superficial parotid lymph nodes at timepoints between 1 h and 15 days post-exposure and then miRNA expression was analyzed using array and real-time quantitative PCR analysis. Consistent changes in miRNA expression were identified for miR-21, miR-22, miR-27b, miR-31, miR-126, miR-155, miR-210, and miR-301a. Following TDI exposure, peak expression was observed by Day 4 for the majority of miRNA evaluated with trends in expression correlated to exposure concentration. Confirmed and predicted targets were identified using Diana-microT, miRanda, miRwalk, and Targetscan algorithms. Evaluation of mRNA expression of cytokine and transcription factor targets suggests that miRNA may have a central role early in TDI sensitization. Understanding the role of these miRNA and their specific mechanism of action in sensitization to TDI may provide pertinent information for the identification of other chemical sensitizers while also contributing to the treatment and prevention of allergic disease.
MeSH term(s)	Administration, Cutaneous ; Animals ; Asthma, Occupational/chemically induced ; Asthma, Occupational/genetics ; Asthma, Occupational/immunology ; Cytokines/metabolism ; Disease Models, Animal ; Female ; Humans ; Irritants/administration & dosage ; Lymph Nodes/drug effects ; Lymph Nodes/physiology ; Mice ; Mice, Inbred BALB C ; MicroRNAs/analysis ; Microarray Analysis ; Toluene 2,4-Diisocyanate/administration & dosage ; Transcription Factors/metabolism
Chemical Substances	Cytokines ; Irritants ; MicroRNAs ; Transcription Factors ; Toluene 2,4-Diisocyanate (17X7AFZ1GH)
Language	English
Publishing date	2013-09-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2205064-4
ISSN	1547-6901 ; 1547-691X
ISSN (online)	1547-6901
ISSN	1547-691X
DOI	10.3109/1547691X.2013.835891
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Zs.A 6167: Show issues

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Article ; Online: JNK1 activation predicts the prognostic outcome of the human hepatocellular carcinoma.

Chang, Qingshan / Chen, Jianguo / Beezhold, Kevin J / Castranova, Vince / Shi, Xianglin / Chen, Fei

Molecular cancer

2009 Volume 8, Page(s) 64

Abstract: Background: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with an extremely poor prognosis. The classification of HCC based on the molecular signature is not well-established.: Results: In the present study, we reported ... ...

Abstract	Background: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with an extremely poor prognosis. The classification of HCC based on the molecular signature is not well-established. Results: In the present study, we reported HCC signature genes based on the JNK1 activation status in 31 HCC specimens relative to the matched distal noncancerous liver tissue from 31 patients. The HCCs with high JNK1 (H-JNK1) and low JNK1 (L-JNK1) were sub-grouped. Two different signature gene sets for both H-JNK1 and L-JNK1 HCC were identified through gene expression profiling. A striking overlap of signature genes was observed between the H-JNK1 HCC and the hepatoblastoma or hepatoblastoma-type HCC. Many established biomarkers for hepatic progenitor cells were over-expressed in H-JNK1 HCC, including AFP, TACSTD1, KRT19, KRT7, THY1, and PROM1. In addition, the majority of the most up-regulated genes were those associated with metastasis and earlier recurrence, whereas the genes for normal liver function were substantially down-regulated in H-JNK1 HCC tissue. A Kaplan-Meier plot demonstrated that the survival of the patients with H-JNK1 HCC was severely impaired. Conclusion: Accordingly, we believe that the H-JNK1 HCC may originate from hepatic progenitor cells and is associated with poorer prognosis. The status of JNK1 activation in HCC tissue, thus, might be a new biomarker for HCC prognosis and therapeutic targeting.
MeSH term(s)	Adult ; Aged ; Carcinoma, Hepatocellular/enzymology ; Carcinoma, Hepatocellular/genetics ; Enzyme Activation ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Kaplan-Meier Estimate ; Liver Neoplasms/enzymology ; Liver Neoplasms/genetics ; Male ; Middle Aged ; Mitogen-Activated Protein Kinase 8/genetics ; Mitogen-Activated Protein Kinase 8/metabolism ; Prognosis ; Signal Transduction ; Tissue Array Analysis
Chemical Substances	Mitogen-Activated Protein Kinase 8 (EC 2.7.11.24)
Language	English
Publishing date	2009-08-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, U.S. Gov't, P.H.S.
ISSN	1476-4598
ISSN (online)	1476-4598
DOI	10.1186/1476-4598-8-64
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Article ; Online: JNK and STAT3 signaling pathways converge on Akt-mediated phosphorylation of EZH2 in bronchial epithelial cells induced by arsenic.

