RAF1; Raf-1 proto-oncogene, serine/threonine kinase (3p25)

Gene Summary

Gene:RAF1; Raf-1 proto-oncogene, serine/threonine kinase
Aliases: NS5, CRAF, Raf-1, c-Raf, CMD1NN
Summary:This gene is the cellular homolog of viral raf gene (v-raf). The encoded protein is a MAP kinase kinase kinase (MAP3K), which functions downstream of the Ras family of membrane associated GTPases to which it binds directly. Once activated, the cellular RAF1 protein can phosphorylate to activate the dual specificity protein kinases MEK1 and MEK2, which in turn phosphorylate to activate the serine/threonine specific protein kinases, ERK1 and ERK2. Activated ERKs are pleiotropic effectors of cell physiology and play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration. Mutations in this gene are associated with Noonan syndrome 5 and LEOPARD syndrome 2. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:RAF proto-oncogene serine/threonine-protein kinase
Updated:26 January, 2015


What does this gene/protein do?
Show (49)


What pathways are this gene/protein implicaed in?
- Angiotensin II mediated activation of JNK Pathway via Pyk2 dependent signaling BIOCARTA
- Aspirin Blocks Signaling Pathway Involved in Platelet Activation BIOCARTA
- BCR Signaling Pathway BIOCARTA
- Bioactive Peptide Induced Signaling Pathway BIOCARTA
- Cadmium induces DNA synthesis and proliferation in macrophages BIOCARTA
- CCR3 signaling in Eosinophils BIOCARTA
- Ceramide Signaling Pathway BIOCARTA
- CXCR4 Signaling Pathway BIOCARTA
- EGF Signaling Pathway BIOCARTA
- EPO Signaling Pathway BIOCARTA
- Erk and PI-3 Kinase Are Necessary for Collagen Binding in Corneal Epithelia BIOCARTA
- Erk1/Erk2 Mapk Signaling pathway BIOCARTA
- Fc Epsilon Receptor I Signaling in Mast Cells BIOCARTA
- fMLP induced chemokine gene expression in HMC-1 cells BIOCARTA
- Growth Hormone Signaling Pathway BIOCARTA
- IGF-1 Signaling Pathway BIOCARTA
- IL 2 signaling pathway BIOCARTA
- IL 3 signaling pathway BIOCARTA
- IL 6 signaling pathway BIOCARTA
- IL-2 Receptor Beta Chain in T cell Activation BIOCARTA
- Influence of Ras and Rho proteins on G1 to S Transition BIOCARTA
- Inhibition of Cellular Proliferation by Gleevec BIOCARTA
- Insulin Signaling Pathway BIOCARTA
- Integrin Signaling Pathway BIOCARTA
- Keratinocyte Differentiation BIOCARTA
- Links between Pyk2 and Map Kinases BIOCARTA
- MAPKinase Signaling Pathway BIOCARTA
- Multiple antiapoptotic pathways from IGF-1R signaling lead to BAD phosphorylation BIOCARTA
- Nerve growth factor pathway (NGF) BIOCARTA
- NFAT and Hypertrophy of the heart (Transcription in the broken heart) BIOCARTA
- PDGF Signaling Pathway BIOCARTA
- Phosphorylation of MEK1 by cdk5/p35 down regulates the MAP kinase pathway BIOCARTA
- Ras Signaling Pathway BIOCARTA
- Role of BIOCARTA
- Role of ERBB2 in Signal Transduction and Oncology BIOCARTA
- Role of MAL in Rho-Mediated Activation of SRF BIOCARTA
- Roles of BIOCARTA
- Signaling of Hepatocyte Growth Factor Receptor BIOCARTA
- Signaling Pathway from G-Protein Families BIOCARTA
- Sprouty regulation of tyrosine kinase signals BIOCARTA
- T Cell Receptor Signaling Pathway BIOCARTA
- TPO Signaling Pathway BIOCARTA
- Colorectal cancer KEGG
- Dorso-ventral axis formation KEGG
- Fc epsilon RI signaling pathway KEGG
- Focal adhesion KEGG
- Gap junction KEGG
- GnRH signaling pathway KEGG
- Insulin signaling pathway KEGG
- Long-term depression KEGG
- Long-term potentiation KEGG
- MAPK signaling pathway KEGG
- Natural killer cell mediated cytotoxicity KEGG
- Regulation of actin cytoskeleton KEGG
- VEGF signaling pathway KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 26 January 2015 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.

  • Lung Cancer
  • Receptors, Prostaglandin E, EP4 Subtype
  • Cancer RNA
  • Cell Line
  • Extracellular Signal-Regulated MAP Kinases
  • Proto-Oncogene Proteins
  • Oligonucleotide Array Sequence Analysis
  • Tumor Suppressor Proteins
  • Chromosome Mapping
  • Gene Expression Profiling
  • Drug Resistance
  • Non-Small Cell Lung Cancer
  • Cancer DNA
  • Gene Amplification
  • Phosphorylation
  • Bladder Cancer
  • Molecular Sequence Data
  • Mitogen-Activated Protein Kinase 3
  • BRAF
  • Brain and CNS Tumours
  • Mitogen-Activated Protein Kinase 1
  • MAP Kinase Signaling System
  • RAS Genes
  • Cell Proliferation
  • Mitogen-Activated Protein Kinases
  • Zonula Occludens-1 Protein
  • Transfection
  • CRAF
  • Receptors, Thyroid Hormone
  • Melanoma
  • Childhood Cancer
  • Western Blotting
  • Chromosome 3
  • Cancer Gene Expression Regulation
  • Adolescents
  • Mutation
  • Oncogenes
  • DNA Mutational Analysis
  • Restriction Fragment Length Polymorphism
  • Breast Cancer
  • Noonan Syndrome
Tag cloud generated 26 January, 2015 using data from PubMed, MeSH and CancerIndex

