MAP2K4

Gene Summary

Gene:MAP2K4; mitogen-activated protein kinase kinase 4
Aliases: JNKK, MEK4, MKK4, SEK1, SKK1, JNKK1, SERK1, MAPKK4, PRKMK4, SAPKK1, SAPKK-1
Location:17p12
Summary:This gene encodes a member of the mitogen-activated protein kinase (MAPK) family. Members of this family 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. They form a three-tiered signaling module composed of MAPKKKs, MAPKKs, and MAPKs. This protein is phosphorylated at serine and threonine residues by MAPKKKs and subsequently phosphorylates downstream MAPK targets at threonine and tyrosine residues. A similar protein in mouse has been reported to play a role in liver organogenesis. A pseudogene of this gene is located on the long arm of chromosome X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:dual specificity mitogen-activated protein kinase kinase 4
Source:NCBIAccessed: 11 March, 2017

Ontology:

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 (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Latest Publications: MAP2K4 (cancer-related)

Iqbal B, Masood A, Lone MM, et al.
Polymorphism of Metastasis Suppressor Genes MKK4 and NME1 in Kashmiri Patients with Breast Cancer.
Breast J. 2016; 22(6):673-677 [PubMed] Related Publications
Genetic polymorphisms in metastatic suppressor genes like MKK4 and NME1 are not well studied in breast cancer. Hence, we analyzed the relationship between MKK4 and NME1 polymorphisms and breast cancer risk in Kashmir, India. The different genotypes of NME1 and MKK4 genes were analyzed by polymerase chain reaction and restriction fragment length polymorphism in 130 breast cancer cases and 200 age- and sex-matched controls. Conditional logistic regression models were used to assess the association of various genotypes with breast cancer. In this study, we found an inverse association between MKK4 promoter polymorphism and breast cancer risk. As compared to TT (wild) genotype, individuals with TG (heterozygous) (OR = 0.32; 95% CI = (0.17-0.58) and GG (mutant) (OR = 0.13; CI = 0.04-0.40) genotypes showed decreased risk of breast cancer. When participants were classified on the basis of lymph node involvement, a strong association between NME1 heterozygous genotype (OR = 3.82; CI = (1.54-9.44) and breast cancer was found.

Aherne ST, Smyth P, Freeley M, et al.
Altered expression of mir-222 and mir-25 influences diverse gene expression changes in transformed normal and anaplastic thyroid cells, and impacts on MEK and TRAIL protein expression.
Int J Mol Med. 2016; 38(2):433-45 [PubMed] Free Access to Full Article Related Publications
Thyroid cancer is the most common endocrine malignancy and accounts for the majority of endocrine cancer-related deaths each year. Our group and others have previously demonstrated dysfunctional microRNA (miRNA or miR) expression in the context of thyroid cancer. The objective of the present study was to investigate the impact of synthetic manipulation of expression of miR-25 and miR-222 in benign and malignant thyroid cells. miR-25 and miR-222 expression was upregulated in 8505C (an anaplastic thyroid cell line) and Nthy-ori (a SV40-immortalised thyroid cell line) cells, respectively. A transcriptomics-based approach was utilised to identify targets of the two miRNAs and real-time PCR and western blotting were used to validate a subset of the targets. Almost 100 mRNAs of diverse functions were found to be either directly or indirectly targeted by both miR-222 and miR-25 [fold change ≥2, false discovery rate (FDR) ≤0.05]. Gene ontology analysis showed the miR-25 gene target list to be significantly enriched for genes involved in cell adhesion. Fluidigm real-time PCR technologies were used to validate the downregulation of 23 and 22 genes in response to miR-25 and miR-222 overexpression, respectively. The reduction of the expression of two miR-25 protein targets, TNF-related apoptosis‑inducing ligand (TRAIL) and mitogen-activated protein kinase kinase 4 (MEK4), was also validated. Manipulating the expression of both miR-222 and miR-25 influenced diverse gene expression changes in thyroid cells. Increased expression of miR-25 reduced MEK4 and TRAIL protein expression, and cell adhesion and apoptosis are important aspects of miR-25 functioning in thyroid cells.

Dieci MV, Smutná V, Scott V, et al.
Whole exome sequencing of rare aggressive breast cancer histologies.
Breast Cancer Res Treat. 2016; 156(1):21-32 [PubMed] Related Publications
Little is known about mutational landscape of rare breast cancer (BC) subtypes. The aim of the study was to apply next generation sequencing to three different subtypes of rare BCs in order to identify new genes related to cancer progression. We performed whole exome and targeted sequencing of 29 micropapillary, 23 metaplastic, and 27 pleomorphic lobular BCs. Micropapillary BCs exhibit a profile comparable to common BCs: PIK3CA, TP53, GATA3, and MAP2K4 were the most frequently mutated genes. Metaplastic BCs presented a high frequency of TP53 (78 %) and PIK3CA (48 %) mutations and were recurrently mutated on KDM6A (13 %), a gene involved in histone demethylation. Pleomorphic lobular carcinoma exhibited high mutation rate of PIK3CA (30 %), TP53 (22 %), and CDH1 (41 %) and also presented mutations in PYGM, a gene involved in glycogen metabolism, in 8 out of 27 samples (30 %). Further analyses of publicly available datasets showed that PYGM is dramatically underexpressed in common cancers as compared to normal tissues and that low expression in tumors is correlated with poor relapse-free survival. Immunohistochemical staining on formalin-fixed paraffin-embedded tissues available in our cohort of patients confirmed higher PYGM expression in normal breast tissue compared to equivalent tumoral zone. Next generation sequencing methods applied on rare cancer subtypes can serve as a useful tool in order to uncover new potential therapeutic targets. Sequencing of pleomorphic lobular carcinoma identified a high rate of alterations in PYGM. These findings emphasize the role of glycogen metabolism in cancer progression.

