Gene Summary

Gene:JUN; Jun proto-oncogene, AP-1 transcription factor subunit
Aliases: AP1, p39, AP-1, cJUN, c-Jun
Summary:This gene is the putative transforming gene of avian sarcoma virus 17. It encodes a protein which is highly similar to the viral protein, and which interacts directly with specific target DNA sequences to regulate gene expression. This gene is intronless and is mapped to 1p32-p31, a chromosomal region involved in both translocations and deletions in human malignancies. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transcription factor AP-1
Source:NCBIAccessed: 01 September, 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 01 September 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.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: JUN (cancer-related)

Yoon H, Kim M, Jang K, et al.
p27 transcriptionally coregulates cJun to drive programs of tumor progression.
Proc Natl Acad Sci U S A. 2019; 116(14):7005-7014 [PubMed] Free Access to Full Article Related Publications
p27 shifts from CDK inhibitor to oncogene when phosphorylated by PI3K effector kinases. Here, we show that p27 is a cJun coregulator, whose assembly and chromatin association is governed by p27 phosphorylation. In breast and bladder cancer cells with high p27pT157pT198 or expressing a CDK-binding defective p27pT157pT198 phosphomimetic (p27CK-DD), cJun is activated and interacts with p27, and p27/cJun complexes localize to the nucleus. p27/cJun up-regulates

Kaya P, Lee SR, Lee YH, et al.
Curcumae Radix Extract Decreases Mammary Tumor-Derived Lung Metastasis via Suppression of C-C Chemokine Receptor Type 7 Expression.
Nutrients. 2019; 11(2) [PubMed] Free Access to Full Article Related Publications
Curcumae radix is the dry root of

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.

Meng L, Ma W, Lin S, et al.
Tetrahedral DNA Nanostructure-Delivered DNAzyme for Gene Silencing to Suppress Cell Growth.
ACS Appl Mater Interfaces. 2019; 11(7):6850-6857 [PubMed] Related Publications
DNAzymes are synthetic oligonucleotides that are capable of cleavaging target mRNA to exert gene-silencing activity and are considered as promising therapeutic agents. Dz13 is a DNAzyme that cleaves the mRNA of c-Jun and suppresses the growth of squamous cell carcinomas. However, DNAzymes exhibit low cellular uptake efficacy and require a suitable drug delivery system. In this study, we directly added the Dz13 sequence to the 5'-end of single-stranded DNA to form modified tetrahedral DNA nanostructures (TDN-Dz13). The TDNs were used to deliver the single-stranded DNAzyme Dz13 into cells. Dz13 delivered by the TDNs showed high cellular uptake efficiency and still maintained intracellular gene-silencing activity to cleave the target c-Jun mRNA, which reduced cell proliferation. This study may help find a convenient approach for the delivery of DNAzymes to regulate target genes.

Ataei N, Aghaei M, Panjehpour M
Evidences for involvement of estrogen receptor induced ERK1/2 activation in ovarian cancer cell proliferation by Cadmium Chloride.
Toxicol In Vitro. 2019; 56:184-193 [PubMed] Related Publications
Cadmium (Cd) as a human carcinogen and one of the most toxic industrial and environmental pollutant mimics the estrogenic effects in cell proliferation. So, it might have a role in the incidence and etiology of hormone-related cancers such as ovarian cancer as the most lethal gynecologic malignancy. This study aimed to evaluate the estrogenic effect and underlying mechanism of Cd in ovarian cancer cell line proliferation. OVCAR3 and SKOV3 cell lines were treated with different concentrations of CdCl

Romagnolo DF, Donovan MG, Doetschman TC, Selmin OI
Nutrients. 2019; 11(1) [PubMed] Article available free on PMC after 01/05/2020 Related Publications
The farnesoid-X-receptor (FXR) protects against inflammation and cancer of the colon through maintenance of intestinal bile acid (BA) homeostasis. Conversely, higher levels of BA and cyclooxygenase-2 (COX-2) are risk factors for inflammation and cancer of the colon. In the United States,

Zheng M, Zhou Q, Liu X, et al.
CTHRC1 overexpression promotes cervical carcinoma progression by activating the Wnt/PCP signaling pathway.
Oncol Rep. 2019; 41(3):1531-1538 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
The tumorigenesis and metastasis of tumors are associated with human collagen triple helix repeats containing 1 (CTHRC1). To study the effects and possible impacting mechanisms of CTHRC1 on human cervical carcinoma development, samples of paraffin‑embedded cervical carcinoma and HeLa cells were examined. Immunofluorescence, cell wound scratch assay, western blot analysis and Transwell invasion assay were used to evaluate HeLa cells in response to silencing of the CTHRC1 gene in cervical carcinoma. The expression levels of gap‑associated proteins of the Wnt/PCP pathway in paraffin‑embedded cervical carcinoma samples were also evaluated by immunohistochemical staining. CTHRC1 promoted the migration and invasion of HeLa cells in vitro, downregulated Ror2 and p‑c‑Jun and activated the Wnt/PCP pathway. Furthermore, the expression of p‑c‑Jun, Ror2 and Wnt5a was increased after overexpression of CTHRC1 as revealed in HeLa cells compared to control group. The present experiments revealed that CTHRC1 promoted HeLa cell progression by activating the Wnt/PCP signaling pathway and may play a key role in the invasion and metastasis of cervical carcinoma.