Notable (7)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
MelanomaRAF1 and Melanoma View Publications26
Lung CancerRAF1 and Lung Cancer View Publications15
Breast CancerRAF1 and Breast Cancer View Publications10
Lung Cancer, Non-Small CellRAF1 and Non-Small Cell Lung Cancer View Publications8
Brain and CNS TumoursRAF1 and Astrocytoma View Publications8
Bladder CancerRAF1 and Bladder Cancer View Publications3
Noonan SyndromeRAF1 mutation in Noonan Syndrome View Publications8

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

Related Links

Latest Publications: RAF1 (cancer-related)

Kordi-Tamandani DM, Saberi E, Jamali S, Ladiz MA
ERK and RAF1 genes: analysis of methylation and expression profiles in patients with oral squamous cell carcinoma.
Br J Biomed Sci. 2014; 71(3):100-3 [PubMed] Related Publications
The Ras/RAF/MEK/ERK1/2 pathway is important in the control of growth signals, differentiation and cell survival. Over-expression and activation of this pathway have been reported in different types of cancer. This study analyses the promoter methylation and RNA expression profiles of ERK and RAF1 genes with risk of oral squamous cell carcinoma (OSCC) along with the promoter methylation status of ERK and RAF1 genes using a methylation-specific polymerase chain reaction (MS-PCR) in 86 paraffin-wax embedded samples of OSCC and 68 normal control tissues. Furthermore, ERK and RAF1 expression was analysed in 19 cases and 20 normal samples by real-time reverse transcription PCR. Frequency of promoter methylation was detected for ERK (93.02% and 6.98%) and RAF1 (95.35% and 4.65%) genes in cases and controls, respectively. Messenger RNA (mRNA) expression analysis indicated statistically significant difference between cases and controls for ERK (P < 0.002) and RAF1 (P < 0.006). The authors believe that this is the first report to show that expression of ERK and RAF1 is involved in risk of OSCC.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology Oral Cancer

Kunze K, Spieker T, Gamerdinger U, et al.
A recurrent activating PLCG1 mutation in cardiac angiosarcomas increases apoptosis resistance and invasiveness of endothelial cells.
Cancer Res. 2014; 74(21):6173-83 [PubMed] Related Publications
Primary cardiac angiosarcomas are rare tumors with unfavorable prognosis. Pathogenic driver mutations are largely unknown. We therefore analyzed a collection of cases for genomic aberrations using SNP arrays and targeted next-generation sequencing (tNGS) of oncogenes and tumor-suppressor genes. Recurrent gains of chromosome 1q and a small region of chromosome 4 encompassing KDR and KIT were identified by SNP array analysis. Repeatedly mutated genes identified by tNGS were KDR with different nonsynonymous mutations, MLL2 with different nonsense mutations, and PLCG1 with a recurrent nonsynonymous mutation (R707Q) in the highly conserved autoinhibitory SH2 domain in three of 10 cases. PLCγ1 is usually activated by Y783 phosphorylation and activates protein kinase C and Ca(2+)-dependent second messengers, with effects on cellular proliferation, migration, and invasiveness. Ectopic expression of the PLCγ1-R707Q mutant in endothelial cells revealed reduced PLCγ1-Y783 phosphorylation with concomitant increased c-RAF/MEK/ERK1/2 phosphorylation, increased IP3 amounts, and increased Ca(2+)-dependent calcineurin activation compared with ectopic expressed PLCγ1-wild-type. Furthermore, cofilin, whose activation is associated with actin skeleton reorganization, showed decreased phosphorylation, and thus activation after expression of PLCγ1-R707Q compared with PLCγ1-wild-type. At the cellular level, expression of PLCγ1-R707Q in endothelial cells had no influence on proliferation rate, but increased apoptosis resistance and migration and invasiveness in in vitro assays. Together, these findings indicate that the PLCγ1-R707Q mutation causes constitutive activation of PLCγ1 and may represent an alternative way of activation of KDR/PLCγ1 signaling besides KDR activation in angiosarcomas, with implications for VEGF/KDR targeted therapies.

Related: Apoptosis Signal Transduction

Tecleab A, Zhang X, Sebti SM
Ral GTPase down-regulation stabilizes and reactivates p53 to inhibit malignant transformation.
J Biol Chem. 2014; 289(45):31296-309 [PubMed] Article available free on PMC after 07/11/2015 Related Publications
Ral GTPases are critical effectors of Ras, yet the molecular mechanism by which they induce malignant transformation is not well understood. In this study, we found the expression of K-Ras, RalB, and sometimes RalA, but not AKT1/2 and c-Raf, to be required for maintaining low levels of p53 in human cancer cells that harbor mutant K-Ras and wild-type p53. Down-regulation of K-Ras, RalB, and sometimes RalA increases p53 protein levels and results in a p53-dependent up-regulation of the expression of p21(WAF). K-Ras, RalA, and RalB depletion increases p53 stability as demonstrated by ataxia telangiectasia-mutated kinase activation, increased Ser-15 phosphorylation, and a significant (up to 6-fold) increase in p53 half-life. Furthermore, depletion of K-Ras and RalB inhibits anchorage-independent growth and invasion and interferes with cell cycle progression in a p53-dependent manner. Depletion of RalA inhibits invasion in a p53-dependent manner. Thus, expression of K-Ras and RalB and possibly RalA proteins is critical for maintaining low levels of p53, and down-regulation of these GTPases reactivates p53 by significantly enhancing its stability, and this contributes to suppression of malignant transformation.