Hoang B, Shi Y, Frost PJ, et al.
SGK Kinase Activity in Multiple Myeloma Cells Protects against ER Stress Apoptosis via a SEK-Dependent Mechanism.
Mol Cancer Res. 2016; 14(4):397-407 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
UNLABELLED: To assess the role of the serum and glucocorticoid-regulated kinase (SGK) kinase in multiple myeloma, we ectopically expressed wild type or a phosphomimetic version of SGK into multiple myeloma cell lines. These cells were specifically resistant to the ER stress inducers tunicamycin, thapsigargin, and bortezomib. In contrast, there was no alteration of sensitivity to dexamethasone, serum starvation, or mTORC inhibitors. Mining of genomic data from a public database indicated that low baseline SGK expression in multiple myeloma patients correlated with enhanced ability to undergo a complete response to subsequent bortezomib treatment and a longer time to progression and overall survival following treatment. SGK overexpressing multiple myeloma cells were also relatively resistant to bortezomib in a murine xenograft model. Parental/control multiple myeloma cells demonstrated a rapid upregulation of SGK expression and activity (phosphorylation of NDRG-1) during exposure to bortezomib and an SGK inhibitor significantly enhanced bortezomib-induced apoptosis in cell lines and primary multiple myeloma cells. In addition, a multiple myeloma cell line selected for bortezomib resistance demonstrated enhanced SGK expression and SGK activity. Mechanistically, SGK overexpression constrained an ER stress-induced JNK proapoptotic pathway and experiments with a SEK mutant supported the notion that SGK's protection against bortezomib was mediated via its phosphorylation of SEK (MAP2K4) which abated SEK/JNK signaling. These data support a role for SGK inhibitors in the clinical setting for myeloma patients receiving treatment with ER stress inducers like bortezomib.
IMPLICATIONS: Enhanced SGK expression and activity in multiple myeloma cells contributes to resistance to ER stress, including bortezomib challenge.

He W, Wu Y, Tang X, et al.
HDAC inhibitors suppress c-Jun/Fra-1-mediated proliferation through transcriptionally downregulating MKK7 and Raf1 in neuroblastoma cells.
Oncotarget. 2016; 7(6):6727-47 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Activator protein 1 (AP-1) is a transcriptional factor composed of the dimeric members of bZIP proteins, which are frequently deregulated in human cancer cells. In this study, we aimed to identify an oncogenic AP-1 dimer critical for the proliferation of neuroblastoma cells and to investigate whether histone deacetylase inhibitors (HDACIs), a new generation of anticancer agents, could target the AP-1 dimer. We report here that HDACIs including trichostatin A, suberoylanilidehydroxamic acid, valproic acid and M344 can transcriptionally suppress both c-Jun and Fra-1, preceding their inhibition of cell growth. c-Jun preferentially interacting with Fra-1 as a heterodimer is responsible for AP-1 activity and critical for cell growth. Mechanistically, HDACIs suppress Fra-1 expression through transcriptionally downregulating Raf1 and subsequently decreasing MEK1/2-ERK1/2 activity. Unexpectedly, HDACI treatment caused MKK7 downregulation at both the protein and mRNA levels. Deletion analysis of the 5'-flanking sequence of the MKK7 gene revealed that a major element responsible for the downregulation by HDACI is located at -149 to -3 relative to the transcriptional start site. Knockdown of MKK7 but not MKK4 remarkably decreased JNK/c-Jun activity and proliferation, whereas ectopic MKK7-JNK1 reversed HDACI-induced c-Jun suppression. Furthermore, suppression of both MKK-7/c-Jun and Raf-1/Fra-1 activities was involved in the tumor growth inhibitory effects induced by SAHA in SH-SY5Y xenograft mice. Collectively, these findings demonstrated that c-Jun/Fra-1 dimer is critical for neuroblastoma cell growth and that HDACIs act as effective suppressors of the two oncogenes through transcriptionally downregulating MKK7 and Raf1.

Peng B, Chai Y, Li Y, et al.
CIP2A overexpression induces autoimmune response and enhances JNK signaling pathway in human lung cancer.
BMC Cancer. 2015; 15:895 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Cancerous inhibitor of PP2A (CIP2A) is a recently characterized oncoprotein, which promotes cancer cell proliferation. But the role of CIP2A in lung cancer progression is still not well understood.
METHODS: The expression level of CIP2A in lung cancer tissues was examined by immunohistochemistry. CIP2A-associated cell proliferation was performed by knock down or overexpression of CIP2A in lung cancer cells. Phospho-array was used to screen kinase candidates related to expression change of CIP2A. Western-blot and luciferase reporter assay were used to validate phospho-array results.
RESULTS: Overexpression of CIP2A in lung cancer not only triggers immune response in lung cancer patients but also promotes lung cancer cell proliferation. By phospho-array, several kinase candidates were identified, one of which is c-Jun activated kinases (JNK). The knock down of CIP2A decreased JNK phosphorylation, and the phosphorylation of downstream transcriptional factors, ATF2 and c-Jun, whose transcriptional activity were decreased as well. Furthermore, the expression level of CIP2A also affected the phosphorylation of the upstream kinase of JNK, MKK4/MKK7. At last, treatment with JNK inhibitor partially abolished CIP2A-induced cell proliferation.
CONCLUSION: CIP2A is a tumor-associated autoantigen in lung cancer, which promote lung cancer proliferation partially through MKK4/7-JNK signaling pathway.

Geng P, Ou J, Xie G, et al.
Mitogen-Activated Protein Kinase Kinase 4 Gene Polymorphism and Cancer Risk.
Medicine (Baltimore). 2015; 94(44):e0938 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
A number of epidemiological studies have assessed the association of -1304T > G polymorphism in the MKK4 gene and risk of cancer, but the results lack of statistical power due to the limited subjects used in these studies. This study was devised to identify the genetic effects of the -1304T > G polymorphism on cancer risk in a large meta-analysis.Eligible studies were identified by searching both Chinese and English databases. General as well as subgroup analyses were performed for 8 independent case-control publications with a total of 4623 cases and 5256 cancer-free controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the association.Overall, this meta-analysis showed that the association between the -1304T > G polymorphism and cancer risk was statistically significant (GG vs TT: OR = 0.63, 95% CI, 0.52-0.75; GG + TG vs TT: OR = 0.85, 95% CI, 0.79-0.91; GG vs TG + TT: OR = 0.67, 95% CI, 0.56-0.80; G vs T: OR = 0.82, 95% CI, 0.77-0.88; TG vs TT: OR = 0.86, 95% CI, 0.79-0.93).Our meta-analysis reveals that the presence of the -1304T > G polymorphism is likely to decrease risk of cancer. Future larger studies are necessary to validate the current finding.