Chang C, Xi L, Zhang J, et al.
Roles of
J Genet. 2018; 97(5):1155-1168 [PubMed] Related Publications
To analyse the mechanism of tumourigenic transformation of NIH3T3 cells at the transcriptional level, we used cancerogen 3-methylcholanthrene (3-MCA) and cancerogenic substance phorbol-12-myristate-13-acetate (PMA) to transform NIH3T3 cells and the assessment of transformation was performed using Giemsa staining and methylcellulose colony formation assay. Changes in gene expression profile were detected by Mouse Genome 430 2.0 microarray; and quantitative real-time polymerase chain reaction and Western blotting were used to verify the expression changes of mRNAs and proteins, respectively. With the aid of bioinformatics method, five signalling pathways were identified to participate in different stages of NIH3T3 cell transformation. Further, our study suggested that oncogenes

Kessler BE, Mishall KM, Kellett MD, et al.
Resistance to Src inhibition alters the BRAF-mutant tumor secretome to promote an invasive phenotype and therapeutic escape through a FAK>p130Cas>c-Jun signaling axis.
Oncogene. 2019; 38(14):2565-2579 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
Few therapy options exist for patients with advanced papillary and anaplastic thyroid cancer. We and others have previously identified c-Src as a key mediator of thyroid cancer pro-tumorigenic processes and a promising therapeutic target for thyroid cancer. To increase the efficacy of targeting Src in the clinic, we sought to define mechanisms of resistance to the Src inhibitor, dasatinib, to identify key pathways to target in combination. Using a panel of thyroid cancer cell lines expressing clinically relevant mutations in BRAF or RAS, which were previously developed to be resistant to dasatinib, we identified a switch to a more invasive phenotype in the BRAF-mutant cells as a potential therapy escape mechanism. This phenotype switch is driven by FAK kinase activity, and signaling through the p130Cas>c-Jun signaling axis. We have further shown this more invasive phenotype is accompanied by alterations in the secretome through the increased expression of pro-inflammatory cytokines, including IL-1β, and the pro-invasive metalloprotease, MMP-9. Furthermore, IL-1β signals via a feedforward autocrine loop to promote invasion through a FAK>p130Cas>c-Jun>MMP-9 signaling axis. We further demonstrate that upfront combined inhibition of FAK and Src synergistically inhibits growth and invasion, and induces apoptosis in a panel of BRAF- and RAS-mutant thyroid cancer cell lines. Together our data demonstrate that acquired resistance to single-agent Src inhibition promotes a more invasive phenotype through an IL-1β>FAK>p130Cas>c-Jun >MMP signaling axis, and that combined inhibition of FAK and Src has the potential to block this inhibitor-induced phenotype switch.

Tanioka M, Mott KR, Hollern DP, et al.
Identification of Jun loss promotes resistance to histone deacetylase inhibitor entinostat through Myc signaling in luminal breast cancer.
Genome Med. 2018; 10(1):86 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: Based on promising phase II data, the histone deacetylase inhibitor entinostat is in phase III trials for patients with metastatic estrogen receptor-positive breast cancer. Predictors of sensitivity and resistance, however, remain unknown.
METHODS: A total of eight cell lines and nine mouse models of breast cancer were treated with entinostat. Luminal cell lines were treated with or without entinostat at their IC
RESULTS: Luminal models displayed enhanced sensitivity to entinostat as compared to basal-like or claudin-low models. Both in vitro and in vivo luminal models showed significant downregulation of Myc gene signatures following entinostat treatment. Myc gene signatures became upregulated on tumor progression in vivo and overexpression of Myc conferred resistance to entinostat in vitro. Further examination of resistance mechanisms in MMTV/Neu tumors identified a portion of mouse chromosome 4 that had DNA copy number loss and low gene expression. Within this region, Jun was computationally identified to be a driver gene of resistance. Jun knockdown in cell lines resulted in upregulation of Myc signatures and made these lines more resistant to entinostat. Jun-deleted samples, found in 17-23% of luminal patients, had significantly higher Myc signature scores that predicted worse survival.
CONCLUSIONS: Entinostat inhibited luminal breast cancer through Myc signaling, which was upregulated by Jun DNA loss to promote resistance to entinostat in our models. Jun DNA copy number loss, and/or high MYC signatures, might represent biomarkers for entinostat responsiveness in luminal breast cancer.

Šuštić T, van Wageningen S, Bosdriesz E, et al.
A role for the unfolded protein response stress sensor ERN1 in regulating the response to MEK inhibitors in KRAS mutant colon cancers.
Genome Med. 2018; 10(1):90 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: Mutations in KRAS are frequent in human cancer, yet effective targeted therapeutics for these cancers are still lacking. Attempts to drug the MEK kinases downstream of KRAS have had limited success in clinical trials. Understanding the specific genomic vulnerabilities of KRAS-driven cancers may uncover novel patient-tailored treatment options.
METHODS: We first searched for synthetic lethal (SL) genetic interactions with mutant RAS in yeast with the ultimate aim to identify novel cancer-specific targets for therapy. Our method used selective ploidy ablation, which enables replication of cancer-specific gene expression changes in the yeast gene disruption library. Second, we used a genome-wide CRISPR/Cas9-based genetic screen in KRAS mutant human colon cancer cells to understand the mechanistic connection between the synthetic lethal interaction discovered in yeast and downstream RAS signaling in human cells.
RESULTS: We identify loss of the endoplasmic reticulum (ER) stress sensor IRE1 as synthetic lethal with activated RAS mutants in yeast. In KRAS mutant colorectal cancer cell lines, genetic ablation of the human ortholog of IRE1, ERN1, does not affect growth but sensitizes to MEK inhibition. However, an ERN1 kinase inhibitor failed to show synergy with MEK inhibition, suggesting that a non-kinase function of ERN1 confers MEK inhibitor resistance. To investigate how ERN1 modulates MEK inhibitor responses, we performed genetic screens in ERN1 knockout KRAS mutant colon cancer cells to identify genes whose inactivation confers resistance to MEK inhibition. This genetic screen identified multiple negative regulators of JUN N-terminal kinase (JNK) /JUN signaling. Consistently, compounds targeting JNK/MAPK8 or TAK1/MAP3K7, which relay signals from ERN1 to JUN, display synergy with MEK inhibition.
CONCLUSIONS: We identify the ERN1-JNK-JUN pathway as a novel regulator of MEK inhibitor response in KRAS mutant colon cancer. The notion that multiple signaling pathways can activate JUN may explain why KRAS mutant tumor cells are traditionally seen as highly refractory to MEK inhibitor therapy. Our findings emphasize the need for the development of new therapeutics targeting JUN activating kinases, TAK1 and JNK, to sensitize KRAS mutant cancer cells to MEK inhibitors.