Related: CDKN1A Signal Transduction TP53 RALB RALA

Liu Z, Liu Y, Li L, et al.
MiR-7-5p is frequently downregulated in glioblastoma microvasculature and inhibits vascular endothelial cell proliferation by targeting RAF1.
Tumour Biol. 2014; 35(10):10177-84 [PubMed] Related Publications
The aberrant expression of microRNAs (miRNAs) is always associated with tumor development and progression. Microvascular proliferation is one of the unique pathologic features of glioblastoma (GBM) . In this study, the microvasculature from GBM or normal brain tissue derived from neurosurgeries was purified and total RNA was isolated from purified microvasculature. The difference of miRNA expression profiles between glioblastoma microvasculature and normal brain capillaries was investigated. It was found that miR-7-5p in GBM microvessels was significantly reduced compared with that in normal brain capillaries. In the in vitro experiments, overexpression of miR-7-5p significantly inhibited human umbilical vein endothelial cell proliferation. Forced expression of miR-7-5p in human umbilical vein endothelial cells in vitro significantly reduced the protein level of RAF1 and repressed the activity of the luciferase, a reporter vector carrying the 3'-untranslated region of RAF1. These findings indicate that RAF1 is one of the miR-7-5p target genes. Furthermore, a significant inverse correlation between miR-7-5p expression and RAF1 protein level in GBM microvasculature was found. These data suggest that miR-7-5p functions as a tumor suppressor gene to regulate GBM microvascular endothelial cell proliferation potentially by targeting the RAF1 oncogene, implicating an important role for miR-7-5p in the pathogenesis of GBM. It may serve as a guide for the antitumor angiogenesis drug development.

Related: MicroRNAs

Huang W, Ye M, Zhang LR, et al.
FW-04-806 inhibits proliferation and induces apoptosis in human breast cancer cells by binding to N-terminus of Hsp90 and disrupting Hsp90-Cdc37 complex formation.
Mol Cancer. 2014; 13:150 [PubMed] Article available free on PMC after 07/11/2015 Related Publications
BACKGROUND: Heat shock protein 90 (Hsp90) is a promising therapeutic target and inhibition of Hsp90 will presumably result in suppression of multiple signaling pathways. FW-04-806, a bis-oxazolyl macrolide compound extracted from China-native Streptomyces FIM-04-806, was reported to be identical in structure to the polyketide Conglobatin.
METHODS: We adopted the methods of chemproteomics, computational docking, immunoprecipitation, siRNA gene knock down, Quantitative Real-time PCR and xenograft models on the research of FW-04-806 antitumor mechanism, through the HER2-overexpressing breast cancer SKBR3 and HER2-underexpressing breast cancer MCF-7 cell line.
RESULTS: We have verified the direct binding of FW-04-806 to the N-terminal domain of Hsp90 and found that FW-04-806 inhibits Hsp90/cell division cycle protein 37 (Cdc37) chaperone/co-chaperone interactions, but does not affect ATP-binding capability of Hsp90, thereby leading to the degradation of multiple Hsp90 client proteins via the proteasome pathway. In breast cancer cell lines, FW-04-806 inhibits cell proliferation, caused G2/M cell cycle arrest, induced apoptosis, and downregulated Hsp90 client proteins HER2, Akt, Raf-1 and their phosphorylated forms (p-HER2, p-Akt) in a dose and time-dependent manner. Importantly, FW-04-806 displays a better anti-tumor effect in HER2-overexpressed SKBR3 tumor xenograft model than in HER2-underexpressed MCF-7 model. The result is consistent with cell proliferation assay and in vitro apoptosis assay applied for SKBR-3 and MCF-7. Furthermore, FW-04-806 has a favorable toxicity profile.
CONCLUSIONS: As a novel Hsp90 inhibitor, FW-04-806 binds to the N-terminal of Hsp90 and inhibits Hsp90/Cdc37 interaction, resulting in the disassociation of Hsp90/Cdc37/client complexes and the degradation of Hsp90 client proteins. FW-04-806 displays promising antitumor activity against breast cancer cells both in vitro and in vivo, especially for HER2-overexpressed breast cancer cells.