Chen Y, Lin C, Liu Y, Jiang Y
HMGB1 promotes HCC progression partly by downregulating p21 via ERK/c-Myc pathway and upregulating MMP-2.
Tumour Biol. 2016; 37(4):4399-408 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
High-mobility group box 1 (HMGB1) was found to be over-expressed in many kinds of human cancer, which binds with several receptors and activates RAGE-Ras-MAPK, Toll-like receptors, NF-κB, and Src family kinase signaling pathways and plays a crucial role in tumorigenesis and cancer progression. However, the function and mechanism of HMGB1 in hepatocellular carcinoma (HCC) remain unclear. The aim of this study was to investigate the effect of HMGB1 on HCC progression and explore new molecular mechanism. HMGB1 transient knockdown, stable knockdown, and re-expression were performed by transfection with specific siRNA, shRNA, or expression vector in HCCLM3 cells. Results showed that transient knockdown HMGB1 prevented cell proliferation, promoted apoptosis, induced S phase arrest, and inhibited migration and invasion in vitro, and stable knockdown HMGB1 inhibited xenograft growth in Balb/c athymic mice in vivo. Molecular mechanism investigation revealed that knockdown HMGB1 significantly reduced the activation of MAPKs, including ERK1/2, p38, SAPK/JNK, as well as MAPKKs (MEK1/2, SEK1) and its substrates (c-Jun, c-Myc); downregulated NF-κB/p65 expression and phosphorylation level; decreased MMP-2 expression and activity; and upregulated p21 expression. Interestingly, c-Myc was firstly found to be involved in the promoting function of HMGB1 on HCC progression, which provided a novel clue for the inhibitory effect of HMGB1 on p21 expression by a p53-independent pathway. Collectively, these findings indicated that HMGB1 promoted HCC progression partly by enhancing the ERK1/2 and NF-κB pathways, upregulating MMP-2, and downregulating p21 via an ERK/c-Myc pathway.

Kadakia KC, Tomlins SA, Sanghvi SK, et al.
Comprehensive serial molecular profiling of an "N of 1" exceptional non-responder with metastatic prostate cancer progressing to small cell carcinoma on treatment.
J Hematol Oncol. 2015; 8:109 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
IMPORTANCE: Small cell carcinoma/neuroendocrine prostate cancer (NePC) is a lethal, poorly understood prostate cancer (PCa) subtype. Controversy exists about the origin of NePC in this setting.
OBJECTIVE: To molecularly profile archived biopsy specimens from a case of early-onset PCa that rapidly progressed to NePC to identify drivers of the aggressive course and mechanisms of NePC origin and progression.
DESIGN, SETTING, AND PARTICIPANTS: A 47-year-old patient presented with metastatic prostatic adenocarcinoma (Gleason score 9). After a 6-month response to androgen deprivation therapy, the patient developed jaundice and liver biopsy revealed exclusively NePC. Targeted next generation sequencing (NGS) from formalin-fixed paraffin-embedded (FFPE)-isolated DNA was performed from the diagnostic prostate biopsy and the liver biopsy at progression.
INTERVENTION: Androgen deprivation therapy for adenocarcinoma followed by multiagent chemotherapy for NePC.
MAIN OUTCOMES AND MEASURES: Identification of the mutational landscape in primary adenocarcinoma and NePC liver metastasis. Whether the NePC arose independently or was derived from the primary adenocarcinoma was considered based on mutational profiles.
RESULTS: A deleterious somatic SMAD4 L535fs variant was present in both prostate and liver specimens; however, a TP53 R282W mutation was exclusively enriched in the liver specimen. Copy number analysis identified concordant, low-level alterations in both specimens, with focal MYCL amplification and homozygous PTEN, RB1, and MAP2K4 losses identified exclusively in the NePC specimen. Integration with published genomic profiles identified MYCL as a recurrently amplified in NePC.
CONCLUSIONS AND RELEVANCE: NGS of routine biopsy samples from an exceptional non-responder identified SMAD4 as a driver of the aggressive course and supports derivation of NePC from primary adenocarcinoma (transdifferentiation).

Jones CL, Gearheart CM, Fosmire S, et al.
MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia.
Blood. 2015; 126(19):2202-12 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The outcome for pediatric acute lymphoblastic leukemia (ALL) patients who relapse is dismal. A hallmark of relapsed disease is acquired resistance to multiple chemotherapeutic agents, particularly glucocorticoids. In this study, we performed a genome-scale short hairpin RNA screen to identify mediators of prednisolone sensitivity in ALL cell lines. The incorporation of these data with an integrated analysis of relapse-specific genetic and epigenetic changes allowed us to identify the mitogen-activated protein kinase (MAPK) pathway as a mediator of prednisolone resistance in pediatric ALL. We show that knockdown of the specific MAPK pathway members MEK2 and MEK4 increased sensitivity to prednisolone through distinct mechanisms. MEK4 knockdown increased sensitivity specifically to prednisolone by increasing the levels of the glucocorticoid receptor. MEK2 knockdown increased sensitivity to all chemotherapy agents tested by increasing the levels of p53. Furthermore, we demonstrate that inhibition of MEK1/2 with trametinib increased sensitivity of ALL cells and primary samples to chemotherapy in vitro and in vivo. To confirm a role for MAPK signaling in patients with relapsed ALL, we measured the activation of the MEK1/2 target ERK in matched diagnosis-relapse primary samples and observed increased phosphorylated ERK levels at relapse. Furthermore, relapse samples have an enhanced response to MEK inhibition compared to matched diagnosis samples in xenograft models. Together, our data indicate that inhibition of the MAPK pathway increases chemosensitivity to glucocorticoids and possibly other agents and that the MAPK pathway is an attractive target for prevention and/or treatment of relapsed disease.

Abba MC, Gong T, Lu Y, et al.
A Molecular Portrait of High-Grade Ductal Carcinoma In Situ.
Cancer Res. 2015; 75(18):3980-90 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Ductal carcinoma in situ (DCIS) is a noninvasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer whereas others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome, and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty-two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM, and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor-intrinsic subtypes, proliferative, immune scores, and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like, or ERBB2(+)) displayed signatures characteristic of activated Treg cells (CD4(+)/CD25(+)/FOXP3(+)) and CTLA4(+)/CD86(+) complexes indicative of a tumor-associated immunosuppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly, ncRNA and methylation profiles reproduce changes observed postinvasion. Among the most significant findings, we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a preinvasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer.

Hildebrandt MA, Roth JA, Vaporciyan AA, et al.
Genetic variation in the TNF/TRAF2/ASK1/p38 kinase signaling pathway as markers for postoperative pulmonary complications in lung cancer patients.
Sci Rep. 2015; 5:12068 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Post-operative pulmonary complications are the most common morbidity associated with lung resection in non-small cell lung cancer (NSCLC) patients. The TNF/TRAF2/ASK1/p38 kinase pathway is activated by stress stimuli and inflammatory signals. We hypothesized that genetic polymorphisms within this pathway may contribute to risk of complications. In this case-only study, we genotyped 173 germline genetic variants in a discovery population of 264 NSCLC patients who underwent a lobectomy followed by genotyping of the top variants in a replication population of 264 patients. Complications data was obtained from a prospective database at MD Anderson. MAP2K4:rs12452497 was significantly associated with a decreased risk in both phases, resulting in a 40% reduction in the pooled population (95% CI:0.43-0.83, P = 0.0018). In total, seven variants were significant for risk in the pooled analysis. Gene-based analysis supported the involvement of TRAF2, MAP2K4, and MAP3K5 as mediating complications risk and a highly significant trend was identified between the number of risk genotypes and complications risk (P = 1.63 × 10(-8)). An inverse relationship was observed between association with clinical outcomes and complications for two variants. These results implicate the TNF/TRAF2/ASK1/p38 kinase pathway in modulating risk of pulmonary complications following lobectomy and may be useful biomarkers to identify patients at high risk.

