Gene Summary

Gene:MAPK3; mitogen-activated protein kinase 3
Aliases: ERK1, ERT2, ERK-1, PRKM3, P44ERK1, P44MAPK, HS44KDAP, HUMKER1A, p44-ERK1, p44-MAPK
Summary:The protein encoded by this gene is a member of the MAP kinase family. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act in a signaling cascade that regulates various cellular processes such as proliferation, differentiation, and cell cycle progression in response to a variety of extracellular signals. This kinase is activated by upstream kinases, resulting in its translocation to the nucleus where it phosphorylates nuclear targets. Alternatively spliced transcript variants encoding different protein isoforms have been described. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:mitogen-activated protein kinase 3
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Latest Publications: MAPK3 (cancer-related)

Wu TK, Chen CH, Pan YR, et al.
Cetrimonium Bromide Inhibits Cell Migration and Invasion of Human Hepatic SK-HEP-1 Cells Through Modulating the Canonical and Non-canonical TGF-β Signaling Pathways.
Anticancer Res. 2019; 39(7):3621-3631 [PubMed] Related Publications
BACKGROUND/AIM: Cetrimonium bromide (CTAB), a quaternary ammonium surfactant, is an antiseptic agent against bacteria and fungi. However, the mechanisms by which its pharmacological actions affect epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) cells, such as adenocarcinoma in SK-HEP-1 cells, have not been investigated. We, thereby, investigated whether CTAB inhibits cellular mobility and invasiveness of human hepatic adenocarcinoma in SK-HEP-1 cells.
MATERIALS AND METHODS: SK-HEP-1 cells were treated with CTAB, and subsequent migration and invasion were measured by wound healing and transwell assays. Protein expression was detected by immunoblotting analysis.
RESULTS: Our data revealed that treatment of SK-HEP-1 cells with CTAB altered their mesenchymal spindle-like morphology. CTAB exerted inhibitory effects on the migration and invasion of SK-HEP-1 cells dose-dependently, and reduced protein levels of matrix metalloproteinase-2 (MMP-2), MMP-9, snail, slug, twist, vimentin, fibronectin, N-cadherin, Smad2, Smad3, Smad4, phosphoinositide-3-kinase (PI3K), p-PI3K, Akt, p-Akt, β-catenin, mammalian target of rapamycin (mTOR), p-mTOR, p-p70S6K, p-extracellular signal-regulated kinases (ERK)1/2, p-p38 mitogen-activated protein kinase (MAPK) and p-c-Jun N-terminal kinase (JNK), but increased protein levels of tissue inhibitor matrix metalloproteinase-1 (TIMP-1), TIMP-2, claudin-1 and p-GSK3β. Based on these observations, we suggest that CTAB not only inhibits the canonical transforming growth factor-β (TGF-β) signaling pathway though reducing SMADs (an acronym from the fusion of Caenorhabditis elegans Sma genes and the Drosophila Mad, Mothers against decapentaplegic proteins), but also restrains the non-canonical TGF-β signaling including MAPK pathways like ERK1/2, p38 MAPK, JNK and PI3K.
CONCLUSION: CTAB is involved in the suppression of TGF-β-mediated mesenchymal phenotype and could be a potent medical agent for use in controlling the migration and invasion of hepatic adenocarcinoma.

Jia H, Xu M, Bo Y, et al.
Ras-ERK1/2 signaling accelerates the progression of colorectal cancer via mediation of H2BK5ac.
Life Sci. 2019; 230:89-96 [PubMed] Related Publications
AIMS: Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) is a key downstream gene of Ras pathway. Activation of Ras-ERK1/2 has been testified to be linked to the progression of diverse cancers. Nonetheless, whether Ras-ERK1/2-tumorigenic pathway is mediated by epigenetic factors remains indistinct. The purpose of the research attempted to disclose the functions of H2BK5ac in Ras-ERK1/2-evoked CRC cell phenotypes.
MATERIALS AND METHODS: Western blot assay was implemented for exploration of the relevancy between Ras-ERK1/2 and H2BK5ac. H2BK5Q was established and its functions in cell viability, colony formation and migration were appraised via utilizing MTT, soft-agar colony formation and Transwell assays. The mRNA and transcription of ERK1/2 downstream genes were estimated via RT-qPCR and ChIP assays. HDAC2 functions in SW48 cell phenotypes were evaluated after co-transfection with pEGFP-Ras
KEY FINDINGS: H2BK5ac expression was evidently repressed by Ras-ERK1/2 pathway in SW48 cells. Moreover, Ras-ERK1/2-elevated cell viability, the number of colonies and migration were both impeded by H2BK5ac. The mRNA and transcriptions of CYR61, IGFBP3, WNT16B, NT5E, GDF15 and CARD16 were both mediated by H2BK5ac. Additionally, HDAC2 silence overtly recovered H2BK5ac expression inhibited by Ras-ERK1/2, meanwhile abated Ras-ERK1/2-affected SW48 cell phenotypes. Beyond that, restrained H2BK5ac induced by Ras-ERK1/2 was concerned with MDM2-mediated ATF2 degradation.
SIGNIFICANCE: These investigations testified that Ras-ERK1/2 pathway affected SW48 cell phenotypes through repressing H2BK5ac expression. Otherwise, declined H2BK5ac might be linked to MDM2-mediated ATF2 degradation.