Related: Apoptosis Breast Cancer

Liu H, Qian C, Shen Z
Anti-tumor activity of oridonin on SNU-5 subcutaneous xenograft model via regulation of c-Met pathway.
Tumour Biol. 2014; 35(9):9139-46 [PubMed] Related Publications
Gastric cancer is the leading cause of cancer death worldwide. Oridonin, a diterpenoid isolated from Rabdosia rubescens, has attracted considerable attention as a potential treatment for gastric cancer based on its anti-tumor effects in many tumor cell lines. However, detailed anti-tumor mechanisms of oridonin remain a matter of speculation. In the present study, a gastric carcinoma cell line harboring c-Met gene amplification SNU-5 was used to investigate the underlying mechanisms. The results showed that in vitro, oridonin potently inhibited c-Met phosphorylation and c-Met-dependent cell proliferation (IC50 value, 36.8 μM), meanwhile down-regulated the expression of the downstream signaling molecules including phospho-c-Raf, phospho-Erk, and phospho-Akt. In vivo, oridonin showed efficacy at well-tolerated doses, including marked cytoreductive anti-tumor activity in SNU-5 subcutaneous xenograft model. The anti-tumor efficacy of oridonin was dose-dependent and showed strong inhibition of c-Met phosphorylation. Additional mechanism of action studies showed dose-dependent inhibition of c-Met-dependent signal transduction, tumor cell proliferation (Ki67), and reduction of microvessel density (CD31). These results suggested that the anti-tumor activity of oridonin may be mediated by direct effects on tumor cell growth or survival as well as anti-angiogenic mechanisms. In summary, the results indicated that oridonin exerted anti-tumor growth on human gastric cancer SNU-5 in vitro and in vivo by direct regulation of c-Met signaling pathway and the anti-tumor effects was mainly based on its anti-proliferation and anti-angiogenesis.

Related: MKI67 Angiogenesis and Cancer AKT1 MET gene Signal Transduction Stomach Cancer Gastric Cancer

Tan WJ, Lai JC, Thike AA, et al.
Novel genetic aberrations in breast phyllodes tumours: comparison between prognostically distinct groups.
Breast Cancer Res Treat. 2014; 145(3):635-45 [PubMed] Related Publications
Phyllodes tumours of the breast are uncommon fibroepithelial neoplasms which pose management challenges due to difficulties in accurate prediction of clinical behaviour, as histological assessment has its limitations. Molecular studies have improved the understanding of these rare tumours but such findings are scant. We aimed to investigate genetic aberrations in phyllodes tumours stratified according to clinical behaviour, to identify potential genes contributing to disease progression. Twenty phyllodes tumours were separated into prognostically distinct categories depending on whether they had recurred/metastasized within the follow-up period. DNA extracted from FFPE materials was subjected to Affymetrix OncoScan™ FFPE Express molecular inversion probe microarray platform for analysis of copy number changes and mutational status. Results were cross validated with Sanger sequencing, FISH and immunohistochemistry. A higher number of chromosomal aberrations were observed in cases which recurred/metastasized, with median events of 19 compared to 3.5 in cases which did not recur/metastasize. High-level amplification and homozygous deletions were detected exclusively in the former group. Regions of high-level amplification included MDM4 (1q32.1), RAF1 (3p25), EGFR (7p12) and PDZD2 (5p13.3). EGFR amplification was confirmed on FISH and accompanied by intense EGFR immunostaining. Regions of homozygous deletion included CDKN2A (9p21) and MACROD2 (20p12.1). Homozygous deletion of 9p21 which involved CDKN2A was accompanied by loss of protein expression. No mutations were identified in all samples. These findings provide insights into identifying target genes and pathways exploited by phyllodes tumours, which would aid future development of individualised therapy.

Related: Breast Cancer MDM4 gene EGFR

Been RA, Linden MA, Hager CJ, et al.
Genetic signature of histiocytic sarcoma revealed by a sleeping beauty transposon genetic screen in mice.
PLoS One. 2014; 9(5):e97280 [PubMed] Article available free on PMC after 07/11/2015 Related Publications
Histiocytic sarcoma is a rare, aggressive neoplasm that responds poorly to therapy. Histiocytic sarcoma is thought to arise from macrophage precursor cells via genetic changes that are largely undefined. To improve our understanding of the etiology of histiocytic sarcoma we conducted a forward genetic screen in mice using the Sleeping Beauty transposon as a mutagen to identify genetic drivers of histiocytic sarcoma. Sleeping Beauty mutagenesis was targeted to myeloid lineage cells using the Lysozyme2 promoter. Mice with activated Sleeping Beauty mutagenesis had significantly shortened lifespan and the majority of these mice developed tumors resembling human histiocytic sarcoma. Analysis of transposon insertions identified 27 common insertion sites containing 28 candidate cancer genes. Several of these genes are known drivers of hematological neoplasms, like Raf1, Fli1, and Mitf, while others are well-known cancer genes, including Nf1, Myc, Jak2, and Pten. Importantly, several new potential drivers of histiocytic sarcoma were identified and could serve as targets for therapy for histiocytic sarcoma patients.