Zhao HF, Wang J, Tony To SS
The phosphatidylinositol 3-kinase/Akt and c-Jun N-terminal kinase signaling in cancer: Alliance or contradiction? (Review).
Int J Oncol. 2015; 47(2):429-36 [PubMed] Related Publications
The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and c-Jun N-terminal kinase (JNK) pathway are responsible for regulating a variety of cellular processes including cell growth, migration, invasion and apoptosis. These two pathways are essential to the development and progression of tumors. The dual roles of JNK signaling in apoptosis and tumor development determine the different interactions between the PI3K/Akt and JNK pathways. Activation of PI3K/Akt signaling can inhibit stress- and cytokine-induced JNK activation through Akt antagonizing and the formation of the JIP1-JNK module, as well as the activities of upstream kinases ASK1, MKK4/7 and MLK. On the other hand, hyperactivation of Akt and JNK is also found in cancers that harbor EGFR overexpression or loss of PTEN. Understanding the activation mechanism of PI3K/Akt and JNK pathways, as well as the interplays between these two pathways in cancer may contribute to the identification of novel therapeutic targets. In the present report, we summarized the current understanding of the PI3K/Akt and JNK signaling networks, as well as their biological roles in cancers. In addition, the interactions and regulatory network between PI3K/Akt and JNK pathways in cancer were discussed.

Shen K, Xie J, Wang H, et al.
Cambogin Induces Caspase-Independent Apoptosis through the ROS/JNK Pathway and Epigenetic Regulation in Breast Cancer Cells.
Mol Cancer Ther. 2015; 14(7):1738-49 [PubMed] Related Publications
Cambogin is a polycyclic polyprenylated acylphoroglucinol (PPAP) from the Garcinia genus, which has been used traditionally for cancer treatment across Southeastern Asia. In this study, we found that cambogin inhibited breast cancer cell proliferation and induced cell apoptosis in vitro. Cambogin induced the activation of the caspase-independent mitochondrial apoptotic pathway, as indicated by an increase in the ratio of Bax/Bcl-2 and the nuclear translocation of apoptosis inducing factor (AIF). Two-dimensional gel electrophoresis and mass spectrometry revealed that the expression of proteins involving in the radical oxygen species (ROS) pathway was among the most affected upon cambogin treatment. Cambogin enhanced cellular ROS production, and induced the activation of the ASK1-MKK4/MKK7-JNK/SAPK signaling pathway. Pretreatment with ROS scavenger N-acetylcysteine (NAC), an antioxidant, or the JNK inhibitor SP600125 was able to restore cell viability in the presence of cambogin. Importantly, cambogin treatment led to the activation of activating transcription factor-2 (ATF-2) and the trimethylation of histone H3K9 in the activator protein 1 (AP-1) binding region of the Bcl-2 gene promoter. Finally, cambogin exhibited a potential antitumor effect in MCF-7 breast cancer xenografts without apparent toxicity. Taken in conjunction, the present study indicates that cambogin can induce breast adenocarcinoma cell apoptosis and therefore represents therapeutic potential for cancer treatment.

Lee JH, Kim JE, Jang YJ, et al.
Dehydroglyasperin C suppresses TPA-induced cell transformation through direct inhibition of MKK4 and PI3K.
Mol Carcinog. 2016; 55(5):552-62 [PubMed] Related Publications
Bioactive natural compounds from plant-derived sources have received substantial interest due to their potential therapeutic and preventive effects toward various human diseases. Licorice (Glycyrrhiza), a frequently-used component in traditional oriental medicines, has been incorporated into recipes not only to enhance taste, but also to treat various conditions including inflammation, chronic fatigue syndrome, and even cancer. Dehydroglyasperin C (DGC) is a major isoflavone found in the root of licorice. In the present study, we investigated the cancer chemopreventive effect of DGC and the underlying molecular mechanisms involved, by analyzing its effects on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic cell transformation and cyclooxygenase (COX)-2 expression in JB6 P+ mouse epidermal cells. DGC treatment attenuated TPA-induced activator protein-1 (AP-1) and nuclear factor-κB (NF-κB) transcriptional activation, two major regulators of TPA-induced cell transformation, and COX-2 expression. TPA-induced phosphorylation of p38, JNK1/2 and Akt was also suppressed by DGC. Kinase assay data revealed that DGC inhibited the kinase activity of MKK4 and PI3K and this outcome was due to direct physical binding with DGC. Notably, DGC bound directly to MKK4 and PI3K in an ATP-competitive manner. Taken together, these results suggest that DGC exhibits cancer chemopreventive potential via its inhibitory effect on TPA-induced neoplastic cell transformation and COX-2 modulation through regulation of the MKK4 and PI3K pathways.

Bozdogan O, Yulug IG, Vargel I, et al.
Differential expression patterns of metastasis suppressor proteins in basal cell carcinoma.
Int J Dermatol. 2015; 54(8):905-15 [PubMed] Related Publications
BACKGROUND: Basal cell carcinomas (BCCs) are common malignant skin tumors. Despite having a significant invasion capacity, they metastasize only rarely. Our aim in this study was to detect the expression patterns of the NM23-H1, NDRG1, E-cadherin, RHOGDI2, CD82/KAI1, MKK4, and AKAP12 metastasis suppressor proteins in BCCs.
METHODS: A total of 96 BCC and 10 normal skin samples were included for the immunohistochemical study. Eleven frozen BCC samples were also studied by quantitative real time polymerase chain reaction (qRT-PCR) to detect the gene expression profile.
RESULTS: NM23-H1 was strongly and diffusely expressed in all types of BCC. Significant cytoplasmic expression of NDRG1 and E-cadherin was also detected. However, AKAP12 and CD82/KAI1 expression was significantly decreased. The expressions of the other proteins were somewhere between the two extremes. Similarly, qRT-PCR analysis showed down-regulation of AKAP12 and up-regulation of NM23-H1 and NDRG1 in BCC. Morphologically aggressive BCCs showed significantly higher cytoplasmic NDRG1 expression scores and lower CD82/KAI1 scores than non-aggressive BCCs.
CONCLUSION: The relatively preserved levels of NM23-H1, NDRG1, and E-cadherin proteins may have a positive effect on the non-metastasizing features of these tumors.