Pires LV, Yi Y, Cheng JC, et al.
Lapatinib Inhibits Amphiregulin-induced BeWo Choriocarcinoma Cell Proliferation by Reducing ERK1/2 and AKT Signaling Pathways.
Anticancer Res. 2019; 39(5):2377-2383 [PubMed] Related Publications
BACKGROUND: Human choriocarcinoma is the most aggressive type of gestational trophoblastic neoplasia. The expression of epidermal growth factor receptor (EGFR) in choriocarcinomas is significantly higher than those of trophoblastic cells in healthy placentas. Lapatinib is a potent EGFR and human epidermal growth factor receptor 2 (HER2) inhibitor that inhibits cell proliferation and induces apoptosis in various human cancer cells. Amphiregulin (AREG) is the most abundant EGFR ligand in amniotic fluid during human pregnancy.
AIM: To explore the role of AREG in human choriocarcinoma cell proliferation.
MATERIALS AND METHODS: The effect of lapatinib and AREG on cell proliferation was examined by the MTT assay. Western blots were used to investigate EGFR and HER2 expression, and the activation of caspase-3, extracellular signal-regulated kinases 1/2 (ERK1/2) and phosphatidylinositol 3-kinase /protein kinase B (PI3K/AKT) signaling pathways.
RESULTS: Treatment with lapatinib reduced BeWo cell proliferation by inducing apoptosis. Moreover, AREG treatment stimulated BeWo cell proliferation by activating ERK1/2 and PI3K/AKT signaling pathways, which was blocked by lapatinib.
CONCLUSION: Targeting EGFR/HER2 might be a useful therapeutic strategy for human choriocarcinoma.

Lupinacci FCS, Kuasne H, Roffé M, et al.
Polysome Profiling of a Human Glioblastoma Reveals Intratumoral Heterogeneity.
Int J Mol Sci. 2019; 20(9) [PubMed] Free Access to Full Article Related Publications
Glioblastoma (GBM) is one of the most aggressive cancers, with median survival of less than 2 years. Despite of considerable advance in molecular classification of GBMs, no improvements in therapy have been described. The scenario is further complicated by tumor heterogeneity and the relationship among genetic, transcriptional and functional findings. Classically, gene expression has been evaluated by steady-state mRNA, however, this does not take translational control into consideration, which contributes considerably to the composition of the proteome. In this study, we evaluated the transcriptomic and translatomic signature of a GBM obtained from a single patient focusing in tumor heterogeneity. In a sampling of eight fragments, we investigated the translation rates, mTORC1 and ERK1/2 pathways and identified both total and polysome associated mRNAs. An increased translation rate was observed in fragments with high-grade histological features. High-grade histology was also associated with the expression of genes related to extracellular matrix (ECM) and angiogenesis, in both transcriptomes and translatomes. However, genes associated with epithelial to mesenchymal transition and stress response, were observed only in translatomes from high-grade fragments. Overall, our results demonstrate that isolation of translated mRNA can be used to identify biomarkers and reveal previously unrecognized determinants of heterogeneity in GBMs.

Sale MJ, Balmanno K, Saxena J, et al.
MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAF
Nat Commun. 2019; 10(1):2030 [PubMed] Free Access to Full Article Related Publications
Acquired resistance to MEK1/2 inhibitors (MEKi) arises through amplification of BRAF

Cai G, Yu W, Song D, et al.
Discovery of fluorescent coumarin-benzo[b]thiophene 1, 1-dioxide conjugates as mitochondria-targeting antitumor STAT3 inhibitors.
Eur J Med Chem. 2019; 174:236-251 [PubMed] Related Publications
STAT3 has been extensively studied as a potential antitumor target. Though studies on regulating STAT3 mainly focus on the inhibition of STAT3 phosphorylation at Tyr705 residue, the phosphorylation at Ser727 residue of STAT3 protein is also closely associated with the mitochondrial import of STAT3 protein. N, N-diethyl-7-aminocoumarin is a fluorescent mitochondria-targeting probe. In this study, a series of STAT3 inhibitors were developed by connecting N, N-diethyl-7-aminocoumarin fluorophore with benzo [b]thiophene 1, 1-dioxide moiety. All designed compounds displayed potent anti-proliferative activity against cancer cells. The representative compound 7a was mainly accumulated in mitochondria visualized by its fluorescence. STAT3 phosphorylation was inhibited by compound 7a at both Tyr705 and Ser727 residues. Compound 7a inhibited STAT3 phosphorylation whereas had no influence on the phosphorylation levels of STAT1, JAK2, Src and Erk1/2, indicating good selectivity of compound 7a. Moreover, compound 7a down-regulated the expression of STAT3 target genes Bcl-2 and Cyclin D1, increased ROS production and remarkably reduced the mitochondrial membrane potential to induce mitochondrial apoptotic pathway. Furthermore, compound 7ain vivo suppressed breast cancer 4T1 implanted tumor growth. Taken together, these results highlighted that compound 7a might be a promising mitochondria-targeting STAT3 inhibitor for cancer therapy.

Moncho-Amor V, Pintado-Berninches L, Ibañez de Cáceres I, et al.
Role of Dusp6 Phosphatase as a Tumor Suppressor in Non-Small Cell Lung Cancer.
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications
DUSP6/MKP3 is a dual-specific phosphatase that regulates extracellular regulated kinase ERK1/2 and ERK5 activity, with an increasingly recognized role as tumor suppressor. In silico studies from Gene expression Omnibus (GEO) and Cancer Genome atlas (TCGA) databases reveal poor prognosis in those Non-small cell lung cancer (NSCLC) patients with low expression levels of