Tang YQ, Jaganath IB, Manikam R, Sekaran SD
Inhibition of MAPKs, Myc/Max, NFκB, and hypoxia pathways by Phyllanthus prevents proliferation, metastasis and angiogenesis in human melanoma (MeWo) cancer cell line.
Int J Med Sci. 2014; 11(6):564-77 [PubMed] Article available free on PMC after 07/11/2015 Related Publications
BACKGROUND: Melanoma is the most fatal form of skin cancer. Different signalling pathways and proteins will be differentially expressed to pace with the tumour growth. Thus, these signalling molecules and proteins are become potential targets to halt the progression of cancer. The present works were attempted to investigate the underlying molecular mechanisms of anticancer effects of Phyllanthus (P.amarus, P.niruri, P.urinaria and P.watsonii) on skin melanoma, MeWo cells.
METHODS: The ten cancer-related pathways reporter array was performed by transfection of plasmid construct of transcription factor-responsive reporter of each pathway in MeWo cells. The affected pathways in MeWo cells after treatment of Phyllanthus extracts were determined using luciferase assay. Western blot, 2D gel electrophoresis and mass spectrometry analysis were performed to identity and confirm the affected proteins and signalling molecules in treated cells.
RESULTS: The ten-pathway reporter array revealed five different cancer-related signalling pathways were altered by Phyllanthus species in MeWo cells; NFκB, Myc/Max, Hypoxia, MAPK/ERK and MAPK/JNK (p<0.05). Western blot revealed that their intracellular signalling molecules including pan-Ras, c-Raf, RSK, phospho-Elk1, c-myc, Akt, HIF-1α, Bcl-2, and VEGF were down-regulated with concurrent of up-regulation; Bax, phospho-JNK-1/2 and phospho-GSK3β, in MeWo cells upon Phyllanthus treatment (p<0.05). Proteomics-based approach was performed and MS/MS results revealed that 52 differential expressed proteins were identified (p<0.05) and involved in tumour growth, metastasis, apoptosis, glycogenesis and glycolysis, angiogenesis, protein synthesis and energy metabolism.
CONCLUSION: This study provides insight into the regulation on multiple survival signalling pathways by Phyllanthus in melanoma and might be a therapeutic target for cancer treatment.

Related: Melanoma Angiogenesis and Cancer Signal Transduction Skin Cancer

Wang CY, Chao TT, Tai WT, et al.
Signal transducer and activator of transcription 3 as molecular therapy for non-small-cell lung cancer.
J Thorac Oncol. 2014; 9(4):488-96 [PubMed] Related Publications
INTRODUCTION: Targeting signal transducer and activator of transcription 3 (STAT3), a transcription factor that modulates survival-directed transcription, is often persistently activated in epidermal growth factor receptor (EGFR) wild-type non-small-cell lung cancer (NSCLC). The aim of this study was to determine whether sorafenib and its derivative can inhibit EGFR wild-type NSCLC via STAT3 inactivation.
METHODS: EGFR wild-type NSCLC cell lines (A549 H292 H322 H358 and H460) were treated with sorafenib or SC-1, a sorafenib derivative that closely resembled sorafenib structurally but was devoid of kinase inhibitory activity. Apoptosis and signal transduction were analyzed. In vivo efficacy was determined in nude mice with H460 and A549 xenograft.
RESULTS: SC-1 had better effects than sorafenib on growth inhibition and apoptosis in all tested EGFR wild-type NSCLC lines. SC-1 reduced STAT3 phosphorylation at tyrosine 705 in all tested EGFR wild-type NSCLC cells. The expression of STAT3-driven genes, including cylcin D1 and survivin, was also repressed by SC-1. Ectopic expression of STAT3 in H460 cells abolished apoptosis in SC-1-treated cells. Sorafenib and SC-1 enhanced Src homology-2 containing protein tyrosine phosphatase-1 (SHP-1) activity, whereas knockdown of SHP-1, but not SHP-2 or protein-tyrosine phosphatase 1B (PTP-1B), by small interference RNA reduced SC-1-induced apoptosis. SC-1 significantly reduced H460 and A549 tumor growth in vivo through SHP-1/STAT3 pathway.
CONCLUSIONS: SC-1 provides proof that targeting STAT3 signaling pathway may be a novel approach for the treatment of EGFR wild-type NSCLC.

Related: Apoptosis Non-Small Cell Lung Cancer Lung Cancer STAT3 Sorafenib (Nexavar)

Shiota M, Itsumi M, Yokomizo A, et al.
Targeting ribosomal S6 kinases/Y-box binding protein-1 signaling improves cellular sensitivity to taxane in prostate cancer.
Prostate. 2014; 74(8):829-38 [PubMed] Related Publications
BACKGROUND: Taxanes are the only cytotoxic chemotherapeutic agents proved to prolong the survival in patients with castration-resistant prostate cancer. However, because of intrinsic and acquired resistances to taxanes, their therapeutical efficiencies are modest, bringing only a few months of survival benefit. Y-box binding protein-1 (YB-1) promotes cancer cell resistance to various anticancer treatments, including taxanes. Here, we aimed to elucidate the mechanism of taxane resistance by YB-1 and examined overcoming resistance by targeting YB-1 signaling.
METHODS: Gene and protein expression levels were evaluated by quantitative real-time polymerase chain reaction and Western blot analysis, respectively. We evaluated the sensitivity of prostate cancer cells to taxanes using cytotoxicity assays.
RESULTS: Natural taxane paclitaxel from Taxus brevifolia activated the Raf-1/extracellular signal-regulated kinase (ERK) pathway, leading to an activation of ribosomal S6 kinases (RSK)/YB-1 signaling. Activated Raf-1/ERK pathway was blunted by YB-1 knockdown in prostate cancer cells, indicating regulation between Raf-1/ERK signaling and YB-1. In addition, ERK or RSK was activated in taxane-resistant prostate cancer cells, resulting in YB-1 activation. YB-1 knockdown as well as RSK inhibition using RSK-specific siRNA or the small molecule inhibitor SL0101 successfully blocked activation of YB-1, leading to suppression of prostate cancer growth and sensitization to paclitaxel.
CONCLUSIONS: Taken together, these findings indicate that RSK/YB-1 signaling contributes to taxane resistance, and implicate the therapeutics targeting RSK/YB-1 signaling such as RSK inhibitor as a promising novel therapy against prostate cancer, especially in combination with taxane.