Lee C, Lee SH, Kim DS, et al.
Altered gene expression profile after exposure to transforming growth factor β1 in the 253J human bladder cancer cell line.
Korean J Urol. 2014; 55(8):542-50 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PURPOSE: Transforming growth factor β1 (TGF-β1) inhibits the growth of bladder cancer cells and this effect is prominent and constant in 253J bladder cancer cells. We performed a microarray analysis to search for genes that were altered after TGF-β1 treatment to understand the growth inhibitory action of TGF-β1.
MATERIALS AND METHODS: 253J bladder cancer cells were exposed to TGF-β1 and total RNA was extracted at 6, 24, and 48 hours after exposure. The RNA was hybridized onto a human 22K oligonucleotide microarray and the data were analyzed by using GeneSpring 7.1.
RESULTS: In the microarray analysis, a total of 1,974 genes showing changes of more than 2.0 fold were selected. The selected genes were further subdivided into five highly cohesive clusters with high probability according to the time-dependent expression pattern. A total of 310 genes showing changes of more than 2.0 fold in repeated arrays were identified by use of simple t-tests. Of these genes, those having a known function were listed according to clusters. Microarray analysis showed increased expression of molecules known to be related to Smad-dependent signal transduction, such as SARA and Smad4, and also those known to be related to the mitogen-activated protein kinase (MAPK) pathway, such as MAPKK1 and MAPKK4.
CONCLUSIONS: A list of genes showing significantly altered expression profiles after TGF-β1 treatment was made according to five highly cohesive clusters. The data suggest that the growth inhibitory effect of TGF-β1 in bladder cancer may occur through the Smad-dependent pathway, possibly via activation of the extracellular signal-related kinase 1 and Jun amino-terminal kinases Mitogen-activated protein kinase pathway.

Marino N, Collins JW, Shen C, et al.
Identification and validation of genes with expression patterns inverse to multiple metastasis suppressor genes in breast cancer cell lines.
Clin Exp Metastasis. 2014; 31(7):771-86 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Metastasis suppressor genes (MSGs) have contributed to an understanding of regulatory pathways unique to the lethal metastatic process. When re-expressed in experimental models, MSGs block cancer spread to, and colonization of distant sites without affecting primary tumor formation. Genes have been identified with expression patterns inverse to a single MSG, and found to encode functional, druggable signaling pathways. We now hypothesize that common signaling pathways mediate the effects of multiple MSGs. By gene expression profiling of human MCF7 breast carcinoma cells expressing a scrambled siRNA, or siRNAs to each of 19 validated MSGs (NME1, BRMS1, CD82, CDH1, CDH2, CDH11, CASP8, MAP2K4, MAP2K6, MAP2K7, MAPK14, GSN, ARHGDIB, AKAP12, DRG1, CD44, PEBP1, RRM1, KISS1), we identified genes whose expression was significantly opposite to at least five MSGs. Five genes were selected for further analysis: PDE5A, UGT1A, IL11RA, DNM3 and OAS1. After stable downregulation of each candidate gene in the aggressive human breast cancer cell line MDA-MB-231T, in vitro motility was significantly inhibited. Two stable clones downregulating PDE5A (phosphodiesterase 5A), an enzyme involved in the regulation of cGMP-specific signaling, exhibited no difference in cell proliferation, but reduced motility by 47 and 66 % compared to the empty vector-expressing cells (p = 0.01 and p = 0.005). In an experimental metastasis assay, two shPDE5A-MDA-MB-231T clones produced 47-62 % fewer lung metastases than shRNA-scramble expressing cells (p = 0.045 and p = 0.009 respectively). This study demonstrates that previously unrecognized genes are inversely related to the expression of multiple MSGs, contribute to aspects of metastasis, and may stand as novel therapeutic targets.

Pavese JM, Ogden IM, Voll EA, et al.
Mitogen-activated protein kinase kinase 4 (MAP2K4) promotes human prostate cancer metastasis.
PLoS One. 2014; 9(7):e102289 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Prostate cancer (PCa) is the second leading cause of cancer death in the US. Death from PCa primarily results from metastasis. Mitogen-activated protein kinase kinase 4 (MAP2K4) is overexpressed in invasive PCa lesions in humans, and can be inhibited by small molecule therapeutics that demonstrate favorable activity in phase II studies. However, MAP2K4's role in regulating metastatic behavior is controversial and unknown. To investigate, we engineered human PCa cell lines which overexpress either wild type or constitutive active MAP2K4. Orthotopic implantation into mice demonstrated MAP2K4 increases formation of distant metastasis. Constitutive active MAP2K4, though not wild type, increases tumor size and circulating tumor cells in the blood and bone marrow. Complementary in vitro studies establish stable MAP2K4 overexpression promotes cell invasion, but does not affect cell growth or migration. MAP2K4 overexpression increases the expression of heat shock protein 27 (HSP27) protein and protease production, with the largest effect upon matrix metalloproteinase 2 (MMP-2), both in vitro and in mouse tumor samples. Further, MAP2K4-mediated increases in cell invasion are dependent upon heat shock protein 27 (HSP27) and MMP-2, but not upon MAP2K4's immediate downstream targets, p38 MAPK or JNK. We demonstrate that MAP2K4 increases human PCa metastasis, and prolonged over expression induces long term changes in cell signaling pathways leading to independence from p38 MAPK and JNK. These findings provide a mechanistic explanation for human studies linking increases in HSP27 and MMP-2 to progression to metastatic disease. MAP2K4 is validated as an important therapeutic target for inhibiting human PCa metastasis.

