Gene Summary

Gene:MAPK8; mitogen-activated protein kinase 8
Aliases: JNK, JNK1, PRKM8, SAPK1, JNK-46, JNK1A2, SAPK1c, JNK21B1/2
Summary:The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. This kinase is activated by various cell stimuli, and targets specific transcription factors, and thus mediates immediate-early gene expression in response to cell stimuli. The activation of this kinase by tumor-necrosis factor alpha (TNF-alpha) is found to be required for TNF-alpha induced apoptosis. This kinase is also involved in UV radiation induced apoptosis, which is thought to be related to cytochrom c-mediated cell death pathway. Studies of the mouse counterpart of this gene suggested that this kinase play a key role in T cell proliferation, apoptosis and differentiation. Several alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Apr 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:mitogen-activated protein kinase 8
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (42)
Pathways:What pathways are this gene/protein implicaed in?
Show (48)

Cancer Overview

Research Indicators

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

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Transcription Factor AP-1
  • Signal Transduction
  • Messenger RNA
  • Cancer Gene Expression Regulation
  • Breast Cancer
  • Mitogen-Activated Protein Kinase 9
  • X-Box Binding Protein 1
  • Mitogen-Activated Protein Kinase 8
  • Cell Survival
  • Cell Proliferation
  • Statistics as Topic
  • Wnt Proteins
  • Xenograft Models
  • Neoplasms, Experimental
  • Young Adult
  • Tumor Microenvironment
  • Phosphorylation
  • Tissue Array Analysis
  • Wound Healing
  • siRNA
  • Antineoplastic Agents
  • Chromosome 10
  • MAP Kinase Signaling System
  • p21-Activated Kinases
  • Western Blotting
  • Wnt-5a Protein
  • Cell Movement
  • Protein-Serine-Threonine Kinases
  • Xenopus laevis
  • Enzyme Activation
  • Apoptosis
  • Transfection
  • Lung Cancer
  • Mitogen-Activated Protein Kinases
  • RNA Interference
  • Mitogen-Activated Protein Kinase 3
  • Dose-Response Relationship, Drug
  • Reactive Oxygen Species
  • fms-Like Tyrosine Kinase 3
  • Survivin
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MAPK8 (cancer-related)

Bishayee K, Habib K, Sadra A, Huh SO
Targeting the Difficult-to-Drug CD71 and MYCN with Gambogic Acid and Vorinostat in a Class of Neuroblastomas.
Cell Physiol Biochem. 2019; 53(1):258-280 [PubMed] Related Publications
BACKGROUND/AIMS: Although neuroblastoma is a heterogeneous cancer, a substantial portion overexpresses CD71 (transferrin receptor 1) and MYCN. This study provides a mechanistically driven rationale for a combination therapy targeting neuroblastomas that doubly overexpress or have amplified CD71 and MYCN. For this subset, CD71 was targeted by its natural ligand, gambogic acid (GA), and MYCN was targeted with an HDAC inhibitor, vorinostat. A combination of GA and vorinostat was then tested for efficacy in cancer and non-cancer cells.
METHODS: Microarray analysis of cohorts of neuroblastoma patients indicated a subset of neuroblastomas overexpressing both CD71 and MYCN. The viability with proliferation changes were measured by MTT and colony formation assays in neuroblastoma cells. Transfection with CD71 or MYCN along with quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect expression changes. For pathway analysis, gene ontology (GO) and Protein-protein interaction analyses were performed to evaluate the potential mechanisms of GA and vorinostat in treated cells.
RESULTS: For both GA and vorinostat, their pathways were explored for specificity and dependence on their targets for efficacy. For GA-treated cells, the viability/proliferation loss due to GA was dependent on the expression of CD71 and involved activation of caspase-3 and degradation of EGFR. It relied on the JNK-IRE1-mTORC1 pathway. The drug vorinostat also reduced cell viability/proliferation in the treated cells and this was dependent on the presence of MYCN as MYCN siRNA transfection led to a blunting of vorinostat efficacy and conversely, MYCN overexpression improved the vorinostat potency in those cells. Vorinostat inhibition of MYCN led to an increase of the pro-apoptotic miR183 levels and this, in turn, reduced the viability/proliferation of these cells. The combination treatment with GA and vorinostat synergistically reduced cell survival in the MYCN and CD71 overexpressing tumor cells. The same treatment had no effect or minimal effect on HEK293 and HEF cells used as models of non-cancer cells.
CONCLUSION: A combination therapy with GA and vorinostat may be suitable for MYCN and CD71 overexpressing neuroblastomas.

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.

Xu F, Song Y, Guo A
Anti-Apoptotic Effects of Docosahexaenoic Acid in IL-1β-Induced Human Chondrosarcoma Cell Death through Involvement of the MAPK Signaling Pathway.
Cytogenet Genome Res. 2019; 158(1):17-24 [PubMed] Related Publications
Osteoarthritis (OA) is a degenerative disease characterized by progressive articular cartilage destruction and joint marginal osteophyte formation with different degrees of synovitis. Docosahexaenoic acid (DHA) is an unsaturated fatty acid with anti-inflammatory, antioxidant, and antiapoptotic functions. In this study, the human chondrosarcoma cell line SW1353 was cultured in vitro, and an OA cell model was constructed with inflammatory factor IL-1β stimulation. After cells were treated with DHA, cell apoptosis was measured. Western blot assay was used to detect protein expression of apoptosis-related factors (Bax, Bcl-2, and cleaved caspase-3) and mitogen-activated protein kinase (MAPK) signaling pathway family members, including extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK), and p38 MAPK. Our results show that IL-1β promotes the apoptosis of SW1353 cells, increases the expression of Bax and cleaved caspase-3, and activates the MAPK signaling pathway. In contrast, DHA inhibits the expression of IL-1β, inhibits IL-1β-induced cell apoptosis, and has a certain inhibitory effect on the activation of the MAPK signaling pathway. When the MAPK signaling pathway is inhibited by its inhibitors, the effects of DHA on SW1353 cells are weakened. Thus, DHA enhances the apoptosis of SW1353 cells through the MAPK signaling pathway.

