• Acute myeloid leukemia
• FLT3 mutation
• Fms-like tyrosine kinase 3
• anticancer drug discovery
• patent review

• Humans
• fms-Like Tyrosine Kinase 3/genetics
• fms-Like Tyrosine Kinase 3/antagonists & inhibitors
• Patents as Topic
• Leukemia, Myeloid, Acute/genetics
• Leukemia, Myeloid, Acute/drug therapy
• Leukemia, Myeloid, Acute/pathology
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/adverse effects
• Protein Kinase Inhibitors/administration & dosage
• Animals
• Mutation
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/adverse effects
• Drug Development
• Drug Resistance, Neoplasm
• Precision Medicine/methods
• Prognosis
• Staurosporine/analogs & derivatives

• Chi-let-7d-5p
• Dermal papilla cells
• Melatonin
• WNT2
• miRNA

• Animals
• Melatonin/pharmacology
• Melatonin/metabolism
• Goats/genetics
• Goats/metabolism
• MicroRNAs/metabolism
• MicroRNAs/genetics
• Cell Proliferation/drug effects
• Wnt2 Protein/metabolism
• Wnt2 Protein/genetics
• Hair Follicle/metabolism
• Hair Follicle/drug effects
• Hair Follicle/cytology

• delivery systems
• drug resistance
• hepatocellular carcinoma
• microRNAs
• targeted therapy
• tumor heterogeneity

• Humans
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/therapy
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Liver Neoplasms/genetics
• Liver Neoplasms/therapy
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Gene Expression Regulation, Neoplastic
• Animals
• Biomarkers, Tumor/genetics

• AHR
• EGFR
• developmental tissue closure
• dioxin
• epithelial morphogenesis
• gene-environment interactions
• the S1PR-MAP3K1-JNK pathway

• Animals
• Female
• Mice
• Basic Helix-Loop-Helix Transcription Factors/metabolism
• Basic Helix-Loop-Helix Transcription Factors/genetics
• Dioxins/toxicity
• ErbB Receptors/metabolism
• ErbB Receptors/genetics
• Eyelids/metabolism
• Eyelids/abnormalities
• Gene-Environment Interaction
• JNK Mitogen-Activated Protein Kinases/metabolism
• JNK Mitogen-Activated Protein Kinases/genetics
• MAP Kinase Kinase Kinase 1/metabolism
• MAP Kinase Kinase Kinase 1/genetics
• MAP Kinase Signaling System/drug effects
• Mice, Knockout
• Receptor Cross-Talk
• Receptors, Aryl Hydrocarbon/metabolism
• Receptors, Aryl Hydrocarbon/genetics
• Signal Transduction/drug effects

• P30 ES006096 NIEHS NIH HHS
• R01 HD098106 NICHD NIH HHS
• R21 ES033342 NIEHS NIH HHS

• BDNF
• CREB
• Depression
• GSK
• MAPK
• PTSD

• Humans
• Stress Disorders, Post-Traumatic/psychology
• Quality of Life
• Comorbidity
• Mental Health
• Depressive Disorder/drug therapy

• Female reproductive tract
• Imperforate vagina
• MAP3K1
• Müllerian duct
• WNT signaling

• Animals
• Female
• Mice
• Epithelial Cells/metabolism
• Epithelium/metabolism
• Vagina/metabolism
• Wnt Signaling Pathway
• MAP Kinase Kinase Kinase 1/genetics
• MAP Kinase Kinase Kinase 1/metabolism

• R01 HD098106 NICHD NIH HHS
• P30 ES006096 NIEHS NIH HHS
• R21 ES033342 NIEHS NIH HHS
• R01 ES010807 NIEHS NIH HHS
• R01HD098106 NIH HHS
• National Institutes of Health
• University of Cincinnati

• Rats
• Animals
• NF-kappa B/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Macrophages/metabolism
• Inflammation/metabolism
• Signal Transduction
• Osteomyelitis/pathology

• 82272544 MOST | National Natural Science Foundation of China (NSFC)

• Breast Cancer
• Hormone receptor-positive
• MAP3K1
• NF-κB
• Prognosis

• Humans
• Animals
• Mice
• Female
• Breast Neoplasms/pathology
• NF-kappa B
• Receptor, ErbB-2/genetics
• Receptor, ErbB-2/metabolism
• Tamoxifen
• Disease-Free Survival
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase Kinase 1/genetics