Related: Paclitaxel Prostate Cancer Signal Transduction

Liu Z, Jiang Z, Huang J, et al.
miR-7 inhibits glioblastoma growth by simultaneously interfering with the PI3K/ATK and Raf/MEK/ERK pathways.
Int J Oncol. 2014; 44(5):1571-80 [PubMed] Related Publications
Epidermal growth factor receptor (EGFR) signaling regulates glioblastoma cell proliferation, survival, migration and invasion and plays a key role in tumor progression. We show that microRNA-7 (miR-7) is a common regulator of the phosphoinositide-3-kinase (PI3K)/ATK and Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways, both of which are launched by EGFR through its two direct targets, the transcription factors PI3K and Raf-1, respectively. Enforced expression of miR-7 markedly decreased expression of PI3K, phosphorylated Akt, Raf-1, phosphorylated MEK 1/2, and cyclin D1, as well as slightly reduced expression of EGFR. Forced expression of PI3K or Raf-1 transcripts lacking the 3'-untranslated region (3'-UTR) partially reversed the effects of miR-7 on cell growth inhibition and cell cycle arrest in glioma cells. Additionally, transient expression of miR-7 in glioblastoma cells strongly inhibited in vivo glioblastoma xenograft growth. We conclude that miR-7 is a potential tumor suppressor in glioblastoma that acts by targeting multiple oncogenes related to the downstream pathway of EGFR and may serve as a novel therapeutic target for malignant gliomas.

Related: Apoptosis MicroRNAs EGFR

Imielinski M, Greulich H, Kaplan B, et al.
Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma.
J Clin Invest. 2014; 124(4):1582-6 [PubMed] Article available free on PMC after 07/11/2015 Related Publications
Targeted cancer therapies often induce "outlier" responses in molecularly defined patient subsets. One patient with advanced-stage lung adenocarcinoma, who was treated with oral sorafenib, demonstrated a near-complete clinical and radiographic remission for 5 years. Whole-genome sequencing and RNA sequencing of primary tumor and normal samples from this patient identified a somatic mutation, ARAF S214C, present in the cancer genome and expressed at high levels. Additional mutations affecting this residue of ARAF and a nearby residue in the related kinase RAF1 were demonstrated across 1% of an independent cohort of lung adenocarcinoma cases. The ARAF mutations were shown to transform immortalized human airway epithelial cells in a sorafenib-sensitive manner. These results suggest that mutant ARAF is an oncogenic driver in lung adenocarcinoma and an indicator of sorafenib response.

Related: Lung Cancer ARAF BRAF Sorafenib (Nexavar)

Krayem M, Journe F, Wiedig M, et al.
Prominent role of cyclic adenosine monophosphate signalling pathway in the sensitivity of (WT)BRAF/(WT)NRAS melanoma cells to vemurafenib.
Eur J Cancer. 2014; 50(7):1310-20 [PubMed] Related Publications
Vemurafenib improves survival in patients with melanoma bearing the (V600E)BRAF mutation, but it did not show any benefit in clinical trials focusing on wild type tumours while it may well inhibit (WT)BRAF considering the dosage used and the bioavailability of the drug. As tumours may contain a mixture of mutant and wild type BRAF cells and this has been also put forward as a resistance mechanism, we aimed to evaluate the sensitivity/resistance of six, randomly selected, (WT)BRAF/(WT)NRAS lines to vemurafenib and found four sensitive. The sensitivity to the drug was accompanied by a potent inhibition of both phospho-ERK and phospho-AKT, and a significant induction of apoptosis while absent in lines with intrinsic or acquired resistance. Phospho-CRAF expression was low in all sensitive lines and high in resistant ones, and MEK inhibition can effectively potentiate the drug effect. A possible explanation for CRAF modulation is cyclic adenosine monophosphate (cAMP), a mediator of melanocortin receptor 1 (MC1R) signalling, since it can actually inhibit CRAF. Indeed, we measured cAMP and found that all four sensitive lines contained significantly higher constitutive cAMP levels than the resistant ones. Consequently, vemurafenib and cAMP stimulator combination resulted in a substantial synergistic effect in lines with both intrinsic and acquired resistance but only restricted to those where cAMP was effectively increased. The use of a cAMP agonist overcame such restriction. In conclusion, we report that (WT)BRAF/(WT)NRAS melanoma lines with low phospho-CRAF and high cAMP levels may be sensitive to vemurafenib and that CRAF inhibition through cAMP stimulation may overcome the resistance to the drug.