Jour G, Scarborough JD, Jones RL, et al.
Molecular profiling of soft tissue sarcomas using next-generation sequencing: a pilot study toward precision therapeutics.
Hum Pathol. 2014; 45(8):1563-71 [PubMed] Related Publications
Next-generation sequencing (NGS) can provide in-depth detection of numerous gene alterations. To date, there are very few reports describing the use of this technique in soft tissue sarcomas. Herein, we aim to test the utility of NGS in identifying targetable mutations in these tumors. NGS was performed using a clinically validated multiplexed gene sequencing panel interrogating the full coding sequence of 194 cancer-related genes. A custom bioinformatics pipeline was developed to detect all classes of mutations directly from the NGS data, including single-nucleotide variants, small insertions and deletions, copy number variation, and complex structural variations. Twenty-five soft tissue sarcomas were analyzed; 18 of these patients had metastatic disease and 7 primary locally advanced tumors. Targetable mutations for which clinical trials are available were identified in 60% of the cases. MAP2K4, AURKA, AURKB, and c-MYC amplification were recurrent events in leiomyosarcomas. Frequent non-targetable variants included copy losses of the TP53 (24%), PTEN (16%), and CDKN2A (20%). Additional frameshift mutations, deletion mutations, and single-nucleotide variants involving numerous genes, including RB1, NOTCH1, PIK3CA, PDGFRB, EPHA5, KDM6A, NF1, and FLT4 genes, were also identified. NGS is useful in identifying targetable mutations in soft tissue sarcomas that can serve as a rationale for inclusion of patients with advanced disease in ongoing clinical trials and allow for better risk stratification.

Romanov VS, Brichkina AI, Morrison H, et al.
Novel mechanism of JNK pathway activation by adenoviral E1A.
Oncotarget. 2014; 5(8):2176-86 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The adenoviral oncoprotein E1A influences cellular regulation by interacting with a number of cellular proteins. In collaboration with complementary oncogenes, E1A fully transforms primary cells. As part of this action, E1A inhibits transcription of c-Jun:Fos target genes while promoting that of c-Jun:ATF2-dependent genes including jun. Both c-Jun and ATF2 are hyperphosphorylated in response to E1A. In the current study, E1A was fused with the ligand binding domain of the estrogen receptor (E1A-ER) to monitor the immediate effect of E1A activation. With this approach we now show that E1A activates c-Jun N-terminal kinase (JNK), the upstream kinases MKK4 and MKK7, as well as the small GTPase Rac1. Activation of the JNK pathway requires the N-terminal domain of E1A, and, importantly, is independent of transcription. In addition, it requires the presence of ERM proteins. Downregulation of signaling components upstream of JNK inhibits E1A-dependent JNK/c-Jun activation. Taking these findings together, we show that E1A activates the JNK/c-Jun signaling pathway upstream of Rac1 in a transcription-independent manner, demonstrating a novel mechanism of E1A action.

Krause U, Ryan DM, Clough BH, Gregory CA
An unexpected role for a Wnt-inhibitor: Dickkopf-1 triggers a novel cancer survival mechanism through modulation of aldehyde-dehydrogenase-1 activity.
Cell Death Dis. 2014; 5:e1093 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
It is widely accepted that canonical Wnt (cWnt) signaling is required for the differentiation of osteoprogenitors into osteoblasts. Furthermore, tumor-derived secretion of the cWnt-antagonist Dickkopf-1 (Dkk-1) is known to cause bone destruction, inhibition of repair and metastasis in many bone malignancies, but its role in osteosarcoma (OS) is still under debate. In this study, we examined the role of Dkk-1in OS by engineering its overexpression in the osteochondral sarcoma line MOS-J. Consistent with the known role of Dkk-1 in osteoblast differentiation, Dkk-1 inhibited osteogenesis by the MOSJ cells themselves and also in surrounding tissue when implanted in vivo. Surprisingly, Dkk-1 also had unexpected effects on MOSJ cells in that it increased proliferation and resistance to metabolic stress in vitro and caused the formation of larger and more destructive tumors than controls upon orthotopic implantation. These effects were attributed in part to upregulation of the stress response enzyme and cancer stem cell marker aldehyde-dehydrogenase-1 (ALDH1). Direct inhibition of ALDH1 reduced viability under stressful culture conditions, whereas pharmacological inhibition of cWnt or overexpression of ALDH1 had a protective effect. Furthermore, we observed that ALDH1 was transcriptionally activated in a c-Jun-dependent manner through a pathway consisting of RhoA, MAP-kinase-kinase-4 and Jun N-terminal Kinase (JNK), indicating that noncanonical planar cell polarity-like Wnt signaling was the mechanism responsible. Together, our results therefore demonstrate that Dkk-1 enhances resistance of OS cells to stress by tipping the balance of Wnt signaling in favor of the non-canonical Jun-mediated Wnt pathways. In turn, this results in transcriptional activation of ALDH1 through Jun-responsive promoter elements. This is the first report linking Dkk-1 to tumor stress resistance, further supporting the targeting of Dkk-1 not only to prevent and treat osteolytic bone lesions but also to reduce numbers of stress-resistant tumor cells.

Pan W, Wang H, Jianwei R, Ye Z
MicroRNA-27a promotes proliferation, migration and invasion by targeting MAP2K4 in human osteosarcoma cells.
Cell Physiol Biochem. 2014; 33(2):402-12 [PubMed] Related Publications
BACKGROUND: Osteosarcoma is a high-grade malignant bone neoplasm. Although the introduction of chemotherapy has reduced its mortality, more than 50% of patients develop chemoresistance and have an extremely poor prognosis due to pulmonary metastasis. Several molecular pathways contributing to osteosarcoma development and progression have recently been discovered. Various studies have addressed the genes involved in the metastasis of osteosarcoma. However, the highly complex molecular mechanisms of metastasis are still poorly understood. Recently, the decisive role of microRNAs in the regulation of molecular pathways has been uncovered. miRNAs may function as either oncogenes or tumor suppressors, depending on their target genes. miR-27a, a member of an evolutionarily conserved miRNA family, is abnormally increased in several types of cancers. It has been shown to be upregulated in osteosarcoma and plays a pro-metastatic role in osteosarcoma cell lines. However, the effects of miR-27a on osteosarcoma have not been clearly elucidated. The present study thus addressed the miR-27a sensitive mechanisms in osteosarcoma.
METHODS: In this study, three biological programs were used to predict whether MAP2K4 was a target of miR-27a. A specific miR-27a inhibitor was used to inhibit the endogenous activity of miR-27a in the human osteosarcoma cell line MG63. Cell proliferation, colony formation, migration and invasion assays were performed to assess the effects of miR-27a on the proliferation, metastasis and invasion of MG63 cells. The expression levels of several proteins evolved in the JNK/p38 signaling pathway were detected using western blot analysis.
RESULTS: The luciferase activity of the wild-type pGL3-MAP2K4 3'UTR vector was significantly inhibited after the miR-27a precursor or the control precursor was transfected into the MG63 cells. However, the luciferase activity was not inhibited after transfection of the mutant pGL3-MAP2K4 3'UTR vector. The inhibition of miR-27a increased the luciferase activity of the wild-type pGL3-MAP2K4 3'UTR vector after MG63 cells were transfected with the miR-27a inhibitor or the control inhibitor. Thus, MAP2K4 is a potential target of miR-27a and can be directly regulated by miR-27a. Inhibition of miR-27a significantly suppressed cell proliferation after 72 hours compared to the negative control group. Inhibition of miR-27a significantly suppressed colony formation of the MG63 cells by 39 6%. Transwell migration and invasion assays demonstrated that the number of migratory and invasive cells transfected with the miR-27a inhibitor was reduced by 63.5% and 69.1%, respectively. After transfection of the miR-27a inhibitor into the MG63 cells, the level of phospho-JNK1 and phospho-p38 increased by 25% and 29%, respectively, along with the up-regulation of MAP2K4 protein.
CONCLUSION: This is the first study showing that miR-27a can function as an oncogene by targeting MAP2K4 in the osteosarcoma MG63 cell line. Inhibition of miR-27a increases MAP2K4 expression, which in turn inhibits cell proliferation and migration through the JNK/p38 signaling pathway in MG63 cells. These findings may help us understand the molecular mechanism of miR-27a in the tumorigenesis of osteosarcoma and may provide new diagnostic and therapeutic options for the treatment of this neoplasia.