Zhang Q, Lu S, Li T, et al.
ACE2 inhibits breast cancer angiogenesis via suppressing the VEGFa/VEGFR2/ERK pathway.
J Exp Clin Cancer Res. 2019; 38(1):173 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Breast cancer angiogenesis is key for metastasis and predicts a poor prognosis. Angiotensin-converting enzyme 2 (ACE2), as a member of the renin-angiotensin system (RAS), was reported to restrain the progression of hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC) through inhibiting angiogenesis. However, the relationship between ACE2 and breast cancer angiogenesis remains unclear.
METHODS: The prognosis and relative gene selection were analysed using the GEPIA, GEO, TCGA and STRING databases. ACE2 expression in breast cancer tissue was estimated by reverse transcription-quantitative polymerase chain reaction (qPCR). Breast cancer cell migration, proliferation and angiogenesis were assessed by Transwell migration, proliferation, tube formation, and wound healing assays. The expression of vascular endothelial growth factor A (VEGFa) was detected by qPCR and Western blotting. The phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), mitogen-activated protein kinase 1/2 (MEK1/2), and extracellular signal-regulated protein kinase 1/2 (ERK1/2) was examined by Western blotting. Breast cancer metastasis and angiogenesis in vivo were measured using a zebrafish model.
RESULTS: ACE2 was downregulated in breast cancer patients. Patients with higher ACE2 expression had longer relapse-free survival (RFS). In vitro, ACE2 inhibited breast cancer migration. Meanwhile, ACE2 in breast cancer cells inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, tube formation and migration. In the zebrafish model, ACE2 inhibited breast cancer cell metastasis, as demonstrated by analyses of the number of disseminated foci and the metastatic distance. Neo-angiogenesis was also decreased by ACE2. ACE2 downregulated the expression of VEGFa in breast cancer cells. Furthermore, ACE2 in breast cancer cells inactivated the phosphorylation of VEGFR2, MEK1/2, and ERK1/2 in HUVECs.
CONCLUSIONS: Our findings suggest that ACE2, as a potential resister to breast cancer, might inhibit breast cancer angiogenesis through the VEGFa/VEGFR2/ERK pathway.
TRIAL REGISTRATION: Retrospectively registered.

Tang Y, Yang S, Wang M, et al.
Epigenetically altered miR‑193a‑3p promotes HER2 positive breast cancer aggressiveness by targeting GRB7.
Int J Mol Med. 2019; 43(6):2352-2360 [PubMed] Free Access to Full Article Related Publications
Emerging evidence has demonstrated that microRNAs (miRNAs/miRs) have various biological functions in the development of human epidermal growth factor receptor 2 (HER2) positive breast cancer. The aim of the present study is to reveal the mechanism of miR‑193a‑3p inhibiting the progress of HER2 positive breast cancer. The expression of miR‑193a‑3p was evaluated by quantitative polymerase chain reaction (PCR). The methylation status of miR‑193a‑3p was evaluated by PCR and pyrosequencing analysis. Overexpression of miR‑193a‑3p and growth factor receptor bound protein 7 (GRB7) combined with in vitro tumorigenic assays were conducted to determine the carcinostatic capacities of miR‑193a‑3p in HER2 positive breast cancer cells. The association between miR‑193a‑3p and GRB7 was determined by luciferase reporter assay. Protein level was evaluated using western blot analysis. miR‑193a‑3p was downregulated in HER2 positive breast cancer cells and clinical tissues. Methylation‑mediated silencing led to decreased expression of miR‑193a‑3p in HER2 positive breast cancer. Overexpression of miR‑193a‑3p could inhibit proliferation, migration and invasion of breast cancer cells. Overexpression of GRB7 could abolish this effect. miR‑193a‑3p could directly target the 3' untranslated region of GRB7. miR‑193a‑3p could directly or indirectly target extracellular signal‑regulated kinase 1/2 (ERK1/2) and forkhead box M1 (FOXM1) signaling. In conclusion, it was identified that silencing of miR‑193a‑3p through hypermethylation can promote HER2 positive breast cancer progress by targeting GRB7, ERK1/2 and FOXM1 signaling. The function of miR‑193a‑3p in HER2 positive breast cancer implicates its potential application in therapy.

Chen L, Liu YC, Zheng YY, et al.
Furanodienone overcomes temozolomide resistance in glioblastoma through the downregulation of CSPG4-Akt-ERK signalling by inhibiting EGR1-dependent transcription.
Phytother Res. 2019; 33(6):1736-1747 [PubMed] Related Publications
Glioblastoma multiforme (GBM) is a highly aggressive type of brain tumour. Patients with GBM respond poorly to chemotherapy and have poor survival outcomes. Neuron-glial antigen 2 (NG2), also known as chondroitin sulphate proteoglycan 4 (CSPG4), has been shown to contribute to critical processes, such as cell survival, proliferation, and chemotherapy resistance, during glioma progression. In this study, we found that furanodienone (FUR), a diene-type sesquiterpene isolated from the rhizomes of Rhizoma curcumae, exhibited a potential cytotoxic effect on temozolomide (TMZ)-resistant GBM cells in vitro by inhibiting CSPG4 and related signalling pathways. Studies investigating the mechanism demonstrated that FUR suppressed CSPG4-Akt-ERK signalling, inflammatory responses, and cytokine levels but activated caspase-dependent pathways and mitochondrial dysfunction. Furthermore, an immunofluorescence assay and a dual-luciferase reporter assay revealed that inhibition of EGR1-mediated transcription might have contributed to the FUR-dependent blockade of CSPG4 signalling and glioma cell survival. These results established a link between FUR-induced CSPG4 inhibition and the suppression of EGR1-dependent transcription. Attenuation of ERK1/2 and cytokine signalling might have generated the EGR1-dependent negative feedback loop of the CSPG4 pathway during FUR-induced apoptosis. These findings suggested that FUR could be a therapeutic candidate for the treatment of malignant glioma via targeting CSPG4 signalling.