Liu J, Wang T, Creighton CJ, et al.
Nat Commun. 2019; 10(1):2148 [PubMed] Free Access to Full Article Related Publications
Mechanisms of lung squamous cell carcinoma (LSCC) development are poorly understood. Here, we report that JNK1/2 activities attenuate Lkb1-deficiency-driven LSCC initiation and progression through repressing ΔNp63 signaling. In vivo Lkb1 ablation alone is sufficient to induce LSCC development by reducing MKK7 levels and JNK1/2 activities, independent of the AMPKα and mTOR pathways. JNK1/2 activities is positively regulated by MKK7 during LSCC development. Pharmaceutically elevated JNK1/2 activities abates Lkb1 dependent LSCC formation while compound mutations of Jnk1/2 and Lkb1 further accelerate LSCC progression. JNK1/2 is inactivated in a substantial proportion of human LSCC and JNK1/2 activities positively correlates with survival rates of lung, cervical and head and neck squamous cell carcinoma patients. These findings not only determine a suppressive role of the stress response regulators JNK1/2 on LSCC development by acting downstream of the key LSCC suppresser Lkb1, but also demonstrate activating JNK1/2 activities as a therapeutic approach against LSCC.

Gao S, Wang J, Tian S, Luo J
miR‑9 depletion suppresses the proliferation of osteosarcoma cells by targeting p16.
Int J Oncol. 2019; 54(6):1921-1932 [PubMed] Free Access to Full Article Related Publications
Osteosarcoma (OS) is a common primary malignancy in adolescents and children. MicroRNAs (miRNAs or miRs) can regulate the progression of OS. Herein, we explored the target genes and effects of miR‑9 in OS. Cell growth, colony formation and cell cycle were respectively examined using a cell counting kit‑8 (CCK‑8), crystal violet staining and flow cytometry. The target gene of miR‑9 was predicted according to the website. Luciferase activity was examined using a dual luciferase reporter gene assay kit. The corresponding factors levels were analyzed by carrying out reverse transcription‑quantitative PCR (RT‑qPCR) and western blot analysis. A mouse model of OS was also established and the volume and weight of the tumors of the mice with OS were measured. The levels of p16 in the mice with OS were detected by immunohistochemistry (IHC). The data revealed a high expression of miR‑9 and a low expression of p16 in the OS tissue. p16 was found to be the target gene for miR‑9 in OS. miR‑9 depletion decreased the proliferation and colony formation of Saos‑2 cells by arresting the cells at the G1 phase, accompanied by the downregulation of cyclin A, cyclin D1 and c‑Myc expression levels. Moreover, miR‑9 depletion inhibited the phosphorylation of p38, c‑Jun N‑terminal kinase (JNK) and extracellular signal‑regulated kinase (ERK). In vivo, miR‑9 depletion decreased the tumor volume and weight and increased p16 expression in the mouse tumor tissues. Nevertheless, p16 silencing reversed the suppressive effects of miR‑9 inhibitors on OS cells. On the whole, the findings of this study substantiate that miR‑9 depletion suppresses cell proliferation by targeting p16 in OS and by mediating the activation of the ERK/p38/JNK pathway.

Li D, Hao S, Zhang J
Long non-coding RNA UCA1 exerts growth modulation by miR-15a in human thyroid cancer TPC-1 cells.
Artif Cells Nanomed Biotechnol. 2019; 47(1):1815-1822 [PubMed] Related Publications
Thyroid cancer is widely diagnosed as malignancy in endocrine system. This study attempted to validate UCA1 possessed modulatory function on cell proliferation and epithelial mesenchymal transition (EMT) in human thyroid cancer cell line TPC-1. Ectopic expression of UCA1 was induced in TPC-1 cells by transfection. CCK-8 assays were employed to value cell viability. Cell apoptosis analysis was conducted through flow cytometry. We found that overexpressed UCA1 strongly promoted cell proliferation. However, the knockdown of UCA1 suppressed cell proliferation and induced obvious cell apoptosis. Besides, cell EMT was promoted by overexpressed UCA1 and was inhibited by the knockdown of UCA1. Further study revealed that miR-15a level in TPC-1 cells was suppressed by overexpressed UCA1. Simultaneous overexpression of UCA1 and miR-15a partly alleviated UCA1-induced growth, identifying that miR-15a was a possible target of UCA1. At last, the Hippo and JNK signal pathways were activated by overexpressed UCA1 but were then weakened by the adding of miR-15a. In conclusion, our study revealed UCA1/miR-15a axis implicated in thyroid cancer cells EMT, exposing a novel mechanism of thyroid cancer progression.

Liao Y, Guo Z, Xia X, et al.
Inhibition of EGFR signaling with Spautin-1 represents a novel therapeutics for prostate cancer.
J Exp Clin Cancer Res. 2019; 38(1):157 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Prostate cancer (PCa) remains a challenge worldwide. Due to the development of castration-resistance, traditional first-line androgen deprivation therapy (ADT) became powerlessness. Epidermal growth factor receptor (EGFR) is a well characterized therapeutic target to treat colorectal carcinoma and non-small cell lung cancer. Increasing studies have unraveled the significance of EGFR and its downstream signaling in the progression of castration-resistant PCa.
METHOD: MTS, colony formation and Edu staining assays were used to analyze the cell proliferation of PCa cells. Flow cytometry was used to analyze PCa cell cycle distribution and cell apoptosis. Western blot was used to measure the expression of key proteins associated with cell cycle progression, apoptosis and EGFR signaling pathways. Transfection of exogenous small interfering RNA (siRNA) or plasmid was used to intervene specific gene expression. Nude mouse model was employed to test the in vivo effect of Spautin-1.
RESULTS: The current study reveals that Spautin-1, a known inhibitor of ubiquitin-specific peptidase 10 (USP10) and USP13, inhibits EGFR phosphorylation and the activation of its downstream signaling. Inhibition of EGFR signaling induced by Spautin-1 leads to cell cycle arrest and apoptosis of PCa in a USP10/USP13 independent manner. The application of Spautin-1 reduces the expression of glucose transporter 1 (Glut1) and dramatically induces cell death under glucose deprivation condition. In vivo experiments show a potent anti-tumor effect of Spautin-1 alone and in combination with Enzalutamide.
CONCLUSION: This study demonstrates the therapeutic potential of EGFR signaling inhibition by the use of Spautin-1 for PCa treatment.