Acuner Ozbabacan SE, Gursoy A, Nussinov R, Keskin O
The structural pathway of interleukin 1 (IL-1) initiated signaling reveals mechanisms of oncogenic mutations and SNPs in inflammation and cancer.
PLoS Comput Biol. 2014; 10(2):e1003470 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Interleukin-1 (IL-1) is a large cytokine family closely related to innate immunity and inflammation. IL-1 proteins are key players in signaling pathways such as apoptosis, TLR, MAPK, NLR and NF-κB. The IL-1 pathway is also associated with cancer, and chronic inflammation increases the risk of tumor development via oncogenic mutations. Here we illustrate that the structures of interfaces between proteins in this pathway bearing the mutations may reveal how. Proteins are frequently regulated via their interactions, which can turn them ON or OFF. We show that oncogenic mutations are significantly at or adjoining interface regions, and can abolish (or enhance) the protein-protein interaction, making the protein constitutively active (or inactive, if it is a repressor). We combine known structures of protein-protein complexes and those that we have predicted for the IL-1 pathway, and integrate them with literature information. In the reconstructed pathway there are 104 interactions between proteins whose three dimensional structures are experimentally identified; only 15 have experimentally-determined structures of the interacting complexes. By predicting the protein-protein complexes throughout the pathway via the PRISM algorithm, the structural coverage increases from 15% to 71%. In silico mutagenesis and comparison of the predicted binding energies reveal the mechanisms of how oncogenic and single nucleotide polymorphism (SNP) mutations can abrogate the interactions or increase the binding affinity of the mutant to the native partner. Computational mapping of mutations on the interface of the predicted complexes may constitute a powerful strategy to explain the mechanisms of activation/inhibition. It can also help explain how an oncogenic mutation or SNP works.

Liu J, Xu D, Wang Q, et al.
LPS induced miR-181a promotes pancreatic cancer cell migration via targeting PTEN and MAP2K4.
Dig Dis Sci. 2014; 59(7):1452-60 [PubMed] Related Publications
BACKGROUND: Pancreatic cancer is aggressive; 80-90 % of pancreatic cancer patients have already developed metastatic cancer at the time of diagnosis. Inflammation has been shown to facilitate pancreatic cancer migration. The toll-like receptors (TLRs) pathway is an important inflammatory signal transduction pathway. However, the mechanism of inflammation pathway to induce pancreatic cancer migration is unclear.
AIMS: The purpose of this study was to investigate how inflammation affects pancreatic cancer migration.
METHODS: RT-PCR was used to detect the TLRs expression files in pancreatic cancer cells and tissues. Pancreatic cancer cells migration was assessed after treatment with TLR4 agonist, lipopolysaccharide (LPS). Moreover, two tumor suppressors, PTEN and MAP2K4, were detected. Then we predicted and proved the miRNA which targeted PTEN and MAP2K4.
RESULTS: We found that the expression of TLR4 was increased in pancreatic cancer cells and tissues. After treatment with LPS, the migration of pancreatic cancer cells was increased and the protein levels of two tumor suppressors, PTEN and MAP2K4, were inhibited. To investigate the possible mechanism, we checked the expression of miR-181a. The result showed that miR-181a was decreased by LPS. Furthermore, we predicted and confirmed that both PTEN and MAP2K4 were miR-181a targets. Pancreatic cancer tissues analysis showed that PTEN and MAP2K4 were all negatively correlated with miR-181a.
CONCLUSIONS: These results suggest that the LPS-TLR4-miR-181a signaling pathway plays a significant role in pancreatic cancer invasion and progression.

Tsai JP, Hsiao PC, Yang SF, et al.
Licochalcone A suppresses migration and invasion of human hepatocellular carcinoma cells through downregulation of MKK4/JNK via NF-κB mediated urokinase plasminogen activator expression.
PLoS One. 2014; 9(1):e86537 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Hepatocellular cell carcinoma (HCC) is one of the most commonly diagnosed cancers worldwide and in Taiwan. Chemoprevention of cancer with dietary bioactive compounds could potentially reverse, suppress, or prevent cancer progression. Licochalcone A (LicA) is a characteristic chalcone of licorice, which is the root of Glycyrrhiza inflate. It had been reported that LicA has anti-inflammatory, anti-microbial, and anti-tumor properties. However, the effects of LicA on the migration and invasion of human HCC cells have not yet been reported. In the present study, it was found that LicA inhibits the migratory and invasion ability of SK-Hep-1 and HA22T/VGH cells in a dose-dependent manner, as assessed by the cell migration and Matrigel cell invasion assay. Using casein zymography, Western blotting, reverse transcriptase polymerase chain reaction, and an immunofluorescence assay, it was found that LicA induces a dose-dependent inhibition of uPA activity and expression, as well as reduces mRNA levels in SK-Hep-1 and HA22T/VGH cells. LicA was also found to inhibit the expression of phosphor-JNK and phosphor-MKK4 in SK-Hep-1 cells. Furthermore, LicA significantly decreased uPA levels in SP600125-treated or si-MKK4-transfected cells alongside a marked reduction in cell migration and invasion, which supports the notion that an inhibition of MKK4/JNK results in anti-metastatic effects. Moreover, LicA inhibited the expression of nuclear NF-κB, as well as the binding ability of NF-κB to the uPA promoter. These findings further our understanding of the role of LicA in suppressing tumor metastasis and its underlying molecular mechanisms, as well as suggest that LicA may be a promising anti-metastatic agent.