Chapman EM, Lant B, Ohashi Y, et al.
A conserved CCM complex promotes apoptosis non-autonomously by regulating zinc homeostasis.
Nat Commun. 2019; 10(1):1791 [PubMed] Free Access to Full Article Related Publications
Apoptotic death of cells damaged by genotoxic stress requires regulatory input from surrounding tissues. The C. elegans scaffold protein KRI-1, ortholog of mammalian KRIT1/CCM1, permits DNA damage-induced apoptosis of cells in the germline by an unknown cell non-autonomous mechanism. We reveal that KRI-1 exists in a complex with CCM-2 in the intestine to negatively regulate the ERK-5/MAPK pathway. This allows the KLF-3 transcription factor to facilitate expression of the SLC39 zinc transporter gene zipt-2.3, which functions to sequester zinc in the intestine. Ablation of KRI-1 results in reduced zinc sequestration in the intestine, inhibition of IR-induced MPK-1/ERK1 activation, and apoptosis in the germline. Zinc localization is also perturbed in the vasculature of krit1

Chen M, Xu M, Zhu C, et al.
Sirtuin2 enhances the tumoricidal function of liver natural killer cells in a mouse hepatocellular carcinoma model.
Cancer Immunol Immunother. 2019; 68(6):961-971 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is the third most lethal cancer in the world. Natural killer (NK) cell-mediated immunity is crucial for tumor surveillance and therapy. Characterization of the regulatory mechanisms of NK cell function is important for developing novel immunotherapies against HCC. In this study, we used a chemical-induced mouse HCC model to identify the upregulation of Sirtuin2 (SIRT2) in liver NK cells. In particular, SIRT2 was predominantly expressed in liver CD94

Zhang J, Hou L, Liang R, et al.
CircDLST promotes the tumorigenesis and metastasis of gastric cancer by sponging miR-502-5p and activating the NRAS/MEK1/ERK1/2 signaling.
Mol Cancer. 2019; 18(1):80 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Accumulating evidence shows that, the dysregulation of circular RNAs (circRNAs) is associated with the progression of multiple malignancies. But, the underlying mechanisms by which has_circ_0032627 (circDLST) contributed to gastric cancer (GC) remain undocumented.
METHODS: The expression and cellular localization of circDLST and its association with clinicopathological characteristics and prognosis in patients with GC was analysed by using fluorescence in situ hybridization. Gain- and loss-of-function experiments as well as a subcutaneous xenograft tumor model and a liver metastasis model from orthotopic implantation of GC tissues were conducted to assess the role of circDLST in GC cells. CircDLST specific binding with miR-502-5p was confirmed by dual luciferase gene report, RNA immunoprecipitation (RIP) assays and RIP-miRNA expression profiling. qRT-PCR and Western blot analysis was used to detect the effects of circDLST on miR-502-5p-mediated NRAS/MEK1/ERK1/2 signaling in GC cells.
RESULTS: The expression levels of circDLST were dramatically elevated in GC tissues as compared with the adjacent normal tissues, and acted as an independent prognostic factor of poor survival in patients with GC. Knockdown of circDLST inhibited the cell viability, colony formation, DNA synthesis, cell invasion and liver metastasis in vitro and in vivo, whereas overexpression of circDLST had the opposite effects. Furthermore, circDLST was co-localized with miR-502-5p in the cytoplasm of GC cells, and acted as a sponge of miR-502-3p in GC cells, which abrogated the tumor promoting effects of circDLST by inactivating the NRAS/MEK1/ERK1/2 signaling in GC cells.
CONCLUSION: CircDLST promotes the tumorigenesis and metastasis of GC cells by sponging miR-502-5p to activate the NRAS/MEK1/ERK1/2 signaling.

Zhou F, Liu X, Gao L, et al.
HIV-1 Tat enhances purinergic P2Y4 receptor signaling to mediate inflammatory cytokine production and neuronal damage via PI3K/Akt and ERK MAPK pathways.
J Neuroinflammation. 2019; 16(1):71 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: HIV-associated neurocognitive disorders (HANDs) afflict more than half of HIV-1-positive individuals. The transactivator of transcription (Tat) produced by HIV virus elicits inflammatory process and is a major neurotoxic mediator that induce neuron damage during HAND pathogenesis. Activated astrocytes are important cells involved in neuroinflammation and neuronal damage. Purinergic receptors expressed in astrocytes participate in a positive feedback loop in virus-induced neurotoxicity. Here, we investigated that whether P2Y4R, a P2Y receptor subtype, that expressed in astrocyte participates in Tat-induced neuronal death in vitro and in vivo.
METHODS: Soluble Tat protein was performed to determine the expression of P2Y4R and proinflammatory cytokines in astrocytes using siRNA technique via real-time PCR, Western blot, and immunofluorescence assays. Cytometric bead array was used to measure proinflammatory cytokine release. The TUNEL staining and MTT cell viability assay were analyzed for HT22 cell apoptosis and viability, and the ApopTag® peroxidase in situ apoptosis detection kit and cresyl violet staining for apoptosis and death of hippocampal neuron in vivo.
RESULTS: We found that Tat challenge increased the expression of P2Y4R in astrocytes. P2Y4R signaling in astrocytes was involved in Tat-induced inflammatory cytokine production via PI3K/Akt- and ERK1/2-dependent pathways. Knockdown of P2Y4R expression significantly reduced inflammatory cytokine production and relieved Tat-mediated neuronal apoptosis in vitro. Furthermore, in vivo challenged with Tat, P2Y4R knockdown mice showed decreased inflammation and neuronal damage, especially in hippocampal CA1 region.
CONCLUSIONS: Our data provide novel insights into astrocyte-mediated neuron damage during HIV-1 infection and suggest a potential therapeutic target for HANDs.