Gao GY, Ma J, Lu P, et al.
Ophiopogonin B induces the autophagy and apoptosis of colon cancer cells by activating JNK/c-Jun signaling pathway.
Biomed Pharmacother. 2018; 108:1208-1215 [PubMed] Related Publications
OBJECTIVE: To investigate the effect of Ophiopogonin B (OP-B) on the autophagy and apoptosis of colon cancer cells via the regulation of JNK/c-Jun signaling pathway.
METHODS: Colon cancer cell lines (HT-29 and HCT-116) were treated with various concentrations of OP-B (0, 5, 10and 20 μmol/l) and JNK inhibitor SP600125. MTT assay, flow cytometry, immunofluorescence staining were used to detect the biological function ofHT-29 and HCT-116 cells, and expressions of autophagy-,apoptotic- and pathway-related proteins were measured by Western Blot. Moreover, a nude mice model with transplanted tumor was used to observe the effect of OP-B on the growth, autophagy and apoptosis of the transplanted tumor of colon cancer.
RESULTS: The results demonstrated that OP-B suppressed the proliferation of HT-29 and HCT-116 cell lines through the G0/G1 phase cell cycle arrest. Moreover, OP-B induced apoptosis by inhibiting the expression of Bax and cleaved caspase 3 and promoting the expression of Bcl-2. Treatment with OP-B also increased the expression of Beclin 1 and the conversion of LC3I to LC3II with the activation of JNK/c-Jun signaling pathway, but reduced the expression of P62, whereas SP600125 (an inhibitor of JNK) reversed these process. In addition, the xenograft model using HCT-116 cells provided further evidence of the inhibition of OP-B on tumor proliferation. Immunohistochemistry detection verified that OP-B enhance the positive expression rate of LC3, and increase the apoptosis index of tumor cells in vivo. Importantly, all these changes induced by OP-B were clearly in a dose-dependent manner.
CONCLUSION: OP-B may induce cell autophagy, apoptosis and cell cycle arrest by activating the JNK/ c-Jun signaling pathway, thereby inhibiting the growth of colon cancer.

He C, Zhang H, Wang B, et al.
SDF-1/CXCR4 axis promotes the growth and sphere formation of hypoxic breast cancer SP cells by c-Jun/ABCG2 pathway.
Biochem Biophys Res Commun. 2018; 505(2):593-599 [PubMed] Related Publications
ATP-binding cassette sub-family G member 2 (ABCG2) confers to the major phenotypes of side population (SP) cells, the cancer stem-like cells. In this study, the SP cells displayed a distinctly higher ABCG2 expression level, sphere formation efficiency (SFE) and growth rate even under hypoxia condition. CXCR4 overexpression by pcDNA-CXCR4 transfection robustly increased ABCG2 expression, and promoted SFE and growth of hypoxic SP cells, while CXCR4 inhibitor AMD3100 could suppress the promotion. Additionally, we found that CXCR4 promoted the expression of c-Jun, a major gene in the oncogenic JNK/c-Jun pathway. Our data on electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays both showed that c-Jun directly bound with the ABCG2 promoter sequence. Moreover, overexpression of JNK/c-Jun promoted ABCG2 expression, SFE, and growth of hypoxic SP cells and the promotion could be rescued by c-Jun inhibitor SP600125. In conclusion, CXCR4 increases the growth and SFE of breast cancer SP cells under hypoxia through c-Jun-mediated transcriptional activation of ABCG2.

Wang Z, Zou F, Tian Y, et al.
Paclitaxel reversed trastuzumab resistance via regulating JUN in human gastric cancer cells identified by FAN analysis.
Future Oncol. 2018; 14(26):2701-2712 [PubMed] Related Publications
AIM: In this study, we aim to use bioinformatics approach to identify paclitaxel-targeted modulators potentially involved in the process of reversing the trastuzumab resistance. Materials & methods: We extracted data from GSE77346 to identify potential trastuzumab resistance-related genes, used bioinformatics analysis and functional/activity network approach to find genes involved in trastuzumab resistance reversal.
RESULTS: We identified hub differentially expressed genes related to trastuzumab resistance, trastuzumab targeting and paclitaxel targeting, respectively. We then found C-Jun may be critical in trastuzumab resistance reversal.  This process may involve transcriptional activation of DUSP1 by JUN, which lead to regulation of DUSP1-related signaling pathways.
CONCLUSION: The present study revealed paclitaxel may reverse the trastuzumab resistance by JUN, which possibly in turn regulated DUSP1 and DUSP1-related signaling pathways.