Chen, Bailing / Liu, Jia / Chang, Qingshan / Beezhold, Kevin / Lu, Yongju / Chen, Fei

Cell cycle (Georgetown, Tex.)

2012 Volume 12, Issue 1, Page(s) 112–121

Abstract: The molecular mechanisms by which arsenic (As ( 3+) ) causes human cancers remain to be fully elucidated. Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb-repressive complexes 2 (PRC2) that promotes trimethylation of lysine 27 of ... ...

Abstract	The molecular mechanisms by which arsenic (As ( 3+) ) causes human cancers remain to be fully elucidated. Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb-repressive complexes 2 (PRC2) that promotes trimethylation of lysine 27 of histone H3, leading to altered expression of tumor suppressors or oncogenes. In the present study, we determined the effect of As ( 3+) on EZH2 phosphorylation and the signaling pathways important for As ( 3+) -induced EZH2 phosphorylation in human bronchial epithelial cell line BEAS-2B. The involvement of kinases in As ( 3+) -induced EZH2 phosphorylation was validated by siRNA-based gene silencing. The data showed that As ( 3+) can induce phosphorylation of EZH2 at serine 21 in human bronchial epithelial cells and that the phosphorylation of EZH2 requires an As ( 3+) -activated signaling cascade from JNK and STAT3 to Akt. Transfection of the cells with siRNA specific for JNK1 revealed that JNK silencing reduced serine727 phosphorylation of STAT3, Akt activation and EZH2 phosphorylation, suggesting that JNK is the upstream kinase involved in As ( 3+) -induced EZH2 phosphorylation. Because As ( 3+) is capable of inducing miRNA-21 (miR-21), a STAT3-regulated miRNA that represses protein translation of PTEN or Spry2, we also tested the role of STAT3 and miR-21 in As ( 3+) -induced EZH2 phosphorylation. Ectopic overexpression of miR-21 promoted Akt activation and phosphorylation of EZH2, whereas inhibiting miR-21 by transfecting the cells with anti-miR-21 inhibited Akt activation and EZH2 phosphorylation. Taken together, these results demonstrate a contribution of the JNK, STAT3 and Akt signaling axis to As ( 3+) -induced EZH2 phosphorylation. Importantly, these findings may reveal new molecular mechanisms underlying As ( 3+) -induced carcinogenesis.
MeSH term(s)	Arsenic/toxicity ; Cell Line ; Enhancer of Zeste Homolog 2 Protein ; Enzyme Activation ; Epithelial Cells/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Membrane Proteins ; MicroRNAs/metabolism ; Mitogen-Activated Protein Kinase 8/antagonists & inhibitors ; Mitogen-Activated Protein Kinase 8/genetics ; Mitogen-Activated Protein Kinase 8/metabolism ; Phosphorylation ; Polycomb Repressive Complex 2/metabolism ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors ; Proto-Oncogene Proteins c-akt/genetics ; Proto-Oncogene Proteins c-akt/metabolism ; RNA Interference ; RNA, Small Interfering/metabolism ; STAT3 Transcription Factor/antagonists & inhibitors ; STAT3 Transcription Factor/metabolism ; Signal Transduction/drug effects ; Transfection
Chemical Substances	Intracellular Signaling Peptides and Proteins ; MIRN21 microRNA, human ; Membrane Proteins ; MicroRNAs ; RNA, Small Interfering ; SPRY2 protein, human ; STAT3 Transcription Factor ; EZH2 protein, human (EC 2.1.1.43) ; Enhancer of Zeste Homolog 2 Protein (EC 2.1.1.43) ; Polycomb Repressive Complex 2 (EC 2.1.1.43) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Mitogen-Activated Protein Kinase 8 (EC 2.7.11.24) ; Arsenic (N712M78A8G)
Language	English
Publishing date	2012-12-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.23030
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Article ; Online: miR-190-mediated downregulation of PHLPP contributes to arsenic-induced Akt activation and carcinogenesis.