Liu S, Han Z, Trivett AL, et al.
Cryptotanshinone has curative dual anti-proliferative and immunotherapeutic effects on mouse Lewis lung carcinoma.
Cancer Immunol Immunother. 2019; 68(7):1059-1071 [PubMed] Free Access to Full Article Related Publications
Lung cancer is currently the leading cause of cancer-related mortality with very limited effective therapy. Screening of a variety of traditional Chinese medicines (TCMs) for their capacity to inhibit the proliferation of human lung cancer A549 cells and to induce the in vitro maturation of human DCs led to the identification of cryptotanshinone (CT), a compound purified from the TCM Salvia miltiorrhiza Bunge. Here, CT was shown to inhibit the proliferation of mouse Lewis lung carcinoma (LLC) cells by upregulating p53, downregulating cyclin B1 and Cdc2, and, consequently, inducing G2/M cell-cycle arrest of LLC cells. In addition, CT promoted maturation of mouse and human DCs with upregulation of costimulatory and MHC molecules and stimulated DCs to produce TNFα, IL-1β, and IL-12p70, but not IL-10 in vitro. CT-induced maturation of DCs depended on MyD88 and also involved the activation of NF-κB, p38, and JNK. CT was effective in the treatment of LLC tumors and, when used in combination with low doses of anti-PD-L1, cured LLC-bearing mice with the induction of subsequent anti-LLC long-term specific immunity. CT treatment promoted T-cell infiltration and elevated the expression of genes typical of Th1 polarization in LLC tumor tissue. The therapeutic effect of CT and low doses of anti-PD-L1 was reduced by depletion of CD4 and CD8 T cells. This paper provides the first report that CT induces immunological antitumor activities and may provide a new promising antitumor immunotherapeutic.

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 F, Yin R, Chen X, et al.
Over-expression of miR-206 decreases the Euthyrox-resistance by targeting MAP4K3 in papillary thyroid carcinoma.
Biomed Pharmacother. 2019; 114:108605 [PubMed] Related Publications
PURPOSE: microRNAs (miRNAs) play a critical role in drug resistance of multiple cancers including papillary thyroid carcinoma (PTC), indicating the potential of miRNAs as chemoresistance regulators in cancer treatment. The aim of this paper is to explore the relationship between miR-206 and chemoresistance of PTC.
METHODS: qRT-PCR was conducted to examine the expression of miR-206 in PTC tissues, parental and TPC-1/euthyrox. The CCK-8 assay, EdU assay and flow cytometry were performed to test cells viability, proliferation and apoptosis, respectively. Luciferase reporter assay was used to confirm the potential target of miR-206. Western blotting analysis was performed to evaluate the expressions of related-proteins.
RESULTS: miR-206 was significantly down-regulated in PTC tissues, parental and TPC-1/euthyrox. Moreover, the expression of miR-206 was exceptionally lower in TPC-1/euthyrox cells than that in TPC-1 cells. Furthermore, we found that over-expression of miR-206 could notably decrease the IC
CONCLUSION: miR-206 contributed to euthyrox resistance in PTC cells through blockage p38 and JNK signaling pathway by targeting MAP4K3, providing a potential therapeutic application for the treatment of patients with euthyrox-resistant PTC in the further.

Zhou J, Zhang S, Li Z, et al.
Yap-Hippo promotes A549 lung cancer cell death via modulating MIEF1-related mitochondrial stress and activating JNK pathway.
Biomed Pharmacother. 2019; 113:108754 [PubMed] Related Publications
Although the role of Yes-associated protein (Yap) has been described in the progression of lung cancer, the downstream effector of the Yap-Hippo pathway has not been identified. Accordingly, the aim of our study is to explore whether Yap modulates the activity of lung cancer by controlling mitochondrial elongation factor 1 (MIEF1)-related mitochondrial stress in a manner dependent on the JNK pathway. Cell viability was determined via MTT, LDH release and immunofluorescence assays. ATP production, the mitochondrial membrane potential, and caspase-9 activity were investigated to assess mitochondrial function. siRNA transfection and pathway blockers were used to observe the roles of MIEF1 and JNK in Yap-modulated cell viability in lung cancer cells in vitro. Yap deletion reduced cell viability in A549 and H358 lung cancer cells. At the molecular level, Yap deletion promoted mitochondrial dysfunction, as evidenced by the decreased mitochondrial potential, increased mitochondrial oxidative stress, augmented mitochondrial pro-apoptotic factor leakage and elevated caspase-9 activity. In addition, we found that Yap modulated mitochondrial stress via MIEF1 and that loss of MIEF1 abolished the regulatory actions of Yap on mitochondrial stress and cell viability. Besides, we provided evidence to support the necessary role of JNK in Yap-mediated MIEF1 upregulation. Inhibition of JNK abolished the promotive effect of Yap deletion on MIEF1 activation. Taken together, our results identified the JNK-MIEF1 pathway and mitochondrial stress as downstream effectors of Yap in lung cancer. This finding suggests a novel approach for the treatment of lung cancer in clinical practice.