• MOST 110-2314-B-002-199- Ministry of Science and Technology, Taiwan
• MOST 07-2314-B-002-132-MY3 Ministry of Science and Technology, Taiwan
• MOHW110-TDU-B-211-144017 Ministry of Health and Welfare

• chemoradiotherapy
• cuproptosis
• immune checkpoint inhibitors
• lower-grade gliomas
• molecular subtypes
• tumor microenvironment

• MAP3K1
• fatty liver
• lipid metabolism
• miR-375
• poultry

MicroRNAs (miRNAs) as small non-coding RNA transcripts bind their complementary sequences in the 3′-untranslated region (3′-UTR) of target messenger RNAs (mRNAs) to regulate their expression. It is known that miR-372 belongs to the miR-371–373 gene cluster and has been found to be abnormally expressed in a variety of cancers, but its precise mechanism in cancer remains to be discovered. In this study, miR-372-3p expression was assessed in 153 frozen tissue samples, including primary diagnosed colon cancer and matched normal and adjacent tissues, using real time quantitative polymerase chain reaction (qPCR). An analysis of qPCR data revealed a significant reduction in miR-372-3p expression (by >2-fold) in colon cancer tissues in 51.5% (34/66) of patients. Consistent with this, mimicking the increased miR-372-3p levels in SW480 colon cancer cells significantly suppressed cell growth and proliferation. Although no direct correlation was found between the low level of miR-372-3p and certain tumor-related factors, such as p53, HRE-2, PMS2, MLH1, MSH2, MSH6, HDAC4, p21, and Wee1, in colon cancer tissues, an inverse relationship between miR-372-3p and Ki67 (a marker of proliferation) or miR-372-3p and MAP3K2(MEKK2), which plays a critical role in the MAPK signaling pathways, was confirmed using tissue samples. The target relationship between miR-372-3p and MAP3K2 was verified using luciferase assays in SW480 colon cancer cells. As expected, miR-372-3p mimics significantly suppressed the luciferase activity of pMIR-luc/MAP3K2 3′-UTR in cells, suggesting that miR-372-3p modulates the expression of MAP3K2 by directly targeting its 3′-UTR. Overall, the results obtained herein suggest that miR-372-3p may function as a tumor-suppressor miRNA in colon cancer by targeting MAP3K2.

• National Natural Science Foundation of China

Background: 46,XY disorders/differences of sex development (46,XY DSD) are congenital conditions that result from abnormal gonadal development (gonadal dysgenesis) or abnormalities in androgen synthesis or action. During early embryonic development, several genes are involved in regulating the initiation and maintenance of testicular or ovarian-specific pathways. Recent reports have shown that MAP3K1 genes mediate the development of the 46,XY DSD, which present as complete or partial gonadal dysgenesis. Previous functional studies have demonstrated that some MAP3K1 variants result in the gain of protein function. However, data on possible mechanisms of MAP3K1 genes in modulating protein functions remain scant.

Methods: This study identified a Han Chinese family with the 46,XY DSD. To assess the history and clinical manifestations for the 46,XY DSD patients, the physical, operational, ultra-sonographical, pathological, and other examinations were performed for family members. Variant analysis was conducted using both trio whole-exome sequencing (trio WES) and Sanger sequencing. On the other hand, we generated transiently transfected testicular teratoma cells (NT2/D1) and ovary-derived granular cells (KGN), with mutant or wild-type MAP3K1 gene. We then performed functional assays such as determination of steady-state levels of gender related factors, protein interaction and luciferase assay system.

Results: Two affected siblings were diagnosed with 46,XY DSD. Our analysis showed a missense c.556A > G/p.R186G variant in the MAP3K1 gene. Functional assays demonstrated that the MAP3K1^R186G variant was associated with significantly decreased affinity to ubiquitin (Ub; 43–49%) and increased affinity to RhoA, which was 3.19 ± 0.18 fold, compared to MAP3K1. The MAP3K1^R186G led to hyperphosphorylation of p38 and GSK3β, and promoted hyperactivation of the Wnt4/β-catenin signaling. In addition, there was increased recruitment of β-catenin into the nucleus, which enhanced the expression of pro-ovarian transcription factor FOXL2 gene, thus contributing to the 46,XY DSD.