Luo D, Xu X, Li J, et al.
The PDK1/c‑Jun pathway activated by TGF‑β induces EMT and promotes proliferation and invasion in human glioblastoma.
Int J Oncol. 2018; 53(5):2067-2080 [PubMed] Related Publications
Glioblastoma multiforme (GBM) is the most common primary malignant tumor affecting the human brain. Despite improvements in therapeutic technologies, patients with GBM have a poor clinical result and the molecular mechanisms responsible for the development of GBM have not yet been fully elucidated. 3-phosphoinositide dependent protein kinase 1 (PDK1) is upregulated in various tumors and promotes tumor invasion. In glioma, transforming growth factor-β (TGF‑β) promotes cell invasion; however, whether TGF‑β directly regulates PDK1 protein and promotes proliferation and invasion is not yet clear. In this study, PDK1 levels were measured in glioma tissues using tissue microarray (TMA) by immunohistochemistry (IHC) and RT‑qPCR. Kaplan-Meier analyses were used to calculate the survival rate of patients with glioma. In vitro, U251 and U87 glioma cell lines were used for functional analyses. Cell proliferation and invasion were analyzed using siRNA transfection, MTT assay, RT‑qPCR, western blot analysis, flow cytometry and invasion assay. In vivo, U251 glioma cell xenografts were established. The results revealed that PDK1 protein was significantly upregulated in glioma tissues compared with non-tumorous tissues. Furthermore, the higher PDK1 levels were associated with a large tumor size (>5.0 cm), a higher WHO grade and a shorter survival of patients with GBM. Univariate and multivariate analyses indicated that PDK1 was an independent prognostic factor. In vivo, PDK1 promoted glioma tumor xenograft growth. In vitro, functional analyses confirmed that TGF‑β upregulated PDK1 protein expression and PDK1 promoted cell migration and invasion, and functioned as an oncogene in GBM, by upregulating c‑Jun protein and inducing epithelial-mesenchymal transition (EMT). c‑Jun protein were overexpressed in glioma tissues and positively correlated with PDK1 levels. Moreover, our findings were further validated by the online Oncomine database. On the whole, the findings of this study indicate that in GBM, PDK1 functions as an oncogene, promoting proliferation and invasion.

Bourguignon LYW, Earle C, Shiina M
Hyaluronan-CD44 interaction promotes HPV 16 E6 oncogene-mediated oropharyngeal cell carcinoma survival and chemoresistance.
Matrix Biol. 2019; 78-79:180-200 [PubMed] Related Publications
Head and neck squamous cell carcinoma (HNSCC) is a malignancy that often involves the oral cavity, pharynx, larynx, or paranasal sinuses. There is a compelling evidence of the human papilloma virus including HPV16 E6 oncogene drives cell transformation and oncogenic processes of HPV positive (HVP+) HNSCC [in particular, Oropharyngeal Squamous Cell Carcinoma (OPSCC)]. In this study, we determined that human OPSCC-derived, HPV16 E6+ cells (UMSCC-104 and UMSCC-47 cell lines) express CD44 and a regulatory transcription factor, c-Jun. Importantly, interaction between matrix hyaluronan (HA) and CD44 (an HA receptor) promotes c-Jun phosphorylation followed by phospho-c-Jun nuclear translocation and co-localization with HPV16 E6 in the nucleus of both UMSCC-104 and UMSCC-47 cells. Further analyses revealed that HPV16 E6 expression is regulated by an upstream promoter containing AP1/c-Jun binding site(s), and chromatin immunoprecipitation (ChIP) assays demonstrated that stimulation of HPV16 E6 expression by HA-CD44 interaction is phospho-c-Jun dependent in these HPV16+ UMSCC-104 and UMSCC-47 cells. This process results in an upregulation of survival proteins, inhibitors of the apoptosis family of proteins (IAPs) and chemoresistance in these HPV16+ cells. Treatment of UMSCC-104 or UMSCC-47 cells with c-Jun-specific or HPV16 E6-specific small interfering RNAs effectively blocks HA/CD44-mediated c-Jun signaling and abrogates HPV16 E6 expression as well as causes downregulation of survival proteins (cIAP-1 and cIAP-2) expression and enhancement of chemosensitivity. Together, these findings suggest that the HA/CD44-induced c-Jun signaling plays a pivotal role in HPV16 E6 upregulation leading to survival protein (cIAP-1/cIAP-2) production and chemoresistance in HPV16+ UMSCC-104 and UMSCC-47 cells. Most importantly, using a mouse xenograft model, we have observed that Cisplatin chemotherapy combined with the suppression of CD44, c-Jun and HPV16 E6 (by treating both UMSCC-104 cells and UMSCC-47 cells with CD44shRNA or c-Jun shRNA or HPV16 E6 shRNA) appears to be more effective in tumor size reduction than chemotherapy alone. Thus, these newly-discovered HA/CD44-c-Jun/HPV16E6 signaling pathways may provide new drug targets for overcoming cisplatin chemoresistance in HPV16E6-positive OPSCC cells.

Zhang LZ, Man QW, Liu JY, et al.
Overexpression of Fra-1, c-Jun and c-Fos in odontogenic keratocysts: potential correlation with proliferative and anti-apoptotic activity.
Histopathology. 2018; 73(6):933-942 [PubMed] Related Publications
AIMS: The purpose of this study was to explore the potential involvement of Fra-1, c-Jun and c-Fos, three vital members of the AP-1 complex, in the pathogenesis of odontogenic keratocysts (OKCs).
METHODS AND RESULTS: Tissue samples, containing 10 normal oral mucosa (OM), 10 dentigerous cysts (DC) and 32 OKC specimens, were applied to investigate the expression levels of Fra-1, c-Jun and c-Fos by immunohistochemistry and real-time-quantitative polymerase chain reaction (RT-qPCR). The association between Fra-1, c-Jun and c-Fos expression levels and markers of proliferation [Ki-67, proliferating cell nuclear antigen (PCNA)], anti-apoptosis (Bcl-2) was then investigated in the OKC serial tissue sections. The results showed that Fra-1, c-Jun and c-Fos expression levels were increased significantly in OKCs compared to these in OM and DC tissue samples. Meanwhile, the expression levels of Fra-1, c-Jun and c-Fos were associated positively with the expression levels of Ki-67, PCNA and Bcl-2, as confirmed further by double-labelling immunofluorescence analysis and hierarchical analysis.
CONCLUSIONS: This study revealed for the first time that Fra-1, c-Jun and c-Fos were overexpressed in OKCs and had a close correlation with proliferation and anti-apoptosis potential of OKCs.