Beezhold, Kevin / Liu, Jia / Kan, Hong / Meighan, Terry / Castranova, Vince / Shi, Xianglin / Chen, Fei

Toxicological sciences : an official journal of the Society of Toxicology

2011 Volume 123, Issue 2, Page(s) 411–420

Abstract: The role of trivalent arsenic (As(3+)) on the regulation of the recently identified noncoding small RNAs, mainly microRNAs, has not been explored so far. In the present study, we provide evidence showing that As(3+) is a potent inducer for the expression ...

Abstract	The role of trivalent arsenic (As(3+)) on the regulation of the recently identified noncoding small RNAs, mainly microRNAs, has not been explored so far. In the present study, we provide evidence showing that As(3+) is a potent inducer for the expression of miR-190 in human bronchial epithelial cells. The induction of miR-190 by As(3+) is concentration dependent and associated with the expression of the host gene of miR-190, talin 2, a gene encoding a high-molecular-weight cytoskeletal protein. The elevated level of miR-190 induced by As(3+) is capable of downregulating the translation of the PH domain leucine-rich repeat protein phosphatase (PHLPP), a negative regulator of Akt signaling. Such a downregulation is occurred through direct interaction of the miR-190 with the 3'-UTR region of the PHLPP mRNA, leading to a diminished PHLPP protein expression and consequently, an enhanced Akt activation and expression of vascular endothelial growth factor, an Akt-regulated protein. Overexpression of miR-190 itself is able to enhance proliferation and malignant transformation of the cells as determined by anchorage-independent growth of the cells in soft agar. Accordingly, the data presented suggest that induction of miR-190 is one of the key mechanisms in As(3+)-induced carcinogenesis.
MeSH term(s)	Arsenic Poisoning ; Arsenic Trioxide ; Arsenicals ; Bronchi/drug effects ; Bronchi/pathology ; Carcinogens, Environmental/toxicity ; Cell Line ; Cell Proliferation/drug effects ; Cell Transformation, Neoplastic/chemically induced ; Down-Regulation/drug effects ; Epithelial Cells/drug effects ; Epithelial Cells/pathology ; Gene Expression Regulation/drug effects ; Gene Silencing ; Humans ; MicroRNAs/biosynthesis ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Oxides/toxicity ; Phosphoprotein Phosphatases/genetics ; Phosphoprotein Phosphatases/metabolism ; RNA, Messenger/metabolism ; Talin/genetics ; Talin/metabolism
Chemical Substances	Arsenicals ; Carcinogens, Environmental ; MicroRNAs ; Nuclear Proteins ; Oxides ; RNA, Messenger ; TLN2 protein, human ; Talin ; PHLPP1 protein, human (EC 3.1.3.16) ; Phosphoprotein Phosphatases (EC 3.1.3.16) ; Arsenic Trioxide (S7V92P67HO)
Language	English
Publishing date	2011-07-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfr188
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Article ; Online: Sequential adaptive changes in a c-Myc-driven model of hepatocellular carcinoma.

Dolezal, James M / Wang, Huabo / Kulkarni, Sucheta / Jackson, Laura / Lu, Jie / Ranganathan, Sarangarajan / Goetzman, Eric S / Bharathi, Sivakama S / Beezhold, Kevin / Byersdorfer, Craig A / Prochownik, Edward V

The Journal of biological chemistry

2017 Volume 292, Issue 24, Page(s) 10068–10086

Abstract: Hepatocellular carcinoma (HCC) is a common cancer that frequently overexpresses the c-Myc (Myc) oncoprotein. Using a mouse model of Myc-induced HCC, we studied the metabolic, biochemical, and molecular changes accompanying HCC progression, regression, ... ...