Related: Apoptosis Melanoma BRAF Signal Transduction Vemurafenib (Zelboraf) NRAS

Li X, Stevens PD, Liu J, et al.
PHLPP is a negative regulator of RAF1, which reduces colorectal cancer cell motility and prevents tumor progression in mice.
Gastroenterology. 2014; 146(5):1301-12.e1-10 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
BACKGROUND & AIMS: Hyperactivation of the RAS-RAF signaling pathway in colorectal tumors is associated with metastasis and poor outcomes of patients. Little is known about how RAS-RAF signaling is turned off once activated. We investigated how the pH domain and leucine-rich repeat protein phosphatases (PHLPPs) control RAS-RAF signaling and colorectal cancer (CRC) development.
METHODS: We used co-immunoprecipitation assays to identify substrates of PHLPP1 and PHLPP2. We studied phosphorylation of RAF1 in CRC cells that express exogenous PHLPP1 or PHLPP2, or lentiviral-based small hairpin RNAs against their transcripts; we measured effects on cell motility, migration, and invasion in vitro. Tumor progression and survival were analyzed in Phlpp1(-/-) Apc(Min) and Apc(Min)/Phlpp1(-/-) mice. Microarray datasets of colorectal tumor and nontumor tissues were analyzed for PHLPP gene expression.
RESULTS: PHLPP1 and 2 were found to dephosphorylate RAF1 at S338, inhibiting its kinase activity in vitro and in CRC cells. In cells, knockdown of PHLPP1 or PHLPP2 increased the amplitude and duration of RAF-MEK-ERK signaling downstream of epidermal growth factor receptor and KRAS, whereas overexpression had the opposite effect. In addition, knockdown of PHLPP1 or PHLPP2 caused CRC cells to express markers of the epithelial-mesenchymal transition, and increased cell migration and invasion. Apc(Min)/Phlpp1(-/-) mice had decreased survival and developed larger intestinal and colon tumors compared to Apc(Min) mice. Whereas Apc(Min) mice developed mostly low-grade adenomas, 20% of the tumors that developed in Apc(Min)/Phlpp1(-/-) mice were invasive adenocarcinomas. Normal villi and adenomas of Apc(Min)/Phlpp1(-/-) mice had significantly fewer apoptotic cells than Apc(Min) mice. Human CRC patient microarray data revealed that the expression of PHLPP1 or PHLPP2 is positively correlated with CDH1.
CONCLUSIONS: PHLPP1 and PHLPP2 dephosphorylate RAF1 to reduce its signaling, increase the invasive and migratory activities of CRC cells, and activate the epithelial-mesenchymal transition. In Apc(Min) mice, loss of PHLPP1 promotes tumor progression.

Related: Apoptosis Colorectal (Bowel) Cancer APC AKT1 Signal Transduction CDH1 PHLPP1

Huang J, Hu W, Bottsford-Miller J, et al.
Cross-talk between EphA2 and BRaf/CRaf is a key determinant of response to Dasatinib.
Clin Cancer Res. 2014; 20(7):1846-55 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
PURPOSE: EphA2 is an attractive therapeutic target because of its diverse roles in cancer growth and progression. Dasatinib is a multikinase inhibitor that targets EphA2 and other kinases. However, reliable predictive markers and a better understanding of the mechanisms of response to this agent are needed.
EXPERIMENTAL DESIGN: The effects of dasatinib on human uterine cancer cell lines were examined using a series of in vitro experiments, including MTT, Western blot analysis, and plasmid transfection. In vivo, an orthotopic mouse model of uterine cancer was utilized to identify the biologic effects of dasatinib. Molecular markers for response prediction and the mechanisms relevant to response to dasatinib were identified by using reverse phase protein array (RPPA), immunoprecipitation, and double immunofluorescence staining.
RESULTS: We show that high levels of CAV-1, EphA2 phosphorylation at S897, and the status of PTEN are key determinants of dasatinib response in uterine carcinoma. A set of markers essential for dasatinib response was also identified and includes CRaf, pCRaf(S338), pMAPK(T202/Y204) (mitogen-activated protein kinase [MAPK] pathway), pS6(S240/244), p70S6k(T389) (mTOR pathway), and pAKT(S473). A novel mechanism for response was discovered whereby high expression level of CAV-1 at the plasma membrane disrupts the BRaf/CRaf heterodimer and thus inhibits the activation of MAPK pathway during dasatinib treatment.
CONCLUSIONS: Our in vitro and in vivo results provide a new understanding of EphA2 targeting by dasatinib and identify key predictors of therapeutic response. These findings have implications for ongoing dasatinib-based clinical trials.

Related: BRAF Dasatinib (Sprycel)

Fan DP, Zhang YM, Hu XC, et al.
Activation of AKT/ERK confers non-small cell lung cancer cells resistance to vinorelbine.
Int J Clin Exp Pathol. 2014; 7(1):134-43 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Vinorelbine is a semi-synthetic vinca-alkaloid approved for the treatment of non-small cell lung cancer (NSCLC). However, the lower objective response rate and higher adverse effects of vinorelbine hinder its wide use in treatment of advanced NSCLC. Therefore, it is of great interest to uncover the biomarkers for sensitivity of NSCLC cells to vinorelbine to allow the identification of patients most likely to benefit from vinorelbine-based chemotherapy and to improve the therapy. In present work, four NSCLC cell lines were divided into vinorelbine-sensitive (VS) group and vinorelbine-resistant (VR) group according to their sensitivities to vinorelbine. And then the gene expression profiles of these two groups was compared, the differentially expressed genes (expression difference higher than 100% and p<0.05, totally 496 genes) were applied to Ingenuity Pathway Analysis (IPA). IPA results showed that NF-κB and PTEN signaling were predicted to be inactivated in VR cell lines, which was partially validated by quantitative PCR or western blotting experiments. The higher expression of RAF1 mRNA and the activation of AKT/ERK proteins in VR NSCLC cell lines may confer resistance to vinorelbine. Our work may provide potential pathway signature for vinorelbine sensitivity and some therapeutic targets for combined therapy.