Meng S, Wang G, Lu Y, Fan Z
Functional cooperation between HIF-1α and c-Jun in mediating primary and acquired resistance to gefitinib in NSCLC cells with activating mutation of EGFR.
Lung Cancer. 2018; 121:82-90 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
OBJECTIVE: Hypoxia-inducible factor 1 (HIF-1) and activator protein 1 (AP-1) are important transcription factors regulating expression of genes involved in cell survival. HIF-1α and c-Jun are key components of HIF-1 and AP-1, respectively, and are regulated by epidermal growth factor receptor (EGFR)-mediated cell signaling and tumor microenvironmental cues. The roles of HIF-1α and c-Jun in development of resistance to EGFR tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC) with activating mutation of EGFR have not been explored. In this study, we investigated the roles of HIF-1α and c-Jun in mediating primary and acquired resistance to gefitinib in NSCLC cells with activating mutation of EGFR.
MATERIALS AND METHODS: Changes in HIF-1α protein and in total and phosphorylated c-Jun levels in relation to changes in total and phosphorylated EGFR levels before and after gefitinib treatment were measured using Western blot analysis in NSCLC cells sensitive or resistant to gefitinib. The impact of overexpression of a constitutively expressed HIF-1α (HIF-1α/ΔODD) or a constitutively active c-Jun upstream regulator (SEK1 S220E/T224D mutant) on cell response to gefitinib was also examined. The effect of pharmacological inhibition of SEK1-JNK-c-Jun pathway on cell response to gefitinib was evaluated.
RESULTS: Downregulation of HIF-1α and total and phosphorylated c-Jun levels correlated with cell inhibitory response to gefitinib better than decrease in phosphorylated EGFR did in NSCLC cells with intrinsic or acquired resistance to gefitinib. Overexpression of HIF-1α/ΔODD or SEK1 S220E/T224D mutant conferred resistance to gefitinib. There exists a positive feed-forward regulation loop between HIF-1 and c-Jun. The JNK inhibitor SP600125 sensitized gefitinib-resistant NSCLC cells to gefitinib.
CONCLUSIONS: HIF-1α and c-Jun functionally cooperate in development of resistance to gefitinib in NSCLC cells. The translational value of inhibiting HIF-1α/c-Jun cooperation in overcoming resistance to EGFR TKI treatment of NSCLC cells with activating mutation of EGFR deserves further investigation.

Cai H, Cho EA, Li Y, et al.
Melanoma protective antitumor immunity activated by catalytic DNA.
Oncogene. 2018; 37(37):5115-5126 [PubMed] Related Publications
Melanoma incidence is increasing worldwide, and although drugs such as BRAF/MEK small-molecule inhibitors and immune checkpoint antibodies improve patient outcomes, most patients ultimately fail these therapies and alternative treatment strategies are urgently needed. DNAzymes have recently undergone clinical trials with signs of efficacy and no serious adverse events attributable to the DNAzyme. Here we investigated c-Jun expression in human primary and metastatic melanoma. We also explored the role of T cell immunity in DNAzyme inhibition of primary melanoma growth and the prevention of growth in non-treated tumors after the cessation of treatment in a mouse model. c-Jun was expressed in 80% of melanoma cells in human primary melanomas (n = 17) and in 83% of metastatic melanoma cells (n = 38). In contrast, c-Jun was expressed in only 11% of melanocytes in benign nevi (n = 24). Dz13, a DNAzyme targeting c-Jun/AP-1, suppressed both Dz13-injected and untreated B16F10 melanoma growth in the same mice, an abscopal effect relieved in each case by administration of anti-CD4/anti-CD8 antibodies. Dz13 increased levels of cleaved caspase-3 within the tumors. New, untreated melanomas grew poorly in mice previously treated with Dz13. Administration of anti-CD4/anti-CD8 antibodies ablated this inhibitory effect and the tumors grew rapidly. Dz13 inhibited c-Jun expression, reduced intratumoral vascularity (vascular lumina area defined by CD31 staining), and increased CD4

Aleksic T, Gray N, Wu X, et al.
Nuclear IGF1R Interacts with Regulatory Regions of Chromatin to Promote RNA Polymerase II Recruitment and Gene Expression Associated with Advanced Tumor Stage.
Cancer Res. 2018; 78(13):3497-3509 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
Internalization of ligand-activated type I IGF receptor (IGF1R) is followed by recycling to the plasma membrane, degradation or nuclear translocation. Nuclear IGF1R reportedly associates with clinical response to IGF1R inhibitory drugs, yet its role in the nucleus is poorly characterized. Here, we investigated the significance of nuclear IGF1R in clinical cancers and cell line models. In prostate cancers, IGF1R was predominantly membrane localized in benign glands, while malignant epithelium contained prominent internalized (nuclear/cytoplasmic) IGF1R, and nuclear IGF1R associated significantly with advanced tumor stage. Using ChIP-seq to assess global chromatin occupancy, we identified IGF1R-binding sites at or near transcription start sites of genes including