Lu L, Liu Q, Wang P, et al.
MicroRNA-148b regulates tumor growth of non-small cell lung cancer through targeting MAPK/JNK pathway.
BMC Cancer. 2019; 19(1):209 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: MicroRNA-148b (miR-148b) has been detected in various types of tumors, and is generally viewed as a tumor suppressor. Our previous study found the decreased expression of miR-148b in human non small cell lung cancer (NSCLC) specimens and cell lines. However, the underlying mechanisms of miR-148b in regulating tumor progression remain unclear.
METHODS: Firstly animal experiments were performed to verify whether miR-148b could inhibit the tumor growth. Then, the underlying mechanisms were studied by transfecting recombinant plasmids containing a miR-148b mimic or a negative control (NC) mimic (shRNA control) into NSCLC cell lines PC14/B and A549 cells. Tumor cells transfected with unpackaged lentiviral vectors was used as blank control. Cell proliferation capabilities were measured by using CCK-8 kit and colony formation assay. Cell cycle arrest was compared to clarify the mechanism underlying the tumor cell proliferation. Annexin V-FITC Apoptosis Detection kit was applied to investigate the effect of miR-148b on cell apoptosis. Furthermore, western blot analysis were performed to study the targeting pathway.
RESULTS: We found that over-expression of miR148b could significantly inhibit tumor growth, while knocking down miR148b could obviously promote tumor growth. Further experiment showed that miR-148b inhibited tumor cell proliferation. Besides, over-expression of miR148b decreased the G2/M phase population of the cell cycle by preventing NSCLC cells from entering the mitotic phase and enhanced tumor cell apoptosis. Further western blot analysis indicated that miR148b could inhibit mitogen-activated protein kinase/Jun N-terminal kinase (MAPK/JNK) signaling by decreasing the expression of phosphorylated (p) JNK.
CONCLUSIONS: These results demonstrate that miR-148b could inhibit the tumor growth and act as tumor suppressor by inhibiting the proliferation and inducing apoptosis of NSCLC cells by blocking the MAPK/JNK pathway.

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.

Zhang Y, He Y, Lu LL, et al.
miRNA-192-5p impacts the sensitivity of breast cancer cells to doxorubicin via targeting peptidylprolyl isomerase A.
Kaohsiung J Med Sci. 2019; 35(1):17-23 [PubMed] Related Publications
The administration of doxorubicin (DOX) is one of the first-line treatments of breast cancer. However, acquisition of resistance remains the major obstacle restricting the clinical application of DOX. MicroRNAs (miRNAs) are small, noncoding RNAs which play crucial role in epigenetic regulation. Recent studies have shown that miRNAs are associated with tumor chemoresistance. Here we aim to explore the role of miRNA-192-5p in resistance to DOX in breast cancer cells. Normal human breast epithelial cell line MCF-10A, breast cancer cell line Michigan Cancer Foundation-7 (MCF-7), and DOX-resistant breast cancer cell line MCF-7/ADR were used here. The expression of miR-192-5p was examined by qPCR, and the expression of peptidylprolyl isomerase A (PPIA) was examined by qPCR and Western blot. The effects of miR-192-5p overexpression on the sensitivity to DOX were confirmed by Methylthiazolyldiphenyl-tetrazolium bromide (MTT) and Annexin-V/PI assay. Downstream molecular mechanisms, including PPIA, BAD, CASP9, Bcl-2, and c-Jun N-terminal kinase (JNK) activation, were detected by Western blot and qPCR. Luciferase reporter assay was used to validate the association between miR-192-5p and PPIA. miR-192-5p was downregulated while PPIA was upregulated in MCF-7/ADR cells. Functionally, miR-192-5p overexpression increased sensitivity to DOX by promoting cell apoptosis. Mechanistically, miR-192-5p overexpression performed its function by activating JNK, augmenting BAD and caspase9 expression, and suppressing Bcl-2 and PPIA expression. Luciferase assay validated that PPIA was a direct target of miR-192-5p. miR-192-5p sensitizes breast cancer cells to DOX by targeting PPIA, suggesting that miR-192-5p might serve as a novel target for reversing DOX resistance and controlling breast tumor growth.

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.

Zhuo H, Zhao Y, Cheng X, et al.
Tumor endothelial cell-derived cadherin-2 promotes angiogenesis and has prognostic significance for lung adenocarcinoma.
Mol Cancer. 2019; 18(1):34 [PubMed] Free Access to Full Article Related Publications
In lung cancer, antiangiogenic strategies targeting tumor-derived endothelial cells (TECs) afford a survival advantage, but the characteristics of TECs have not been comprehensively elucidated. Herein, high-purity (> 98%) TECs were obtained, and these cells retained expression of EC markers and exhibited high viability. ITRAQ-2DLC-MS/MS was performed to profile the proteome and the heterogeneity of ECs. Only 31 of 1820 identified proteins were differentially expressed between adenocarcinoma (ADC)- and squamous cell carcinoma (SCC)-derived TECs (TEC-A and TEC-S, respectively), and cadherin-2 (CDH2) was the most significantly upregulated protein in TEC-A samples. Positive immunostaining for CDH2 (score > 3) was significantly more frequent in the endothelium of ADC tissues than in that of SCC tissues. Loss- or gain-of-function analysis showed that CDH2 significantly promoted in vitro and in vivo angiogenesis and sensitivity to the antagonist exherin. The MAPK/ERK and MAPK/JNK signaling pathways may play crucial roles in CDH2-induced HIF-1α/VEGF-mediated angiogenesis. Moreover, high CDH2 expression in TECs was significantly associated with tumor stage, visceral pleural metastasis, and decreased overall survival in patients with ADC but not SCC. Together, these data indicate the importance of CDH2 in angiogenesis and highlight its potential both for antiangiogenic therapy and as a candidate prognostic marker for ADC.

Lee D, Kim KH, Lee WY, et al.
Multiple Targets of 3-Dehydroxyceanothetric Acid 2-Methyl Ester to Protect Against Cisplatin-Induced Cytotoxicity in Kidney Epithelial LLC-PK1 Cells.
Molecules. 2019; 24(5) [PubMed] Free Access to Full Article Related Publications
Chronic exposure to cisplatin, a potent anticancer drug, causes irreversible kidney damage. In this study, we investigated the protective effect and mechanism of nine lupane- and ceanothane-type triterpenoids isolated from jujube (