Wei Y, Wang F, Sang B, et al.
Activation of KRas-ERK1/2 signaling drives the initiation and progression of glioma by suppressing the acetylation of histone H4 at lysine 16.
Life Sci. 2019; 225:55-63 [PubMed] Related Publications
BACKGROUND/AIMS: Acetylation of H4 at lysine 16 (H4K16ac) has been well-characterized as an acetylated mark, and the expression of which is closely associated with the tumorigenesis of human cancers. This study aimed to reveal whether KRas mutation drives the initiation and progression of glioma via modulation of H4 acetylation.
METHODS: Changes of H4K16 acetylation in human glioblastoma A172 cells following transfection with a plasmid for expression of mutant KRas were tested by western blot analysis. MTT assay, transwell assay, soft-agar colony formation assay, RT-PCR and chromatin immunoprecipitation were carried out to evaluate the effect of H4K16ac on A172 cells growth and migration. Furthermore, the enzymes participating in the deacetylation of H4K16ac were studied by using RT-PCR and western blot analysis.
RESULTS: H4K16ac was found to be deacetylated by KRas-ERK1/2 activation. H4K16Q (a plasmid for mimicking H4K16ac) repressed A172 cells viability, colony formation, and migratory capacity. Besides, H4K16ac was capable of regulating the transcription of several ERK1/2 pathway downstream genes. KRas-ERK1/2 signaling repressed H4 acetylation at K16 via modulation of a histone deacetylase Sirt2, as well as a histone acetyl-transferase TIP60. Moreover, KRas-ERK1/2 inhibited TIP60 via an MDM2-dependnet fashion.
CONCLUSION: Our results suggest that activation of KRas-ERK1/2 signaling participates in the onset and progression of glioma at least partially through modulating acetylation of H4 at K16. KRas-ERK1/2 signaling mediates the acetylation of H4K16 via Sirt2 and MDM2-dependnet degeneration of TIP60.

Ye DM, Ye SC, Yu SQ, et al.
Drug-resistance reversal in colorectal cancer cells by destruction of flotillins, the key lipid rafts proteins.
Neoplasma. 2019; 2019:576-583 [PubMed] Related Publications
Multi-drug resistance (MDR) of tumor cells attenuates the efficacy of anticancer drugs and has become the main reason for chemotherapy failure. It is indispensable to establish an effective way to reverse multi-drug resistance. Our previous work has shown that down-regulation of the ERK/MAPK signaling pathway activity can reverse the drug-resistance of resistant cells. Further-more, the effect of signal transduction is strongly associated with lipid rafts. The drug-resistance is reversed successfully after lipid rafts are destroyed by heptakis(2, 6-di-O-methyl)-β-cyclodextrin (MβCD). However, the reversal of the drug-resistance is not associated with down-regulation of the expression of ERK1/2. Cell membrane permeability may increase when lipid rafts are destroyed by MβCD, causing the reversal of drug-resistance due to an increase in accumulation of the drugs in the cytoplasm. To minimize the influence of MβCD on the cell membrane structure, we selected flotillin, a marker protein of lipid rafts, as the target molecule, to further investigate the mechanism of changes in drug resistance after destruction of the lipid rafts. The effect of flotillin on the reversal of the drug resistance was examined using an RNA interference (RNAi) in a retrovirus system in human drug-resistant strains of colorectal cancer cell line HCT-15. The results demonstrate that flotillin-1 downregulation by RNAi (Flot1-RNAi) reduced the drug resistance, caused cell cycle arrest and decreased the expression of ERK1/2; however, apoptosis was not significantly affected. Knockdown of flotillin-2 by RNAi (Flot2-RNAi) had effects similar to those of Flot1-RNAi except that the effects on expression of ERK1/2 and apoptosis were different. Screening of multiple pathways indicated that the PI3K/Akt signaling pathway was closely related. This experiment demonstrates the association between PI3K and drug resistance through the activation of PI3K and suggests that PI3K may play a key role during the development of resistance in CRC. The results reveal that the levels of IRS-1 and PI3K proteins in the Flot1-RNAi and Flot2-RNAi groups were significantly down-regulated. Knockdown of flotillins by RNAi reduced the resistance of HCT-15/ADM cells; the results investigations of the Akt pathway indicate a decrease in resistance after lipid raft destruction. These data confirm that knockdown of flotillin reduces the resistance of HCT-15/ADM cells, and the mechanism may be relevant to the PI3K/Akt pathway. Additionally, flotillin may be used as a potential target for chemotherapy in the treatment of colorectal cancer.

Zhang J, Liu M, Liu W, Wang W
Ras-ERK1/2 signalling promotes the development of osteosarcoma through regulation of H4K12ac through HAT1.
Artif Cells Nanomed Biotechnol. 2019; 47(1):1207-1215 [PubMed] Related Publications
Histone H4 acetylation at lysine 12 (H4K12ac) has been reported to be associated with the poor prognosis of pancreatic cancer. The study intends to study whether H4K12ac participates in regulating the carcinogenic effect of Ras-ERK1/2 on osteosarcoma (OS). The plasmids of pEGFP-N1, pEGFP-Ras

Baruah MM, Sharma N
In silico identification of key genes and signaling pathways targeted by a panel of signature microRNAs in prostate cancer.
Med Oncol. 2019; 36(5):43 [PubMed] Related Publications
Accumulating evidence have suggested that some microRNAs are aberrantly expressed in prostate cancer. In our previous work, we had identified a panel of four differentially expressed microRNAs in prostate cancer. In the present study, we have investigated common molecular targets of this panel of miRNAs (DEMs) and key hub genes that can serve as potential candidate biomarkers in the pathogenesis and progression of prostate cancer. A joint bioinformatics approach was employed to identify differentially expressed genes (DEGs) in prostate cancer. Gene enrichment analysis followed by the protein-protein interaction (PPI) network construction and selection of hub genes was further performed using String and Cytoscape, respectively. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the identified hub genes was conducted using the Database for Annotation, Visualization and Integrated Discovery (DAVID) tool. In total, 496 genes were identified to be common targets of DEMs in prostate cancer and 13 key hub genes were identified from three modules of the PPI network of the DEGs. Further top five genes viz Rhoa, PI3KCA, CDC42, MAPK3, TP53 were used for Enrichment analysis which revealed their association with vital cellular and functional pathways in prostate cancer indicating their potential as candidate biomarkers in prostate cancer.