Lin B, Hong H, Jiang X, et al.
c‑Jun suppresses the expression of WNT inhibitory factor 1 through transcriptional regulation and interaction with DNA methyltransferase 1 in gallbladder cancer.
Mol Med Rep. 2018; 17(6):8180-8188 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
WNT inhibitory factor 1 (WIF‑1) is involved in the tumorigenicity and progression of several types of tumor, which has been attributed to aberrant hypermethylation of its promoter. However, the role of WIF‑1 in the pathogenesis of gallbladder cancer (GBC) remains to be fully elucidated, and the data available are insufficient to identify the upstream molecular mechanisms involved. In the present study, the methylation status of the WIF‑1 promoter was investigated using methylation‑specific polymerase chain reaction (PCR) and bisulfate sequencing PCR in GBC cells. Immunohistochemistry, reverse transcription‑quantitative PCR and western blotting were used to analyze the expression of WIF‑1 and c‑Jun. In addition, a co‑immunoprecipitation assay was designed to determine the DNA methyltransferase that was implicated in WIF‑1 methylation. The results revealed that the expression of WIF‑1 was low in GBC, and that this was caused by aberrant DNA hypermethylation. However, there were no significant correlations between the expression of WIF‑1 and certain key clinicopathological characteristics of GCB. Subsequently, a negative correlation was found between the protein expression of c‑Jun and WIF‑1 in 50 GBC specimens using immunohistochemistry. The demethylation and re‑expression of WIF‑1 was observed when the expression of c‑Jun was silenced. Finally, it was found that the knockdown of c‑Jun downregulated the expression of DNA methyltransferase 1 (DNMT1) and that c‑Jun interacted with DNMT1. Taken together, the present study suggested that c‑Jun suppressed the expression of WIF‑1 through transcriptional regulation and interaction with DNMT1 in GBC. These findings provide an alternative pathogenesis of GBC, which may be promising as a novel reference for early diagnosis or future treatment.

He W, Zhang H, Wang Y, et al.
CTHRC1 induces non-small cell lung cancer (NSCLC) invasion through upregulating MMP-7/MMP-9.
BMC Cancer. 2018; 18(1):400 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: The strong invasive and metastatic nature of non-small cell lung cancer (NSCLC) leads to poor prognosis. Collagen triple helix repeat containing 1 (CTHRC1) is involved in cell migration, motility and invasion. The object of this study is to investigate the involvement of CTHRC1 in NSCLC invasion and metastasis.
METHODS: A proteomic analysis was performed to identify the different expression proteins between NSCLC and normal tissues. Cell lines stably express CTHRC1, MMP7, MMP9 were established. Invasion and migration were determined by scratch and transwell assays respectively. Clinical correlations of CTHRC1 in a cohort of 230 NSCLC patients were analysed.
RESULTS: CTHRC1 is overexpressed in NSCLC as measured by proteomic analysis. Additionally, CTHRC1 increases tumour cell migration and invasion in vitro. Furthermore, CTHRC1 expression is significantly correlated with matrix metalloproteinase (MMP)7 and MMP9 expression in sera and tumour tissues from NSCLC. The invasion ability mediated by CTHRC1 were mainly MMP7- and MMP9-dependent. MMP7 or MMP9 depletion significantly eradicated the pro-invasive effects mediated by CTHRC1 on NSCLC cells. Clinically, patients with high CTHRC1 expression had poor survival.
CONCLUSIONS: CTHRC1 serves as a pro-metastatic gene that contributes to NSCLC invasion and metastasis, which are mediated by upregulated MMP7 and MMP9 expression. Targeting CTHRC1 may be beneficial for inhibiting NSCLC metastasis.

Cleveland KH, Yeung S, Huang KM, et al.
Phosphoproteome profiling provides insight into the mechanism of action for carvedilol-mediated cancer prevention.
Mol Carcinog. 2018; 57(8):997-1007 [PubMed] Related Publications
Recent studies suggest that the β-blocker drug carvedilol prevents skin carcinogenesis but the mechanism is unknown. Carvedilol is one of a few β-blockers identified as biased agonist based on an ability to promote β-arrestin-mediated processes such as ERK phosphorylation. To understand the role of phosphoproteomic signaling in carvedilol's anticancer activity, the mouse epidermal JB6 P+ cells treated with EGF, carvedilol, or their combination were analyzed using the Phospho Explorer Antibody Array containing 1318 site-specific and phospho-specific antibodies of over 30 signaling pathways. The array data indicated that both EGF and carvedilol increased phosphorylation of ERK's cytosolic target P70S6 K while its nuclear target ELK-1 were activated only by EGF; Furthermore, EGF-induced phosphorylation of ELK-1 and c-Jun was attenuated by carvedilol. Subcellular fractionation analysis indicated that ERK nuclear translocation induced by EGF was blocked by co-treatment with carvedilol. Western blot and luciferase reporter assays confirmed that the biased β-blockers carvedilol and alprenolol blocked EGF-induced phosphorylation and activation of c-Jun/AP-1 and ELK-1. Consistently, both carvedilol and alprenolol strongly prevented EGF-induced neoplastic transformation of JB6 P+ cells. Remarkably, oral carvedilol treatment significantly inhibited the growth of A375 melanoma xenograft in SCID mice. As nuclear translocation of ERK is a key step in carcinogenesis, inhibition of this event is proposed as a novel anticancer mechanism for biased β-blockers such as carvedilol.