Dai X, Geng F, Li M, Liu M
Tripartite motif‑containing 11 regulates the proliferation and apoptosis of breast cancer cells.
Oncol Rep. 2019; 41(4):2567-2574 [PubMed] Related Publications
Breast cancer, an increasing health problem worldwide, is the second major cause of cancer‑associated mortality in females. Studies have focused on the pathogenesis of breast cancer for decades, but the underlying mechanisms have not been fully elucidated. Tripartite motif‑containing 11 (TRIM11), a novel oncogene that was recently identified, was reported to function in various types of cancer, including ovarian and lung cancer. In the present study, high expression levels of TRIM11 were detected in breast cancer tissues by reverse transcription‑quantitative polymerase chain reaction and western blot analysis, which suggested that TRIM11 was likely to function in the progression of breast cancer. Downregulation of TRIM11 in MCF‑7 and MDA‑MB‑231 cells inhibited cell proliferation and promoted cell apoptosis, accompanied by increased phosphatase and tensin homolog deleted on chromosome 10 (PTEN), p53 and Bcl‑2‑associated X protein, and decreased B‑cell lymphoma 2, phosphorylated c‑Jun N‑terminal kinase 1/2 (p‑JNK1/2) and phosphorylated extracellular signal‑regulated kinases 1/2 (p‑ERK1/2), whereas the overexpression of TRIM11 completely reversed these effects. Furthermore, TRIM11 downregulation enhanced the pro‑apoptotic effect of chemotherapy drugs on breast cancer cells, and high levels of TRIM11 expression were observed in cisplatin‑ and paclitaxel‑resistant breast cancer tissues. These data indicated that TRIM11 is crucial to the development of breast cancer, and TRIM11 downregulation may benefit the treatment of breast cancer by regulating ERK1/2 and JNK1/2 signaling and the expression of apoptosis‑associated genes.

Li Y, Xiao F, Li W, et al.
Overexpression of Opa interacting protein 5 increases the progression of liver cancer via BMPR2/JUN/CHEK1/RAC1 dysregulation.
Oncol Rep. 2019; 41(4):2075-2088 [PubMed] Free Access to Full Article Related Publications
Opa interacting protein 5 (OIP5) overexpression is associated with human carcinoma. However, its biological function, underlying mechanism and clinical significance in liver cancer remain unknown. In the present study, the effects of OIP5 expression on liver cancer, and the mechanisms regulating these effects, were investigated. OIP5 expression was measured in human hepatocellular carcinoma (HCC) tissues and liver cancer cell lines. The effect of OIP5 knockdown on tumorigenesis was also detected in nude mice, and differentially‑expressed genes (DEGs) were identified and their biological functions were identified. The results indicated that OIP5 expression was significantly upregulated in HCC tissues and four liver cancer cell lines (P<0.01). Increased OIP5 protein expression significantly predicted reduced survival rate of patients with HCC (P<0.01). OIP5 knockdown resulted in the suppression of proliferation and colony forming abilities, cell cycle arrest at the G0/G1 or G2/M phases, and promotion of cell apoptosis. A total of 628 DEGs, including 87 upregulated and 541 downregulated genes, were identified following OIP5 knockdown. Functional enrichment analysis indicated that DEGs were involved in 'RNA Post‑Transcriptional Modification, Cancer and Organismal Injury and Abnormalities'. Finally, OIP5 knockdown in Huh7 cells dysregulated bone morphogenetic protein receptor type 2/JUN/checkpoint kinase 1/Rac family small GTPase 1 expression. In conclusion, the overall results demonstrated the involvement of OIP5 in the progression of liver cancer and its mechanism of action.

Han SE, Park CH, Nam-Goong IS, et al.
Anticancer Effects of Baicalein in FRO Thyroid Cancer Cells Through the Up-regulation of ERK/p38 MAPK and Akt Pathway.
In Vivo. 2019 Mar-Apr; 33(2):375-382 [PubMed] Free Access to Full Article Related Publications
BACKGROUND/AIM: The aim of the study was to evaluate the anticancer effects of baicalein in FRO anaplastic thyroid cancer (ATC) cells.
MATERIALS AND METHODS: FRO cells were treated with baicalein and viability was measured by the MTT assay. Cell apoptosis was observed by staining with Hoechst dye. The expression of apoptotic proteins (Bax, Bcl-2, PARP, cytochrome c, and caspase-3) and the inflammatory protein Cox-2 and the phosphorylation of MAPKs and Akt were determined by western blot.
RESULTS: Treatment with baicalein inhibited cell proliferation in a time-dependent manner and increased DNA fragmentation and apoptosis in FRO cells. Baicalein at 50 and 100 μM inhibited the expression of Bax, PARP, cytochrome c, cleaved caspase-3, and Cox-2, and increased the expression of Bcl-2. Baicalein increased the phosphorylation of ERK, p38 MAPK, and Akt and decreased JNK phosphorylation.
CONCLUSION: Baicalein caused anticancer effects in FRO ATC cells through induction of apoptosis and regulation of the MAPK and Akt pathway.

Krupenko SA, Krupenko NI
Loss of ALDH1L1 folate enzyme confers a selective metabolic advantage for tumor progression.
Chem Biol Interact. 2019; 302:149-155 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
ALDH1L1 (cytosolic 10-formyltetrahydrofolate dehydrogenase) is the enzyme in folate metabolism commonly downregulated in human cancers. One of the mechanisms of the enzyme downregulation is methylation of the promoter of the ALDH1L1 gene. Recent studies underscored ALDH1L1 as a candidate tumor suppressor and potential marker of aggressive cancers. In agreement with the ALDH1L1 loss in cancer, its re-expression leads to inhibition of proliferation and to apoptosis, but also affects migration and invasion of cancer cells through a specific folate-dependent mechanism involved in invasive phenotype. A growing body of literature evaluated the prognostic value of ALDH1L1 expression for cancer disease, the regulatory role of the enzyme in cellular proliferation, and associated metabolic and signaling cellular responses. Overall, there is a strong indication that the ALDH1L1 silencing provides metabolic advantage for tumor progression at a later stage when unlimited proliferation and enhanced motility become critical processes for the tumor expansion. Whether the ALDH1L1 loss is involved in tumor initiation is still an open question.