Conclusion: Our study identified a missense MAP3K1 variant associated with 46,XY DSD. We demonstrated that MAP3K1^R186G variant enhances binding to the RhoA and improves its own stability, resulting in the activation of the Wnt4/β-catenin/FOXL2 pathway. Taken together, these findings provide novel insights into the molecular mechanisms of 46,XY DSD and promotes better clinical evaluation.

Numerous genome-wide association studies (GWAS) conducted to date revealed genetic variants associated with various diseases, including breast and prostate cancers. Despite the availability of these large-scale data, relatively few variants have been functionally characterized, mainly because the majority of single-nucleotide polymorphisms (SNPs) map to the non-coding regions of the human genome. The functional characterization of these non-coding variants and the identification of their target genes remain challenging.

In this communication, we explore the potential functional mechanisms of non-coding SNPs by integrating GWAS with the high-resolution chromosome conformation capture (Hi-C) data for breast and prostate cancers. We show that more genetic variants map to regulatory elements through the 3D genome structure than the 1D linear genome lacking physical chromatin interactions. Importantly, the association of enhancers, transcription factors, and their target genes with breast and prostate cancers tends to be higher when these regulatory elements are mapped to high-risk SNPs through spatial interactions compared to simply using a linear proximity. Finally, we demonstrate that topologically associating domains (TADs) carrying high-risk SNPs also contain gene regulatory elements whose association with cancer is generally higher than those belonging to control TADs containing no high-risk variants.

Our results suggest that many SNPs may contribute to the cancer development by affecting the expression of certain tumor-related genes through long-range chromatin interactions with gene regulatory elements. Integrating large-scale genetic datasets with the 3D genome structure offers an attractive and unique approach to systematically investigate the functional mechanisms of genetic variants in disease risk and progression.

The online version contains supplementary material available at 10.1186/s12863-021-01021-x.

• 3D genome structure
• Breast cancer
• Chromosome conformation capture
• Enhancers
• Gene regulation
• Genetic variation
• Genome-wide association study
• Prostate cancer
• Single-nucleotide polymorphism
• Topologically associating domains
• Transcription factors

The relationships between drug pharmacodynamics and subsequent changes in cellular signaling processes are complex. Many in vitro cell signaling studies often use drug concentrations above physiologically safe drug levels achievable in a patient's plasma. Drug companies develop agents to inhibit or modify the activities of specific target enzymes, often without a full consideration that their compounds have additional unknown targets. These two negative sequelae, when published together, become impediments against successful developmental therapeutics and translation because this data distorts our understanding of signaling mechanisms and reduces the probability of successfully translating drug-based concepts from the bench to the bedside. This article will discuss cellular signaling in isolation and as it relates to extant single and combined therapeutic drug interventions. This will lead to a hypothetical series standardized sequential approaches describing a rigorous concept to drug development and clinical translation.

• JNK
• MAP3K1
• dioxin
• embryonic eyelid closure
• gene-environment interactions
• genetic crosstalks
• sex development and differentiation

• Animals
• Embryonic Development/genetics
• Gene Expression Regulation, Developmental
• Gene-Environment Interaction
• Humans
• MAP Kinase Kinase Kinase 1/genetics
• MAP Kinase Kinase Kinase 1/metabolism
• Mice
• Sex Differentiation/genetics

• P30 ES006096 NIEHS NIH HHS
• R01 HD098106 NICHD NIH HHS
• R01 EY015227 NEI NIH HHS

• Humans
• Mitogen-Activated Protein Kinase Kinases/metabolism
• Mitogen-Activated Protein Kinases/metabolism
• Phosphorylation
• Proteasome Endopeptidase Complex
• Signal Transduction
• Ubiquitin

• Department of Health

Both prostate and pancreatic cancers are ranked in the top five leading causes of cancer death in American. In prostate cancer, the mainstay of therapeutic approaches is inhibition of the androgen receptor; however, resistance occurs within two years. In pancreatic cancer, there is no targeted therapy available, and patients have the worst survival rate compared to all other types of cancer. We identified a novel MLK1 inhibitor (NSC14465) and demonstrated anti-tumor ability in both prostate and pancreatic cancers.