Lam CF, Yeung HT, Lam YM, Ng RK
Reactive oxygen species activate differentiation gene transcription of acute myeloid leukemia cells via the JNK/c-JUN signaling pathway.
Leuk Res. 2018; 68:112-119 [PubMed] Related Publications
Reactive oxygen species (ROS) and altered cellular redox status are associated with many malignancies. Acute myeloid leukemia (AML) cells are maintained at immature state by differentiation blockade, which involves deregulation of transcription factors in myeloid differentiation. AML cells can be induced to differentiate by phorbol-12-myristate-13-acetate (PMA), which possesses pro-oxidative activity. However, the signaling events mediated by ROS in the activation of transcriptional program during AML differentiation has not been fully elucidated. Here, we investigated AML cell differentiation by treatment with PMA and ROS scavenger N-acetyl-l-cysteine (NAC). We observed elevation of intracellular ROS level in the PMA-treated AML cells, which correlated with differentiated cell morphology and increased CD11b

Wang SW, Chen YR, Chow JM, et al.
Stimulation of Fas/FasL-mediated apoptosis by luteolin through enhancement of histone H3 acetylation and c-Jun activation in HL-60 leukemia cells.
Mol Carcinog. 2018; 57(7):866-877 [PubMed] Related Publications
Luteolin (3',4',5,7-tetrahydroxyflavone), which exists in fruits, vegetables, and medicinal herbs, is used in Chinese traditional medicine for treating various diseases, such as hypertension, inflammatory disorders, and cancer. However, the gene-regulatory role of luteolin in cancer prevention and therapy has not been clarified. Herein, we demonstrated that treatment with luteolin resulted in a significant decrease in the viability of human leukemia cells. In the present study, by evaluating fragmentation of DNA and poly (ADP-ribose) polymerase (PARP), we found that luteolin was able to induce PARP cleavage and nuclear fragmentation as well as an increase in the sub-G

Kany S, Woschek M, Kneip N, et al.
Simvastatin exerts anticancer effects in osteosarcoma cell lines via geranylgeranylation and c-Jun activation.
Int J Oncol. 2018; 52(4):1285-1294 [PubMed] Related Publications
Osteosarcoma is the leading primary bone cancer in young adults and exhibits high chemoresistance rates. Therefore, characterization of both alternative treatment options and the underlying mechanisms is essential. Simvastatin, a cholesterol-lowering drug, has among its pleiotropic effects anticancer potential. Characterizing this potential and the underlying mechanisms in osteosarcoma is the subject of the present study. Human osteosarcoma cells (SaOS-2 and U2OS) were treated with simvastatin (4-66 µM) for 48 or 72 h. The effects of downstream substrate mevalonate (MA) or substrates for isoprenylation farnesyl pyrophosphate (FPP) and geranylgeranyl-pyrophosphate (GGPP) were evaluated using add-back experiments. Tumour growth using MTT assay, apoptosis, cell cycle and signalling cascades involved in simvastatin-induced manipulation were analysed. The results revealed that simvastatin dose-dependently inhibited cell growth. Simvastatin significantly induced apoptosis, increased the Bax/Bcl-2 ratio, and cleavage of caspase-3 and PARP protein. Simvastatin impaired cell cycle progression as shown by significantly increased percentages of cells in the G0/G1 phase and lower percentages of cells in the S phase. Gene expression levels of cell cycle-regulating genes (TP53, CDKN1A and CDK1) were markedly altered. These effects were not completely abolished by FPP, but were reversed by MA and GGPP. JNK and c-Jun phosphorylation was enhanced after simvastatin treatment, while those were abolished when either MA or GGPP were added. In conclusion, simvastatin acts primarily by reducing prenylation to induce apoptosis and reduce osteosarcoma cell growth. Particularly enhanced activation of c-Jun seems to play a pivotal role in osteosarcoma cell death.

Sesarman A, Tefas L, Sylvester B, et al.
Anti-angiogenic and anti-inflammatory effects of long-circulating liposomes co-encapsulating curcumin and doxorubicin on C26 murine colon cancer cells.
Pharmacol Rep. 2018; 70(2):331-339 [PubMed] Related Publications
BACKGROUND: Emerging treatment options for colon cancer are needed to overcome the limitations regarding the side effects of current chemotherapeutics and drug resistance. The goal of this study was to assess the antitumor actions of PEGylated long-circulating liposomes (LCL) co-delivering curcumin (CURC) and doxorubicin (DOX) on murine colon carcinoma cells (C26).
METHODS: The cytotoxicity of CURC and DOX, administered alone or in combination, either in free or LCL form, was evaluated with regard to antiproliferative effects on C26 cells and to protumor processes that might be affected.
RESULTS: Our results indicated that PEGylated LCL-CURC-DOX exerted strong antiproliferative effects on C26 cells, slightly exceeding those induced by free CURC-DOX, but higher than either agent administered alone in their free form. These effects of LCL-CURC-DOX were due to the inhibition of the production of angiogenic/inflammatory proteins in a NF-κB-dependent manner, but were independent of ROS production or AP-1 c-Jun activation. Notable, the anti-angiogenic actions of LCL-CURC-DOX appeared to be much stronger than those induced by the co-administration of CURC and DOX in their free form, on C26 colon cancer cells.
CONCLUSION: LCL-CURC-DOX demonstrated enhanced cytotoxicity on C26 murine colon cancer cells by inhibiting the production of the majority of factors involved in tumor-associated angiogenesis and inflammation and is now being evaluated in vivo regarding its efficacy towards tumor growth in colon cancer.