Al-Gayyar MMH, Bagalagel A, Noor AO, et al.
The therapeutic effects of nicotinamide in hepatocellular carcinoma through blocking IGF-1 and effecting the balance between Nrf2 and PKB.
Biomed Pharmacother. 2019; 112:108653 [PubMed] Related Publications
Insulin growth factor (IGF) family and their receptors play a great role in tumors' development. In addition, IGF-1 enhances cancer progression through regulating cell proliferation, angiogenesis, immune modulation and metastasis. Moreover, nicotinamide is association with protection against cancer. Therefore, we conducted this research to examine the therapeutic effects of nicotinamide against hepatocellular carcinoma (HCC) both in vivo and in vitro through affecting IGF-1 and the balance between PKB and Nrf2. HCC was induced in rats by 200 mg/kg, ip thioacetamide. The rat survival, number and size of tumors and serum α-fetoprotein (AFP) were measured. The gene and protein levels of IGF-1, Nrf2, PKB and JNK-MAPK were assessed in rat livers. In addition, HepG2 cells, human HCC cell lines, were treated with different concentrations of nicotinamide. We found that nicotinamide enhanced the rats' survival and reduced the number and size of hepatic tumors as well as it reduced serum AFP and HepG2 cells survival. Nicotinamide ameliorated HCC-induced reduction in the expression of Nrf2. Moreover, nicotinamide blocked HCC-induced elevation in IGF-1, PKB and JNK-MAPK. In conclusion, nicotinamide produced cytotoxic effects against HCC both in vivo and in vitro. The cytotoxic activity can be explained by inhibition of HCC-induced increased in the expression of IGF-1 and leads to disturbances in the balance between the cell death signal by PKB and MAPK; and the cell survival signal by Nrf2, directing it towards cell survival signals in normal liver cells providing more protection for body against tumor.

Blum AE, Venkitachalam S, Ravillah D, et al.
Systems Biology Analyses Show Hyperactivation of Transforming Growth Factor-β and JNK Signaling Pathways in Esophageal Cancer.
Gastroenterology. 2019; 156(6):1761-1774 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND & AIMS: Esophageal adenocarcinoma (EAC) is resistant to standard chemoradiation treatments, and few targeted therapies are available. We used large-scale tissue profiling and pharmacogenetic analyses to identify deregulated signaling pathways in EAC tissues that might be targeted to slow tumor growth or progression.
METHODS: We collected 397 biopsy specimens from patients with EAC and nonmalignant Barrett's esophagus (BE), with or without dysplasia. We performed RNA-sequencing analyses and used systems biology approaches to identify pathways that are differentially activated in EAC vs nonmalignant dysplastic tissues; pathway activities were confirmed with immunohistochemistry and quantitative real-time polymerase chain reaction analyses of signaling components in patient tissue samples. Human EAC (FLO-1 and EsoAd1), dysplastic BE (CP-B, CP-C, CP-D), and nondysplastic BE (CP-A) cells were incubated with pharmacologic inhibitors or transfected with small interfering RNAs. We measured effects on proliferation, colony formation, migration, and/or growth of xenograft tumors in nude mice.
RESULTS: Comparisons of EAC vs nondysplastic BE tissues showed hyperactivation of transforming growth factor-β (TGFB) and/or Jun N-terminal kinase (JNK) signaling pathways in more than 80% of EAC samples. Immunohistochemical analyses showed increased nuclear localization of phosphorylated JUN and SMAD proteins in EAC tumor tissues compared with nonmalignant tissues. Genes regulated by the TGFB and JNK pathway were overexpressed specifically in EAC and dysplastic BE. Pharmacologic inhibition or knockdown of TGFB or JNK signaling components in EAC cells (FLO-1 or EsoAd1) significantly reduced cell proliferation, colony formation, cell migration, and/or growth of xenograft tumors in mice in a SMAD4-independent manner. Inhibition of the TGFB pathway in BE cell lines reduced the proliferation of dysplastic, but not nondysplastic, cells.
CONCLUSIONS: In a transcriptome analysis of EAC and nondysplastic BE tissues, we found the TGFB and JNK signaling pathways to be hyperactivated in EACs and the genes regulated by these pathways to be overexpressed in EAC and dysplastic BE. Inhibiting these pathways in EAC cells reduces their proliferation, migration, and formation of xenograft tumors. Strategies to block the TGFB and JNK signaling pathways might be developed for treatment of EAC.

García-Vázquez R, Marchat LA, Ruíz-García E, et al.
MicroRNA-143 is Associated With Pathological Complete Response and Regulates Multiple Signaling Proteins in Breast Cancer.
Technol Cancer Res Treat. 2019; 18:1533033819827309 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
Almost 55% to 80% of patients with breast cancer have an unfavorable pathological complete response to chemotherapy. MicroRNAs are small noncoding RNAs involved in cancer progression; however, their utility as predictors of pathological complete response to neoadjuvant chemotherapy is unclear. Here, we investigated if miR-143 could discriminate between pathological complete response and no-polymerase chain reaction of patients with locally advanced triple negative breast cancer that have received a fluorouracil-cisplatin/paclitaxel-based neoadjuvant treatment. Data showed that miR-143 exhibited a significant low expression ( P < .0006) in patients that achieved pathological complete response in comparison to nonresponder group. Receiver operating characteristic curve analysis suggested that miR-143 could be a good predictor of pathological complete response (area under curve = 0.849, P < .0006). Moreover, Kaplan-Meier analysis indicated that before neoadjuvant therapy low levels of miR-143 were associated to increased disease free survival. To gain insights into cellular functions of miR-143, we firstly showed that miR-143 was severely repressed in breast cancer cell lines and tumors in comparison to normal mammary cells and tissues. Ectopic restoration of miR-143 using RNA mimics inhibited both cell proliferation and migration and sensitized breast cancer cells to cisplatin therapy in vitro. To decipher the signaling networks regulated by miR-143, we used a high-throughput enzyme-linked immunosorbent assay-based phosphorylation antibody array. Phospho-proteomic profiling revealed that miR-143 coordinately reduced the protein levels and phosphorylation status of multiple oncoproteins involved in AKT, WNT/β-catenin, SAPK/JNK, FAK, and JAK/STAT signaling pathways. Moreover, low miR-143 and high GSK3-β, RAF1, paxillin, and p21CIP1 expression levels in a large cohort of patients with breast cancer were associated with worst outcome. In summary, miR-143 could be a potential predictor of response to neoadjuvant therapy and it may function as a divergent regulator of diverse signaling networks to suppress cell proliferation and migration in breast cancer.