It was shown that mixed lineage kinase 1 (MLK1) regulates pancreatic cancer growth; however, its role in prostate cancer remains unclear. We showed that MLK1 is a tumor marker in prostate cancer by analyzing clinical gene expression data and identified a novel MLK1 inhibitor (NSC14465) from the compound library of the National Cancer Institute (NCI) using a MLK1 protein structure. The inhibitory effects of MLK1 were validated by an in vitro kinase assay and by monitoring phosphorylation signaling, and the anti-proliferation function was shown in several prostate and pancreatic cancer cell lines. We also demonstrated anti-tumor ability and prevention of cancer-related weight loss in a syngeneic orthotopic mouse model of pancreatic cancer that mimicked the tumor growth environment in the pancreas. Our results demonstrate that the MLK1 inhibitor is an anti-tumor agent for malignant prostate and pancreatic cancers.

• MLK1
• androgen receptor
• pancreatic cancer
• prostate cancer

• bioinformatics
• drug repositioning
• drug target
• druggability
• thyroid cancer
• weighted gene co-expression network analysis

• Biomarkers, Tumor/genetics
• Carcinogenesis/genetics
• Computational Biology/methods
• DNA Methylation/genetics
• Databases, Genetic
• Drug Development/methods
• Gene Expression Regulation, Neoplastic/genetics
• Gene Ontology
• Humans
• MAP Kinase Signaling System/genetics
• Protein Interaction Maps/genetics
• Protein Serine-Threonine Kinases/genetics
• TNF Receptor-Associated Factor 2/genetics
• Thyroid Neoplasms/drug therapy
• Thyroid Neoplasms/genetics

• IRF7
• MEKK3
• Phosphorylation
• TLR7/9
• Type I IFNs

• Apoptosis
• Hair follicle stem cells
• MAP3K1
• Proliferation
• Yangtze River Delta White Goat

• Animals
• Apoptosis/genetics
• Cell Proliferation/genetics
• Gene Silencing
• Goats/genetics
• Goats/growth & development
• Hair Follicle/growth & development
• MAP Kinase Kinase Kinase 1/genetics
• Stem Cells/cytology

• Pancreatic adenosquamous carcinoma
• germline mutation
• somatic mutation
• whole exome sequencing

The aim of this study was to screen the predisposed population and explore possible interactions between genetic polymorphisms and risk factors involved in the tumorigenesis and progression of ESCC (esophageal squamous cell carcinoma), in hope of identifying possible therapeutic targets along the way.

Cases (1043) and controls (1315) were enrolled to evaluate the possible association between MAP3K1 SNPs and ESCC risk. Subgroup analyses include MAP3K1 variants, gender, age, smoking and drinking status.

Among all three single locus polymorphisms of MAP3K1, only the heterozygote genotype of rs702689 AG is shown to be associated with increased risk for developing ESCC (OR=1.272, 95% confidence interval=1.061–1.525, p=0.009). Moreover, stratified analysis results observed altered susceptibility among patients with exposure to risk factors combined with certain genetic variant to ESCC.

This study reveals that MAP3K1 rs702689 AG genotype might facilitate the tumorigenesis in ESCC, particularly among women, patients who were over 63y and those who never drink nor smoke.

• esophageal cancer
• single nucleotide polymorphism

LncRNAs play crucial roles in the development of various cancers including hepatocellular carcinoma (HCC). Nevertheless, the function of the long noncoding RNA (lncRNA) FOXD2‐AS1 in HCC is still poorly understood. In this study, we focused on the role of FOXD2‐AS1 in HCC. We found that FOXD2‐AS1 was significantly upregulated in HCC cells in comparison to normal human liver cells, LO2. In this study, we also demonstrated that miR‐206 expression was greatly reduced in HCC cells. Furthermore, the inhibition of FOXD2‐AS1 repressed HCC cell proliferation, enhanced cell apoptosis, and restrained cell invasion and migration. The knockdown of FOXD2‐AS1 elevated miR‐206 expression, and we validated an interaction between these RNAs. Additionally, miR‐206 mimics inhibited HCC development while miR‐206 mimics had the opposite effect. MAP kinase 1 (MAP3K1) was predicted to be a target of miR‐206. We discovered that FOXD2‐AS1 modulated MAP3K1 expression by sponging miR‐206 in MHCC‐97L and HepG2 cells. Finally, our in vivo experiments validated that the knockdown of FOXD2‐AS1 inhibited HCC progression by modulating the miR‐206/MAP3K1 axis. In conclusion, this work implies FOXD2‐AS1 accelerates HCC progression through sponging miR‐206 and regulating MAP3K1 expression.