Wu J, Tang Q, Ren X, et al.
Reciprocal interaction of HOTAIR and SP1 together enhance the ability of Xiaoji decoction and gefitinib to inhibit EP4 expression.
J Ethnopharmacol. 2019; 237:128-140 [PubMed] Related Publications
ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese herbal prescription Xiaoji decoction (XJD) has long been used for cancer treatment. However, the molecular mechanisms underlying the effects of this medicine, particularly to enhance the efficiency of EGFR-TKI in the treatment of lung cancer have not been well elucidated.
MATERIALS AND METHODS: Cell viability and cell cycle distribution were detected by MTT assay and flow cytometry, respectively. The phosphorylation of ERK1/2 and protein levels of SP1 and EP4 were determined by Western blot. The expression of the HOX transcript antisense RNA (HOTAIR) was measured by qRT-PCR. Transient transfection experiments were used to overexpress the HOTAIR, SP1 and EP4 genes. The interaction between HOTAIR and SP1 were further examined via RNA immunoprecipitation (RIP) assay. A tumor xenograft model was used to confirm the in vitro findings.
RESULTS: We showed that XJD inhibited growth and induced cell arrest of human non-small cell lung cancer (NSCLC) cells. We also found that XJD increased the phosphorylation of ERK1/2 and inhibited levels of HOTAIR and SP1, EP4 proteins, which were blocked by inhibitor of MEK/ERK. There was reciprocal interaction between HOTAIR and SP1. Silencing of HOTAIR reduced EP4 protein levels and repressed the growth of NSCLC cells, while overexpression of HOTAIR and SP1 overcame XJD-reduced EP4 protein expression. Additionally, excessive expressed EP4 reversed the effect of XJD on cell growth. Importantly, there was synergy of XJD with another cancer treatment drug, EGFR-TKI gefitinib, in this process. We also found that XJD inhibited tumor growth in a xenograft nude mice model.
CONCLUSIONS: Our results show that XJD inhibits NSCLC cell growth via ERK1/2-mediated reciprocal repression of HOTAIR and SP1 protein expression, followed by reduced EP4 gene expression. XJD and gefitinib exhibit synergy in this process. The in vitro and in vivo study provides a novel mechanism by which XJD enhances the growth inhibitory effect of gefitinib in gefitinib-resistant NSCLC cells.

Wang Z, Shen J, Sun W, et al.
Antitumor activity of Raddeanin A is mediated by Jun amino-terminal kinase activation and signal transducer and activator of transcription 3 inhibition in human osteosarcoma.
Cancer Sci. 2019; 110(5):1746-1759 [PubMed] Free Access to Full Article Related Publications
Osteosarcoma is the most common primary malignant bone tumor. Raddeanin A (RA) is an active oleanane-type triterpenoid saponin extracted from the traditional Chinese herb Anemone raddeana Regel that exerts antitumor activity against several cancer types. However, the effect of RA on osteosarcoma remains unclear. In the present study, we showed that RA inhibited proliferation and induced apoptosis of osteosarcoma cells in a dose- and time-dependent way in vitro and in vivo. RA treatment resulted in excessive reactive oxygen species (ROS) generation and JNK and ERK1/2 activation. Apoptosis induction was evaluated by the activation of caspase-3, caspase-8, and caspase-9 and poly-ADP ribose polymerase (PARP) cleavage. RA-induced cell death was significantly restored by the ROS scavenger glutathione (GSH), the pharmacological inhibitor of JNK SP600125, or specific JNK knockdown by shRNA. Additionally, signal transducer and activator of transcription 3 (STAT3) activation was suppressed by RA in human osteosarcoma, and this suppression was restored by GSH, SP600125, and JNK-shRNA. Further investigation showed that STAT3 phosphorylation was increased after JNK knockdown. In a tibial xenograft tumor model, RA induced osteosarcoma apoptosis and notably inhibited tumor growth. Taken together, our results show that RA suppresses proliferation and induces apoptosis by modulating the JNK/c-Jun and STAT3 signaling pathways in human osteosarcoma. Therefore, RA may be a promising candidate antitumor drug for osteosarcoma intervention.

Liu Z, Jiang L, Li Y, et al.
Cyclosporine A sensitizes lung cancer cells to crizotinib through inhibition of the Ca2
EBioMedicine. 2019; 42:326-339 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Crizotinib has potent anti-tumor activity in patients with advanced MET-amplified non-small cell lung cancer (NSCLC). However, the therapeutic effect is still not satisfying. Thus, developing approaches that improve the efficacy of crizotinib remains a significant challenge.
METHODS: MET-amplified NSCLC cell lines were treated with crizotinib and cyclosporine A (CsA). Cell viability was determined by MTS assay. The changes of apoptosis, cell cycle and calcineurin-Erk pathways were assessed by western blot. Xenograft mouse model, primary human NSCLC cells and hollow fiber assays were utilized to confirm the effects of CsA.
FINDINGS: We demonstrated that CsA significantly increased the anti-tumor effect of crizotinib on multiple MET-amplified NSCLC cells in vitro and in vivo. Mechanistically, crizotinib treatment led to the activation of Ca
INTERPRETATION: This study provides preclinical evidences that combination therapy of CsA and crizotinib is a promising approach for targeted treatment of MET-amplified lung cancer patients. FUND: This work was supported by the National Natural Science Foundation of China, the Key Projects of Natural Foundation of Zhejiang Province, the Ten thousand plan youth talent support program of Zhejiang Province, the Zhejiang Natural Sciences Foundation Grant, and the Zhejiang medical innovative discipline construction project-2016.