Luo ML, Zhou Z, Sun L, et al.
An ADAM12 and FAK positive feedback loop amplifies the interaction signal of tumor cells with extracellular matrix to promote esophageal cancer metastasis.
Cancer Lett. 2018; 422:118-128 [PubMed] Related Publications
Esophageal squamous cell carcinomas (ESCCs) have a poor prognosis mostly due to early metastasis. To explore the early event of metastasis in ESCC, we established an in vitro selection model to mimic the interaction of tumor cells with extracellular matrix, through which a sub-line of ESCC cells with high invasive ability was generated. By comparing the gene expression profile of the highly invasive sub-line to that of the parental cells, ADAM12-L was identified as a candidate gene promoting ESCC cell invasion. Immunohistochemistry revealed that the ADAM12-L was overexpressed in human ESCC tissues, especially at cancer invasive edge, and ADAM12-L overexpression tightly correlated with increased metastasis and poor outcome of ESCC patients. Indeed, ADAM12-L knockdown reduced the invasion and metastasis of ESCC cells both in vitro and in vivo. Furthermore, we demonstrated that ADAM12-L participated in focal adhesion turnover and promoted the activation of focal adhesion kinase (FAK), which in turn increased ADAM12-L transcription through FAK/JNK/c-Jun axis. Therefore, a loop initiated from the cancer cell upon the engagement with extracellular matrix through FAK and c-Jun to enhance ADAM12-L expression is established, leading to the positive feedback of further FAK activation and prompting metastasis. Our study indicates that overexpression of ADAM12-L can serve as a precision marker to determine the activation of this loop. Targeting ADAM12-L to disrupt this positive feedback loop represents a promising strategy to treat the metastasis of esophageal cancers.

Zhao M, Xu P, Liu Z, et al.
Dual roles of miR-374a by modulated c-Jun respectively targets CCND1-inducing PI3K/AKT signal and PTEN-suppressing Wnt/β-catenin signaling in non-small-cell lung cancer.
Cell Death Dis. 2018; 9(2):78 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
MiR-374a appears to play a complex role in non-small-cell lung cancer (NSCLC). Here, we demonstrate a dual role for miR-374a in NSCLC pathogenesis. The effects and modulatory mechanisms of miR-374a on cell growth, migration, invasion, and in vivo tumorigenesis and metastasis in nude mice were also analyzed. The expression of miR-374a was examined in NSCLC and non-cancerous lung tissues by quantitative real-time reverse transcription-PCR (qRT-PCR), and in situ hybridization, respectively. miR-374a directly targets CCND1 and inactivates PI3K/AKT and Ras-mediated cell cycle signalings, as well as epithelial-mesenchymal transition (EMT). This not only dramatically suppressed cell growth, migration, invasion,and metastasis, but also elevated A549 and pc-9 NSCLC cell sensitivity to cisplatin (DDP) while increasing survival time of tumor-bearing mice. Interestingly, miR-374a serves an inverse function in SPCA-1 and H1975 NSCLC cells by directly targeting PTEN to activate Wnt/β-catenin and Ras signalings and its downstream cascade signals. Surprisingly, transcription factor c-Jun bound to the promoter region of human miR-374a and suppressed miR-374a in A549 and pc-9 cells while inducing it in SPCA-1 and H1975 cells. Increased levels of miR-374a appeared to serve a protective role by targeting CCND1 in early-stage NSCLC (Stages I and II). Inversely, increased miR-374a was an unfavorable factor when targeting PTEN in more advanced staged NSCLC patients. Our studies are the first to demonstrate that miR-374a plays divergent roles in NSCLC pathogenesis at different stages of the disease and implicate the potential application of miR-374a targeting for cancer therapy.

Liu Y, Chen X, Cheng R, et al.
The Jun/miR-22/HuR regulatory axis contributes to tumourigenesis in colorectal cancer.
Mol Cancer. 2018; 17(1):11 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: Colorectal cancer (CRC) is a severe health problem worldwide. Clarifying the mechanisms for the deregulation of oncogenes and tumour suppressors in CRC is vital for its diagnosis, treatment, prognosis and prevention. Hu antigen R (HuR), which is highly upregulated in CRC, functions as a pivotal oncogene to promote CRC progression. However, the underlying cause of its dysregulation is poorly understood.
METHODS: In CRC tissue sample pairs, HuR protein levels were measured by Western blot and immunohistochemical (IHC) staining, respectively. HuR mRNA levels were also monitored by qRT-PCR. Combining meta-analysis and microRNA (miRNA) target prediction software, we predicted miRNAs that targeted HuR. Pull-down assay, Western blot and luciferase assay were utilized to demonstrate the direct binding of miR-22 on HuR's 3'-UTR. The biological effects of HuR and miR-22 were investigated both in vitro by CCK-8, EdU and Transwell assays and in vivo by a xenograft mice model. JASPAR and SABiosciences were used to predict transcriptional factors that could affect miR-22. Luciferase assay was used to explore the validity of putative Jun binding sites for miR-22 regulation. ChIP assay was performed to test the Jun's occupancy on the C17orf91 promoter.
RESULTS: We observed a significant upregulation of HuR in CRC tissue pairs and confirmed the oncogenic function of HuR both in vitro and in vivo. We found that an important tumour-suppressive miRNA, miR-22, was significantly downregulated in CRC tissues and inversely correlated with HuR in both CRC tissues and CRC cell lines. We demonstrated that miR-22 directly bound to the 3'-UTR of HuR and led to inhibition of HuR protein, which repressed CRC proliferation and migration in vitro and decelerated CRC xenografted tumour growth in vivo. Furthermore, we found that the onco-transcription factor Jun could inhibit the transcription of miR-22.
CONCLUSIONS: Our findings highlight the critical roles of the Jun/miR-22/HuR regulatory axis in CRC progression and may provide attractive potential targets for CRC prevention and treatment.

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