Ganeshan VR, Schor NF
p75 neurotrophin receptor and fenretinide-induced signaling in neuroblastoma.
Cancer Chemother Pharmacol. 2014; 73(2):271-9 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PURPOSE: Neuroblastoma is the most common extracranial solid tumor of childhood. The retinoic acid analogue, fenretinide (4-hydroxyphenyl retinamide; 4-HPR), induces apoptosis in neuroblastoma cells in vitro and is currently in clinical trials for children with refractory neuroblastoma. We have previously shown that expression of the p75 neurotrophin receptor (p75NTR) enhances apoptosis induction and mitochondrial accumulation of reactive oxygen species by 4-HPR in neuroblastoma cells. We now examine the signaling events that underlie this effect.
METHODS: Systematic examination of pro- and anti-apoptotic signaling effectors was performed by Western blot. Specific inhibitors of JNK phosphorylation and scavengers of mitochondrial reactive oxygen species were used to demonstrate the roles of these phenomena in the enhancement of fenretinide efficacy.
RESULTS: The present studies demonstrate that enhancement of 4-HPR-induced apoptosis by p75NTR is dependent upon p38MAPK phosphorylation, JNK phosphorylation, caspase 3 activation, Akt cleavage, and decreased Akt phosphorylation. In addition, treatment with 4-HPR results in upregulation of MKK4 and MEKK1, and phosphorylation of MKK3/6. Efforts to enhance the efficacy of 4-HPR and to identify those tumors most likely to respond to it might exploit these effectors of 4-HPR-induced apoptosis.
CONCLUSIONS: Pharmacological agents that enhance MKK4 or MEKK1 expression or JNK expression or phosphorylation may enhance efficacy of 4-HPR in neuroblastomas that do not express high levels of p75NTR.

Johansson I, Ringnér M, Hedenfalk I
The landscape of candidate driver genes differs between male and female breast cancer.
PLoS One. 2013; 8(10):e78299 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The rapidly growing collection of diverse genome-scale data from multiple tumor types sheds light on various aspects of the underlying tumor biology. With the objective to identify genes of importance for breast tumorigenesis in men and to enable comparisons with genes important for breast cancer development in women, we applied the computational framework COpy Number and EXpression In Cancer (CONEXIC) to detect candidate driver genes among all altered passenger genes. Unique to this approach is that each driver gene is associated with several gene modules that are believed to be altered by the driver. Thirty candidate drivers were found in the male breast cancers and 67 in the female breast cancers. We identified many known drivers of breast cancer and other types of cancer, in the female dataset (e.g. GATA3, CCNE1, GRB7, CDK4). In contrast, only three known cancer genes were found among male breast cancers; MAP2K4, LHP, and ZNF217. Many of the candidate drivers identified are known to be involved in processes associated with tumorigenesis, including proliferation, invasion and differentiation. One of the modules identified in male breast cancer was regulated by THY1, a gene involved in invasion and related to epithelial-mesenchymal transition. Furthermore, men with THY1 positive breast cancers had significantly inferior survival. THY1 may thus be a promising novel prognostic marker for male breast cancer. Another module identified among male breast cancers, regulated by SPAG5, was closely associated with proliferation. Our data indicate that male and female breast cancers display highly different landscapes of candidate driver genes, as only a few genes were found in common between the two. Consequently, the pathobiology of male breast cancer may differ from that of female breast cancer and can be associated with differences in prognosis; men diagnosed with breast cancer may consequently require different management and treatment strategies than women.

Guinney J, Ferté C, Dry J, et al.
Modeling RAS phenotype in colorectal cancer uncovers novel molecular traits of RAS dependency and improves prediction of response to targeted agents in patients.
Clin Cancer Res. 2014; 20(1):265-72 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PURPOSE: KRAS wild-type status is an imperfect predictor of sensitivity to anti-EGF receptor (EGFR) monoclonal antibodies in colorectal cancer, motivating efforts to identify novel molecular aberrations driving RAS. This study aimed to build a quantitative readout of RAS pathway activity to (i) uncover molecular surrogates of RAS activity specific to colorectal cancer, (ii) improve the prediction of cetuximab response in patients, and (iii) suggest new treatment strategies.
EXPERIMENTAL DESIGN: A model of RAS pathway activity was trained in a large colorectal cancer dataset and validated in three independent colorectal cancer patient datasets. Novel molecular traits were inferred from The Cancer Genome Atlas colorectal cancer data. The ability of the RAS model to predict resistance to cetuximab was tested in mouse xenografts and three independent patient cohorts. Drug sensitivity correlations between our model and large cell line compendiums were performed.
RESULTS: The performance of the RAS model was remarkably robust across three validation datasets. (i) Our model confirmed the heterogeneity of the RAS phenotype in KRAS wild-type patients, and suggests novel molecular traits driving its phenotype (e.g., MED12 loss, FBXW7 mutation, MAP2K4 mutation). (ii) It improved the prediction of response and progression-free survival (HR, 2.0; P < 0.01) to cetuximab compared with KRAS mutation (xenograft and patient cohorts). (iii) Our model consistently predicted sensitivity to MAP-ERK kinase (MEK) inhibitors (P < 0.01) in two cell panel screens.
CONCLUSIONS: Modeling the RAS phenotype in colorectal cancer allows for the robust interrogation of RAS pathway activity across cell lines, xenografts, and patient cohorts. It demonstrates clinical utility in predicting response to anti-EGFR agents and MEK inhibitors.

Prickett TD, Zerlanko B, Gartner JJ, et al.
Somatic mutations in MAP3K5 attenuate its proapoptotic function in melanoma through increased binding to thioredoxin.
J Invest Dermatol. 2014; 134(2):452-60 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Patients with advanced metastatic melanoma have poor prognosis and the genetics underlying its pathogenesis are poorly understood. High-throughput sequencing has allowed comprehensive discovery of somatic mutations in cancer samples. Here, on analysis of our whole-genome and whole-exome sequencing data of 29 melanoma samples, we identified several genes that harbor recurrent nonsynonymous mutations. These included MAP3K5 (mitogen-activated protein kinase kinase kinase-5), which in a prevalence screen of 288 melanomas was found to harbor a R256C substitution in 5 cases. All MAP3K5-mutated samples were wild type for BRAF, suggesting a mutual exclusivity for these mutations. Functional analysis of the MAP3K5 R256C mutation revealed attenuation of MKK4 (mitogen-activated protein kinase kinase 4) activation through increased binding of the inhibitory protein thioredoxin (TXN/TRX-1/Trx), resulting in increased proliferation and anchorage-independent growth of melanoma cells. This mutation represents a potential target for the design of new therapies to treat melanoma.

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