Hsu FS, Wu JT, Lin JY, et al.
Histone Deacetylase Inhibitor, Trichostatin A, Synergistically Enhances Paclitaxel-Induced Cytotoxicity in Urothelial Carcinoma Cells by Suppressing the ERK Pathway.
Int J Mol Sci. 2019; 20(5) [PubMed] Free Access to Full Article Related Publications
Trichostatin A (TSA), an antifungal antibiotic derived from

Zhang Y, Xiao Y, Dong Q, et al.
Neferine in the Lotus Plumule Potentiates the Antitumor Effect of Imatinib in Primary Chronic Myeloid Leukemia Cells In Vitro.
J Food Sci. 2019; 84(4):904-910 [PubMed] Related Publications
Imatinib, the prototype BCR-ABL tyrosine kinase inhibitor (TKI), is the first-line treatment for Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase. However, a subgroup of patients exhibit poor response or experience relapse. This issue may be overcome by combination therapy using natural compounds. Neferine, a major bisbenzylisoquinoline alkaloid extracted from "lotus plumule" (seed embryo of lotus) commonly used in traditional Chinese medicine and tea, was used herein in the combination treatment of CML. The MTT assay showed that neferine exerted cytotoxicity in primary CML cells in a dose-dependent manner. Moreover, low concentrations of neferine (4 and 8 µM) sensitized primary CML cells to imatinib (CI < 1), and significantly decreased its IC

Fu R, Wang X, Hu Y, et al.
Solamargine inhibits gastric cancer progression by regulating the expression of lncNEAT1_2 via the MAPK signaling pathway.
Int J Oncol. 2019; 54(5):1545-1554 [PubMed] Free Access to Full Article Related Publications
Solamargine, a derivative from the steroidal solasodine in Solanum species, has exhibited anticancer activities in numerous types of cancer; however, its role in gastric cancer (GC) remains unknown. In the present study, it was demonstrated that Solamargine suppressed the viability of five gastric cancer cell lines in a dose‑dependent manner and induced notable alterations in morphology. Treatment with Solamargine promoted cell apoptosis (P<0.01). Solamargine increased the expression of long noncoding RNA (lnc) p53 induced transcript and lnc nuclear paraspeckle assembly transcript 1 (NEAT1)_2 (P<0.01) in GC by reducing the phosphorylation of extracellular signal‑regulated kinase (Erk)1/2 mitogen‑activated protein kinase (MAPK). To gain insight into the potential mechanism, an Erk1/2 inhibitor (U0126) was applied. The results revealed that lncNEAT1_2 expression levels increased, which was consistent with the effects of Solamargine. Downregulation of lncNEAT1_2 in GC cells revealed no effect on the expression levels of total Erk1/2 and, and counteracted the effect of Solamargine. Solamargine was observed to increase the expression of lncNEAT1_2 via the Erk1/2 MAPK signaling pathway. Of note, the knockdown of lncNEAT1_2 reduced the inhibitory effect of Solamargine (P<0.05). Additionally, experiments in vivo and in primary GC cells from patients demonstrated that Solamargine significantly suppressed tumor growth (P<0.05). In vivo analysis of a xenograft mouse model further supported that Solamargine could induce the apoptosis of cancer cells in tumor tissue as observed by a terminal deoxynucleotidyl transferase‑mediated dUTP‑biotin nick end labeling and H&E staining (P<0.05). Experiments in primary GC cells from patients verified the anti‑tumor effect of Solamargine. In summary, the findings of the present study indicated that Solamargine inhibited the progression of GC by regulating lncNeat1_2 via the MAPK pathway.

Ko YC, Hu CY, Liu ZH, et al.
Int J Mol Sci. 2019; 20(5) [PubMed] Free Access to Full Article Related Publications
Internal tandem duplication of FLT3 juxtamembrane domain (FLT3-ITD)-positive acute myeloid leukemia (AML) leads to poor clinical outcomes after chemotherapy. We aimed to establish a cytarabine-resistant line from

Sawayama H, Ogata Y, Ishimoto T, et al.
Glucose transporter 1 regulates the proliferation and cisplatin sensitivity of esophageal cancer.
Cancer Sci. 2019; 110(5):1705-1714 [PubMed] Free Access to Full Article Related Publications
Glucose transporter 1 (GLUT1) expression is a prognostic marker for esophageal squamous cell carcinoma (ESCC). Recent work on GLUT1 and development of specific inhibitors supports the feasibility of GLUT1 inhibition as a treatment for various cancers. The anti-proliferative effects of GLUT1-specific small interfering RNA (siRNA) and a GLUT1 inhibitor were evaluated in ESCC cell lines. Expression of pro-proliferative and anti-proliferative signaling and effector molecules was examined by western blotting and quantitative RT-PCR. GLUT1 expression in pretreatment clinical biopsy samples was measured by immunohistochemistry and correlated with various clinicopathological parameters and response to chemotherapy. The reduction in standardized uptake value (SUV) of