Lu CC, Chiang JH, Tsai FJ, et al.
Metformin triggers the intrinsic apoptotic response in human AGS gastric adenocarcinoma cells by activating AMPK and suppressing mTOR/AKT signaling.
Int J Oncol. 2019; 54(4):1271-1281 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
Metformin is commonly used to treat patients with type 2 diabetes and is associated with a decreased risk of cancer. Previous studies have demonstrated that metformin can act alone or in synergy with certain anticancer agents to achieve anti‑neoplastic effects on various types of tumors via adenosine monophosphate‑activated protein kinase (AMPK) signaling. However, the role of metformin in AMPK‑mediated apoptosis of human gastric cancer cells is poorly understood. In the current study, metformin exhibited a potent anti‑proliferative effect and induced apoptotic characteristics in human AGS gastric adenocarcinoma cells, as demonstrated by MTT assay, morphological observation method, terminal deoxynucleotidyl transferase dUTP nick end labeling and caspase‑3/7 assay kits. Western blot analysis demonstrated that treatment with metformin increased the phosphorylation of AMPK, and decreased the phosphorylation of AKT, mTOR and p70S6k. Compound C (an AMPK inhibitor) suppressed AMPK phosphorylation and significantly abrogated the effects of metformin on AGS cell viability. Metformin also reduced the phosphorylation of mitogen‑activated protein kinases (ERK, JNK and p38). Additionally, metformin significantly increased the cellular ROS level and included loss of mitochondrial membrane potential (ΔΨm). Metformin altered apoptosis‑associated signaling to downregulate the BAD phosphorylation and Bcl‑2, pro‑caspase‑9, pro‑caspase‑3 and pro‑caspase‑7 expression, and to upregulate BAD, cytochrome c, and Apaf‑1 proteins levels in AGS cells. Furthermore, z‑VAD‑fmk (a pan‑caspase inhibitor) was used to assess mitochondria‑mediated caspase‑dependent apoptosis in metformin‑treated AGS cells. The findings demonstrated that metformin induced AMPK‑mediated apoptosis, making it appealing for development as a novel anticancer drug for the treating gastric cancer.

Yang PW, Lu ZY, Pan Q, et al.
MicroRNA-6809-5p mediates luteolin-induced anticancer effects against hepatoma by targeting flotillin 1.
Phytomedicine. 2019; 57:18-29 [PubMed] Related Publications
BACKGROUND: Luteolin (3,4,5,7-tetrahydroxy flavone) is a natural flavonoid abundant in fruits and vegetables. Although luteolin has shown pro-apoptotic activity in hepatocellular carcinoma (HCC) cells, the underlying molecular mechanism has not yet been clarified.
PURPOSE: The aim of this study is to identify novel miRNAs involved in the action of luteolin in HCC cells and to explore the biological roles of these miRNAs.
METHODS: The effect of luteolin on HCC cell growth was assessed using CCK-8 colony formation assay, flow cytometric analysis in vitro, and a xenograft model in vivo. miRNA expression profiles were assessed using next-generation sequencing. Differentially expressed miRNAs were validated by quantitative PCR. Bioinformatics analysis and luciferase reporter assay were utilized to confirm the binding of miR-6809-5p to the 3'-untranslated region (3'-UTR) of flotillin 1 (FLOT1). Furthermore, the effects of ectopic FLOT1 and miR-6809-5 expression on cell proliferation, colony formation, and cell apoptosis were also assessed. Western blotting analysis was used to detect activation of multiple signaling molecules including Erk1/2, p38, JNK, and NF-κB/p65 in the MAPK pathway.
RESULTS: It was found that luteolin significantly inhibited HCC growth and caused apoptosis and cell cycle arrest at the G0/G1 phase in Huh7 cells, at the G2/M phase in HepG2 cells in vitro. Tumorigenic studies revealed that luteolin treatment significantly suppressed HCC growth in vivo. miR-6809-5p was upregulated by luteolin. Overexpression of miR-6809-5p suppressed HCC cell growth, while knockdown of miR-6809-5p reversed the anticancer effect of luteolin. With regards to its signaling mechanism, miR-6809-5p directly targets FLOT1in HCC cells. Enforced expression of FLOT1 prevented miR-6809-5p-mediated growth suppression. Downregulation of FLOT1 exerted growth-suppressive effects on HCC cells. Multiple signaling pathways including Erk1/2, p38, JNK, and NF-κB/p65 were inactivated by miR-6809-5p overexpression or FLOT1 downregulation.
CONCLUSION: These findings indicated that miR-6809-5p mediates the growth-suppressive activity of luteolin in HCC, which is causally linked to FLOT1 downregulation. Induction of miR-6809-5p may provide therapeutic benefits in the treatment of HCC.

Kilbas PO, Akcay IM, Doganay GD, Arisan ED
Bag-1 silencing enhanced chemotherapeutic drug-induced apoptosis in MCF-7 breast cancer cells affecting PI3K/Akt/mTOR and MAPK signaling pathways.
Mol Biol Rep. 2019; 46(1):847-860 [PubMed] Related Publications
The multifunctional anti-apoptotic Bag-1 protein has important roles in apoptosis, proteasome-mediated degradation, transcriptional regulation, and intracellular signaling. Bag-1 promotes cell survival and proliferation, and is overexpressed in breast cancer. Therefore, Bag-1-targeted therapy might be a promising strategy to treat breast cancer. However, the effects of Bag-1 silencing in combination with conventional chemotherapeutic drugs on cell viability and major signaling pathways have not yet been fully investigated in breast cancer cells. In this study, we investigated the cytotoxic effects of Bag-1 silencing, alone and in combination with cisplatin or paclitaxel treatment, in MCF-7 breast cancer cells. Bag-1 knockdown by shRNA or siRNA transfection sensitized MCF-7 cells to apoptosis induced by cisplatin or paclitaxel. Combination of Bag-1 silencing and drug treatment more potently downregulated the pro-survival PI3K/Akt/mTOR and p44/42 mitogen activated protein kinase (MAPK) pathways, and more potently upregulated the stress-activated p38 and SAPK/JNK MAPK pathways. Bag-1-silenced drug-treated cells had also highly reduced proliferative capacity, downregulated cyclin-cyclin dependent kinase complexes and upregulated tumor suppressors p21 and Rb. These results overall indicated that Bag-1 silencing enhanced cisplatin- or paclitaxel-induced cytotoxicity through multiple pathways. In conclusion, Bag-1 targeted therapy might enhance the therapeutic potential of conventional anti-cancer drugs in the treatment of breast cancer.