Abstract	Hepatocellular carcinoma (HCC) is a common cancer that frequently overexpresses the c-Myc (Myc) oncoprotein. Using a mouse model of Myc-induced HCC, we studied the metabolic, biochemical, and molecular changes accompanying HCC progression, regression, and recurrence. These involved altered rates of pyruvate and fatty acid β-oxidation and the likely re-directing of glutamine into biosynthetic rather than energy-generating pathways. Initial tumors also showed reduced mitochondrial mass and differential contributions of electron transport chain complexes I and II to respiration. The uncoupling of complex II's electron transport function from its succinate dehydrogenase activity also suggested a mechanism by which Myc generates reactive oxygen species. RNA sequence studies revealed an orderly progression of transcriptional changes involving pathways pertinent to DNA damage repair, cell cycle progression, insulin-like growth factor signaling, innate immunity, and further metabolic re-programming. Only a subset of functions deregulated in initial tumors was similarly deregulated in recurrent tumors thereby indicating that the latter can "normalize" some behaviors to suit their needs. An interactive and freely available software tool was developed to allow continued analyses of these and other transcriptional profiles. Collectively, these studies define the metabolic, biochemical, and molecular events accompanyingHCCevolution, regression, and recurrence in the absence of any potentially confounding therapies.
MeSH term(s)	Animals ; Carcinogenesis ; Carcinoma, Hepatocellular/metabolism ; Carcinoma, Hepatocellular/pathology ; Carcinoma, Hepatocellular/prevention & control ; DNA Repair ; Electron Transport Complex I/genetics ; Electron Transport Complex I/metabolism ; Electron Transport Complex II/genetics ; Electron Transport Complex II/metabolism ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Humans ; Liver/metabolism ; Liver/pathology ; Liver Neoplasms/metabolism ; Male ; Mice, Transgenic ; Mitochondrial Turnover ; Neoplasm Recurrence, Local/metabolism ; Neoplasm Recurrence, Local/pathology ; Neoplasm Recurrence, Local/physiopathology ; Neoplasm Recurrence, Local/prevention & control ; Neoplasms, Experimental/metabolism ; Neoplasms, Experimental/pathology ; Neoplasms, Experimental/prevention & control ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; Reactive Oxygen Species/metabolism ; Tumor Burden ; Up-Regulation
Chemical Substances	Myc protein, mouse ; Proto-Oncogene Proteins c-myc ; Reactive Oxygen Species ; Electron Transport Complex II (EC 1.3.5.1) ; Electron Transport Complex I (EC 7.1.1.2)
Language	English
Publishing date	2017-04-21
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	10.1074/jbc.M117.782052
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Article ; Online: JNK1 activation predicts the prognostic outcome of the human hepatocellular carcinoma

Shi Xianglin / Castranova Vince / Beezhold Kevin J / Chen Jianguo / Chang Qingshan / Chen Fei

Molecular Cancer, Vol 8, Iss 1, p

2009 Volume 64

Abstract: Abstract Background Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with an extremely poor prognosis. The classification of HCC based on the molecular signature is not well-established. Results In the present study, we reported ...

Abstract	Abstract Background Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with an extremely poor prognosis. The classification of HCC based on the molecular signature is not well-established. Results In the present study, we reported HCC signature genes based on the JNK1 activation status in 31 HCC specimens relative to the matched distal noncancerous liver tissue from 31 patients. The HCCs with high JNK1 (H-JNK1) and low JNK1 (L-JNK1) were sub-grouped. Two different signature gene sets for both H-JNK1 and L-JNK1 HCC were identified through gene expression profiling. A striking overlap of signature genes was observed between the H-JNK1 HCC and the hepatoblastoma or hepatoblastoma-type HCC. Many established biomarkers for hepatic progenitor cells were over-expressed in H-JNK1 HCC, including AFP, TACSTD1, KRT19, KRT7, THY1, and PROM1. In addition, the majority of the most up-regulated genes were those associated with metastasis and earlier recurrence, whereas the genes for normal liver function were substantially down-regulated in H-JNK1 HCC tissue. A Kaplan-Meier plot demonstrated that the survival of the patients with H-JNK1 HCC was severely impaired. Conclusion Accordingly, we believe that the H-JNK1 HCC may originate from hepatic progenitor cells and is associated with poorer prognosis. The status of JNK1 activation in HCC tissue, thus, might be a new biomarker for HCC prognosis and therapeutic targeting.
Keywords	Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Oncology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	610
Language	English
Publishing date	2009-08-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
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