Kang M, Park SH, Park SJ, et al.
p44/42 MAPK signaling is a prime target activated by phenylethyl resorcinol in its anti-melanogenic action.
Phytomedicine. 2019; 58:152877 [PubMed] Related Publications
BACKGROUND: Melanin plays a crucial role in protecting human skin against exposure to ultraviolet (UV) radiation. However, its overproduction induces hyperpigmentation disorders of the skin.
PURPOSE: To investigate effects of phenylethyl resorcinol as one resorcinol derivative on melanogenesis and its mechanisms using B16F10 mouse melanoma cells and human epidermal melanocytes.
METHODS: Effects of phenylethyl resorcinol on melanogenesis and its mechanism of action were examined using several in vitro assays (i.e., cell survival, melanin content, cellular tyrosinase activity, real-time PCR analysis, luciferase-reporter assay, Western blot analysis, and ELISAs for cyclic AMP (cAMP), protein kinase A (PKA), cAMP response element binding (CREB) protein, and mitogen-activated protein kinases (MAPKs)).
RESULTS: Phenylethyl resorcinol reduced both melanin content and tyrosinase activity in these cells. Phenylethyl resorcinol also suppressed tyrosinase activity in cell-free tyrosinase enzyme assay. Although phenylethyl resorcinol decreased mRNA levels of tyrosinase and tyrosinase-related protein (TRP)-2, it did not affect mRNA levels of melanogenic gene microphthalmia-associated transcriptional factor (MITF) or TRP-1. Phenylethyl resorcinol had no effects on cAMP signaling or NF-κB signaling based on results of cyclic AMP response element (CRE)-luciferase reporter assay, cAMP production, protein kinase A (PKA) activity, Western blot assays for phosphorylated CRE-binding protein (CREB), NF-κB-luciferase reporter assay, and Western blot assays for phosphorylated NF-κB. However, phenylethyl resorcinol induced activation of activator protein-1 (AP-1) signaling. Specifically, phenylethyl resorcinol increased AP-1 reporter activity and increased phosphorylation of p44/42 MAPK, but not p38 MAPK or c-Jun N-terminal kinase (JNK). MEK1/2 and Src, upstream molecules of p44/42 MAPK were also phosphorylated by phenylethyl resorcinol. In addition, phenylethyl resorcinol-induced decreases in melanin content, tyrosinase activity, and MITF protein levels were attenuated by PD98059, a p44/42 MAPK inhibitor.
CONCLUSION: These data indicate that the anti-melanogenic activity of phenylethyl resorcinol is mediated by activation of p44/42 MAPK, indicating that phenylethyl resorcinol may be a potential therapeutic agent for treating hyperpigmentation skin disorders.

Wang Y, Sun L, Luo Y, He S
Knockdown of KDM1B inhibits cell proliferation and induces apoptosis of pancreatic cancer cells.
Pathol Res Pract. 2019; 215(5):1054-1060 [PubMed] Related Publications
Pancreatic cancer (PC) is one of the common malignant tumors in digestive tract with a high fatality rate. The oncogenic role of lysine-specific demethylase1 (LSD1/KDM1 A) has been well recognized in PC. While, the role of its homolog LSD2 (KDM1B) in regulating PC progression is poorly understood. In this study, we attempted to evaluate the functional role of KDM1B in PC cells. The expression of KDM1B was detected by immunohistochemistry and immunoblotting in PC tissues and cells. Lentivirus-mediated shRNA was applied to silence KDM1B in PANC-1 and SW1990 cells. Cell proliferation was measured by MTT and Celigo assay. Cell apoptosis was determined by both Caspase-Glo

Xu W, Qian J, Zeng F, et al.
Protein kinase Ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironment.
J Exp Clin Cancer Res. 2019; 38(1):114 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mast cells are being increasingly recognized as critical components in the tumor microenvironment. Protein Kinase D (PKD) is essential for the progression of prostate cancer, but its role in prostate cancer microenvironment remains poorly understood.
METHODS: The expression of PKD, mast cells and microvessel density were examined by IHC. The clinical significance was determined by statistical analyses. The biological function of PKD and the underlying mechanisms were investigated using in vitro and in vivo models.
RESULTS: PKD2/3 contributed to MCs recruitment and tumor angiogenesis in the prostate cancer microenvironment. Clinical data showed that increased activation of PKD at Ser744/748 in prostate cancer was correlated with mast cell infiltration and microvascular density. PKD2/3 silencing of prostate cancer cells markedly decreased MCs migration and tube formation of HUVEC cells. Moreover, PKD2/3 depletion not only reduced SCF, CCL5 and CCL11 expression in prostate cancer cells but also inhibited angiogenic factors in MCs. Conversely, exogenous SCF, CCL5 and CCL11 reversed the effect on MCs migration inhibited by PKD2/3 silencing. Mechanistically, PKD2/3 interacted with Erk1/2 and activated Erk1/2 or NF-κB signaling pathway, leading to AP-1 or NF-κB binding to the promoter of scf, ccl5 and ccl11. Finally, PKD-specific inhibitor significantly reduced tumor volume and tumor growth in mice bearing RM-1 prostate cancer cells, which was attributed to attenuation of mast cell recruitment and tumor angiogenesis.
CONCLUSIONS: These results demonstrate a novel PKDs function that contributes to tumor angiogenesis and progression through mast cells recruitment in prostate cancer microenvironment.

Wang G, Yin L, Peng Y, et al.
Insulin promotes invasion and migration of KRAS
Cell Prolif. 2019; 52(3):e12575 [PubMed] Related Publications
OBJECTIVES: Hyperinsulinemia is a risk factor for pancreatic cancer, but the function of insulin in carcinogenesis is unclear, so this study aimed to elucidate the carcinogenic effects of insulin and the synergistic effect with the KRAS mutation in the early stage of pancreatic cancer.
MATERIALS AND METHODS: A pair of immortalized human pancreatic duct-derived cells, hTERT-HPNE E6/E7/st (HPNE) and its oncogenic KRAS
RESULTS: The migration and invasion ability of HPNE cells was increased after the introduction of the mutated KRAS gene, together with an increased expression of MMP-2. These effects were further enhanced by the simultaneous administration of insulin. The use of MMP-2 siRNA confirmed that MMP-2 was involved in the regulation of cell invasion. Furthermore, there was a concentration- and time-dependent increase in gelatinase activity after insulin treatment, which could be reversed by an insulin receptor tyrosine kinase inhibitor (HNMPA-(AM)
CONCLUSIONS: Taken together, these results suggest that insulin induced migration and invasion in HPNE and HPNE-mut-KRAS through PI3K/AKT and ERK1/2 activation, with MMP-2 gelatinolytic activity playing a vital role in this process. These findings may provide a new therapeutic target for preventing carcinogenesis and the evolution of pancreatic cancer with a background of hyperinsulinemia.

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