Lv C, Fu S, Dong Q, et al.
PAGE4 promotes prostate cancer cells survive under oxidative stress through modulating MAPK/JNK/ERK pathway.
J Exp Clin Cancer Res. 2019; 38(1):24 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: Prostate cancer (PCa) is one of the most common cancers in male worldwide. Oxidative stress has been recognized as one of the driving signals pathologically linked to PCa progression. Nevertheless, the association of oxidative stress with PCa progression remains unclear.
METHODS: Western blot, q-RT-PCR and bioinformatics analyses were used to examine PAGE4 expression. Comet assay and Annexin V/ PI dual staining assay were performed to investigate DNA damage and cell death under oxidative stress. Mouse xenograft model of PCa cells was established to verify the role of PAGE4 in vivo. Transcriptomic analysis was performed to investigate the underlying mechanism for the function of PAGE4 under oxidative stress. Western blot assay was conducted to determine the status of MAPK pathway. Immunohistochemistry was used to identify protein expression of PAGE4 in tumor tissues.
RESULTS: In this study, we found that PAGE4 expression was increased in PCa cells under oxidative stress condition. PAGE4 overexpression protected PCa cells from oxidative stress-inducing cell death by reducing DNA damage. PAGE4 overexpression promoted PCa cells growth in vivo. Mechanistically, PAGE4 promoted the survival of prostate cancer cells through regulating MAPK pathway which reflected in decreasing the phosphorylation of MAP2K4, JNK and c-JUN but increasing phosphorylation of ERK1/2.
CONCLUSION: Our findings indicate that PAGE4 protects PCa cells from DNA damage and apoptosis under oxidative stress by modulating MAPK signalling pathway. PAGE4 expression may serve as a prognostic biomarker for clinical applications.

Zhou J, Shi M, Li M, et al.
Sirtuin 3 inhibition induces mitochondrial stress in tongue cancer by targeting mitochondrial fission and the JNK-Fis1 biological axis.
Cell Stress Chaperones. 2019; 24(2):369-383 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
Sirtuin 3 (Sirt3)-modified mitochondrial fission participates in the progression of several types of cancers. However, its role in tongue cancer requires investigation. The aim of our study is to determine whether Sirt3 knockdown regulates the viability of tongue cancer cells via modulating mitochondrial fission. Two types of tongue cancer cells were used in the present study, and siRNA was transfected into the cells to suppress Sirt3 expression. Mitochondrial function and cell apoptosis were determined via immunofluorescence, Western blotting, ELISA, and qPCR assays. A pathway blocker was applied to verify the role of the JNK-Fis1 signaling pathway in regulation of mitochondrial fission. The present study showed that loss of Sirt3 promoted tongue cancer cell death in a manner dependent on mitochondrial apoptosis. Mitochondrial oxidative stress, energy metabolism disorder, mitochondrial cyt-c liberation, and mitochondrial apoptosis activation were observed after Sirt3 silencing. Furthermore, we demonstrated that Sirt3 knockdown activated mitochondrial stress via triggering Fis1-related mitochondrial fission and that inhibition of Fis1-related mitochondrial fission abrogated the pro-apoptotic effect of Sirt3 knockdown on tongue cancer cells. To this end, we found that Sirt3 modulated Fis1 expression via the c-Jun N-terminal kinases (JNK) signaling pathway and that blockade of the JNK pathway attenuated mitochondrial stress and repressed apoptosis in Sirt3 knockdown cells. Altogether, our results identified a tumor-suppressive role for Sirt3 deficiency in tongue cancer via activation of the JNK-Fis1 axis and subsequent initiation of fatal mitochondrial fission. Given these findings, strategies to repress Sirt3 activity and enhance the JNK-Fis1-mitochondrial fission cascade have clinical benefits for patients with tongue cancer.

Wang G, Cheng L, Chen M, et al.
Comparative Analysis of Expression Profiles of Reg Signaling Pathways-Related Genes Between AHF and HCC.
Biochem Genet. 2019; 57(3):382-402 [PubMed] Related Publications
Regenerating islet-derived protein (Reg) could participate in the occurrence of diabetes mellitus, inflammation, tumors, and other diseased or damaged tissues. However, the correlation of Reg with acute hepatic failure (AHF) and hepatocellular carcinoma (HCC) is poorly defined. To reveal the expression profiles of Reg family and their possible regulatory roles in AHF and HCC, rat models of HCC and AHF were separately established, and Rat Genome 230 2.0 was used to detect expression profiles of Reg-mediated signaling pathways-associated genes from liver tissues in AHF and HCC. The results showed that a total of 79 genes were significantly changed. Among these genes, 67 genes were the AHF-specific genes, 45 genes were the HCC-specific genes, and 33 genes were the common genes. Then, K-means clustering classified these genes into 4 clusters based on the gene expression similarity, and DAVID analysis showed that the above altered genes were mainly associated with stress response, inflammatory response, and cell cycle regulation. Thereafter, IPA software was used to analyze potential effects of these genes, and the predicted results suggested that the Reg-mediated JAK/STAT, NF-κB, MAPK (ERK1/2, P38 and JNK), PLC, and PI3K/AKT signaling pathways may account for the activated inflammation and cell proliferation, and the attenuated apoptosis and cell death during the occurrence of AHF and HCC.

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