• FOXD2-AS1
• MAP3K1
• hepatocellular carcinoma
• miR-206

• MAP3K1
• esophageal cancer
• microRNA-203

• MS analysis
• kinases
• phosphatases
• phosphoproteome
• transient complexes

One of the mitogen-activated protein kinases (MAPKs), c-Jun NH2-terminal protein kinase (JNK) plays an important role in regulating cell fate, such as proliferation, differentiation, development, transformation, and apoptosis. Its activity is induced through the interaction of MAPK kinase kinases (MAP3Ks), MAPK kinases (MAP2Ks), and various scaffolding proteins. Because of the importance of the JNK cascade to intracellular bioactivity, many studies have been conducted to reveal its precise intracellular functions and mechanisms, but its regulatory mechanisms remain elusive. In this review, we discuss the molecular characterization, activation process, and physiological functions of mitogen-activated protein kinase kinase 7 (MKK7), the MAP2K that most specifically controls the activity of JNK. Understanding the role of MKK7/JNK signaling in physiological conditions could spark new hypotheses for targeted anticancer therapies.

• JNK
• MAPK
• MKK7
• apoptosis
• cell proliferation

Glioblastoma (GBM) is the most lethal primary malignant brain tumor in adults with poor survival due to acquired therapeutic resistance and rapid recurrence. Currently, the standard clinical strategy for glioma includes maximum surgical resection, radiotherapy, and temozolomide (TMZ) chemotherapy; however, the median survival of patients with GBM remains poor despite these comprehensive therapies. Therefore, the identification of new prognostic biomarkers is urgently needed to evaluate the malignancy and long‐term outcome of glioma.

To further investigate prognostic biomarkers and potential therapeutic targets for GBM.

In this study, we identified tribbles pseudokinase 2 (TRIB2) as one of the genes that is most correlated with pathological classification, radioresistance, and TMZ resistance in glioma. Additionally, the expression of mitogen‐activated protein kinase kinase kinase 1 (MAP3K1) showed a strong correlation with TRIB2. Moreover, a combined increase in TRIB2 and MAP3K1 was observed in GBM and indicated a poor prognosis of patients with glioma. Finally, enriched TRIB2 expression and MAP3K1 expression were shown to be associated with resistance to TMZ and radiotherapy.

Combined elevation of TRIB2 and MAP3K1 could be novel prognostic biomarkers and potential therapeutic targets to evaluate the malignancy and long‐term outcomes of GBM.

• MAP3K1
• TRIB2
• glioblastoma
• prognosis
• therapy resistance

The aberrant activation of hedgehog (HH) signaling is a leading cause of the development of medulloblastoma, a pediatric tumor of the cerebellum. The FDA-approved HH inhibitor, Vismodegib, which targets the transmembrane transducer SMO, has shown limited efficacy in patients with medulloblastoma, due to compensatory mechanisms that maintain an active HH-GLI signaling status. Thus, the identification of novel actionable mechanisms, directly affecting the activity of the HH-regulated GLI transcription factors is an important goal for these malignancies. In this study, using gene expression and reporter assays, combined with biochemical and cellular analyses, we demonstrate that mitogen-activated kinase kinase kinase 1 (MEKK1), the most upstream kinase of the mitogen-activated protein kinase (MAPK) phosphorylation modules, suppresses HH signaling by associating and phosphorylating GLI1, the most potent HH-regulated transcription factor. Phosphorylation occurred at multiple residues in the C-terminal region of GLI1 and was followed by an increased association with the cytoplasmic proteins 14-3-3. Of note, the enforced expression of MEKK1 or the exposure of medulloblastoma cells to the MEKK1 activator, Nocodazole, resulted in a marked inhibitory effect on GLI1 activity and tumor cell proliferation and viability. Taken together, the results of this study shed light on a novel regulatory mechanism of HH signaling, with potentially relevant implications in cancer therapy.

• Canonical Wnt signaling
• DKK2, JNK
• Embryonic eyelid closure
• MAP3K1
• Wntless

• ASK1
• Adaptor
• MAPK pathway
• Protein binding
• Scaffold

• Animals
• Humans
• MAP Kinase Kinase Kinase 5/genetics
• MAP Kinase Kinase Kinase 5/metabolism
• Mitogen-Activated Protein Kinases/genetics
• Mitogen-Activated Protein Kinases/metabolism
• Protein Binding/genetics
• Protein Binding/physiology
• Signal Transduction/genetics
• Signal Transduction/physiology

• Apoptosis
• IDD
• MAP3K9
• MAPK pathway
• miR-15a

• Intracerebral hemorrhage
• MEKK1
• Neuron
• Neuronal apoptosis
• Rat

Chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) is an orphan nuclear receptor that regulates many key biological processes, including organ development and cell fate determination. Although the biological functions of COUP-TFII have been studied extensively, little is known about what regulates its gene expression, especially the role of inducible extracellular factors in triggering it. Here we report that COUP-TFII expression is regulated specifically by fibroblast growth factor 2 (FGF2), which mediates activation of the MEK1/2 pathway in mesenchymal lineage C3H10T1/2 cells. Although FGF2 treatment increased cell proliferation, the induction of COUP-TFII expression was dispensable. Instead, FGF2-primed cells in which COUP-TFII expression was induced showed a low potential for osteoblast differentiation, as evidenced by decreases in alkaline phosphatase activity and osteogenic marker gene expression. Reducing COUP-TFII by U0126 or siRNA against COUP-TFII prevented the anti-osteogenic effect of FGF2, indicating that COUP-TFII plays a key role in the FGF2-mediated determination of osteoblast differentiation capability. This report is the first to suggest that FGF2 is an extracellular inducer of COUP-TFII expression and may suppress the osteogenic potential of mesenchymal cells by inducing COUP-TFII expression prior to the onset of osteogenic differentiation.

MAP3K1 is a serine/threonine kinase that is activated by a diverse set of stimuli and exerts its effect through various downstream effecter molecules, including JNK, ERK1/2 and p38. In humans, mutant alleles of MAP3K1 are associated with 46,XY sex reversal. Until recently, the only phenotype observed in Map3k1^tm1Yxia mutant mice was open eyelids at birth. Here, we report that homozygous Map3k1^tm1Yxia mice have early-onset profound hearing loss accompanied by the progressive degeneration of cochlear outer hair cells. In the mouse inner ear, MAP3K1 has punctate localization at the apical surface of the supporting cells in close proximity to basal bodies. Although the cytoarchitecture, neuronal wiring and synaptic junctions in the organ of Corti are grossly preserved, Map3k1^tm1Yxia mutant mice have supernumerary functional outer hair cells (OHCs) and Deiters' cells. Loss of MAP3K1 function resulted in the downregulation of Fgfr3, Fgf8, Fgf10 and Atf3 expression in the inner ear. Fgfr3, Fgf8 and Fgf10 have a role in induction of the otic placode or in otic epithelium development in mice, and their functional deficits cause defects in cochlear morphogenesis and hearing loss. Our studies suggest that MAP3K1 has an essential role in the regulation of these key cochlear morphogenesis genes. Collectively, our data highlight the crucial role of MAP3K1 in the development and function of the mouse inner ear and hearing.

Summary:Map3k1 mutant mice exhibit early-onset profound hearing loss and supernumerary outer hair cells, along with dysregulation of the FGF signaling pathway, accentuating its function in otic epithelium development and morphogenesis.

• FGF signaling pathway
• Fgf10
• Fgf8
• Fgfr3
• Hearing loss
• MAPK pathway
• Map3k1
• Mekk1
• Supernumerary outer hair cells

AIM: To investigate the underlying molecular mechanisms of miR-451 to inhibit proliferation of esophageal carcinoma cell line EC9706.

METHODS: Assays for cell growth, apoptosis and invasion were used to evaluate the effects of miR-451 expression on EC cells. Luciferase reporter and Western blot assays were used to test whether cyclin-dependent kinase inhibitor 2D (CDKN2D) and MAP3K1 act as major targets of miR-451.

RESULTS: The results showed that CDKN2D and MAP3K1 are direct targets of miR-451. CDKN2D and MAP3K1 overexpression reversed the effect of miR-451. MiR-451 inhibited the proliferation of EC9706 by targeting CDKN2D and MAP3K1.

CONCLUSION: These findings suggest that miR-451 might be a novel prognostic biomarker and a potential target for the treatment of esophageal squamous cell carcinoma in the future.

• Esophageal squamous cell carcinoma
• MiR-451
• Cyclin-dependent kinase inhibitor 2D
• MAP3K1
• Proliferation

• Carcinoma/enzymology
• Carcinoma/genetics
• Carcinoma/pathology
• Carcinoma, Squamous Cell/enzymology
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/pathology
• Cell Line, Tumor
• Cell Proliferation
• Cyclin-Dependent Kinase Inhibitor p19/genetics
• Cyclin-Dependent Kinase Inhibitor p19/metabolism
• Esophageal Neoplasms/enzymology
• Esophageal Neoplasms/genetics
• Esophageal Neoplasms/pathology
• Esophageal Squamous Cell Carcinoma
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Humans
• MAP Kinase Kinase Kinase 1/genetics
• MAP Kinase Kinase Kinase 1/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Signal Transduction
• Transfection

• Embryonic eyelid closure
• MAP3K1
• c-Jun

• ERK
• MAP3K2
• Ras
• SMYD3
• cancer
• lysine methylation
• lysine methyltransferases

• MAP3K
• MEKK
• apoptosis
• protein kinase

Mixed lineage kinase (MLK) 4, or MLK4, is a member of the MLK family of mitogen-activated protein kinase kinase kinases (MAP3Ks). Typically, MAP3Ks function to activate the mitogen-activated protein kinase (MAPK)-signaling pathways and regulate different cellular responses. However, here we report that MLK4β, unlike the other MLKs, negatively regulates the activities of the MAPKs, p38, c-Jun N-terminal kinase and extracellular signal-regulated kinase, and the MAP2Ks, MEK3 and 6. Our results show that MLK4β inhibits sorbitol- and tumor necrosis factor-induced activation of p38. Furthermore, MLK4β interacts with another MLK family member, MLK3, in HCT116 cells. Exogenous expression of MLK4β inhibits activation of MLK3 and also blocks matrix metalloproteinase-9 gelatinase activity and invasion in SKOV3 ovarian cancer cells. Collectively, our data establish MLK4β as a novel suppressor of MLK3 activation, MAPK signaling and cell invasion.

• han11
• hipk2
• map kinase
• mekk1
• scaffold protein

• Adaptor Proteins, Signal Transducing
• Animals
• Caenorhabditis elegans/genetics
• Caenorhabditis elegans/metabolism
• Caenorhabditis elegans Proteins/genetics
• Caenorhabditis elegans Proteins/metabolism
• Carrier Proteins/genetics
• Carrier Proteins/metabolism
• Cell Line
• Cell Line, Tumor
• Cell Proliferation
• Gene Expression Regulation
• Gene Knockdown Techniques
• Humans
• MAP Kinase Kinase Kinase 1/metabolism
• Osmotic Pressure
• Protein Serine-Threonine Kinases/metabolism
• Protein-Tyrosine Kinases/metabolism
• Dyrk Kinases

• Anticarcinogenic Agents/pharmacology
• Calcium/metabolism
• Carcinogens/pharmacology
• Catechin/analogs & derivatives
• Catechin/pharmacology
• Cell Differentiation/drug effects
• Cell Differentiation/physiology
• Cells, Cultured
• Epidermal Cells
• Humans
• Keratinocytes/cytology
• Keratinocytes/enzymology
• MAP Kinase Kinase 3/genetics
• MAP Kinase Kinase 3/metabolism
• MAP Kinase Kinase 6/genetics
• MAP Kinase Kinase 6/metabolism
• MAP Kinase Kinase Kinase 1/genetics
• MAP Kinase Kinase Kinase 1/metabolism
• MAP Kinase Signaling System/drug effects
• MAP Kinase Signaling System/physiology
• Mitogen-Activated Protein Kinase 13/genetics
• Mitogen-Activated Protein Kinase 13/metabolism
• Promoter Regions, Genetic/physiology
• Protein Kinase C/genetics
• Protein Kinase C/metabolism
• Protein Kinase C-delta/genetics
• Protein Kinase C-delta/metabolism
• Protein Precursors/genetics
• RNA, Small Interfering
• Tetradecanoylphorbol Acetate/pharmacology
• Transcription Factor AP-1/metabolism

• P30 CA134274 NCI NIH HHS
• R01 AR046494 NIAMS NIH HHS
• R01 AR046494-01 NIAMS NIH HHS