Related: Non-Small Cell Lung Cancer Lung Cancer AKT1 Signal Transduction Vinblastine Vinorelbine

Wang Q, Wu X, Wu T, et al.
Clinical significance of RKIP mRNA expression in non-small cell lung cancer.
Tumour Biol. 2014; 35(5):4377-80 [PubMed] Related Publications
Raf-1 kinase inhibitor protein (RKIP) expression was associated with the onset, development, invasion, and metastasis of numerous tumor types including prostate cancer, melanoma, colorectal cancer, liver cancer, and breast cancer. However, RKIP mRNA expression and the clinical significance in non-small cell lung cancers (NSCLC) remain unresolved. Real-time PCR was performed to detect the expression of RKIP mRNA in 126 pairs of lung tumor tissues (TT) and surrounding normal tissues (sNT). Correlations between RKIP mRNA expression and clinicopathological features were evaluated by statistical analysis. In the 126 patients examined, RKIP mRNA expression was significantly lower in lung TT than the sNT (p < 0.05). Our results indicated that downregulation of RKIP mRNA expression was associated with a poorer N-stage (p = 0.019) and poorer pathological TNM stage (p = 0.015). However, no significant association was observed between the expression status of RKIP mRNA and clinicopathologic factors, such as gender, age, histological type, and the size of the tumor (p > 0.05). The level of RKIP mRNA expression was found to be significantly downregulated in NSCLC, and the lower mRNA levels correlated with poorer differentiation, advanced pathologic TNM stage in patients with NSCLC.

Related: Non-Small Cell Lung Cancer Lung Cancer

Chen Z, Cheng Q, Ma Z, et al.
Overexpression of RKIP inhibits cell invasion in glioma cell lines through upregulation of miR-98.
Biomed Res Int. 2013; 2013:695179 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Raf-1 kinase inhibitor protein (RKIP) is a tumor and metastasis suppressor in cancer cells. MicroRNAs (miRNAs) have been suggested to play a vital role in tumor initiation and progression by negatively regulating oncogenes and tumor suppressors. Quite recently, studies have identified some miRNAs operating to promote or suppress tumor invasion or metastasis via regulating metastasis-related genes, providing potential therapeutic targets on antimetastasis strategy. In this study, we found that the expression of RKIP and miR-98 in glioma tissues were significantly lower than that in normal brain tissues. Overexpression of RKIP upregulated miR-98 expression and inhibited glioma cell invasion and miR-98 target gene HMGA2 but had no effect in glioma cell proliferation. Moreover, forced expression of miR-98 accelerated the inhibition of glioma cell invasion and the expression of HMGA2 also had no effect in glioma cell proliferation. Our findings newly described RKIP/miR-98 to HMGA2 link and provided a potential mechanism for glioma cell invasion. RKIP and miR-98 may illustrate the potential therapeutic utility of signaling pathway signatures.

Related: HMGA2 gene MicroRNAs Signal Transduction

Pradhan MP, Desai A, Palakal MJ
Systems biology approach to stage-wise characterization of epigenetic genes in lung adenocarcinoma.
BMC Syst Biol. 2013; 7:141 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
BACKGROUND: Epigenetics refers to the reversible functional modifications of the genome that do not correlate to changes in the DNA sequence. The aim of this study is to understand DNA methylation patterns across different stages of lung adenocarcinoma (LUAD).
RESULTS: Our study identified 72, 93 and 170 significant DNA methylated genes in Stages I, II and III respectively. A set of common 34 significant DNA methylated genes located in the promoter section of the true CpG islands were found across stages, and these were: HOX genes, FOXG1, GRIK3, HAND2, PRKCB, etc. Of the total significant DNA methylated genes, 65 correlated with transcription function. The epigenetic analysis identified the following novel genes across all stages: PTGDR, TLX3, and POU4F2. The stage-wise analysis observed the appearance of NEUROG1 gene in Stage I and its re-appearance in Stage III. The analysis showed similar epigenetic pattern across Stage I and Stage III. Pathway analysis revealed important signaling and metabolic pathways of LUAD to correlate with epigenetics. Epigenetic subnetwork analysis identified a set of seven conserved genes across all stages: UBC, KRAS, PIK3CA, PIK3R3, RAF1, BRAF, and RAP1A. A detailed literature analysis elucidated epigenetic genes like FOXG1, HLA-G, and NKX6-2 to be known as prognostic targets.
CONCLUSION: Integrating epigenetic information for genes with expression data can be useful for comprehending in-depth disease mechanism and for the ultimate goal of better target identification.

Related: Lung Cancer

Ekvall S, Sjörs K, Jonzon A, et al.
Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome.
Am J Med Genet A. 2014; 164A(3):579-87 [PubMed] Related Publications
Neurofibromatosis-Noonan syndrome (NFNS) is a rare condition with clinical features of both neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). All three syndromes belong to the RASopathies, which are caused by dysregulation of the RAS-MAPK pathway. The major gene involved in NFNS is NF1, but co-occurring NF1 and PTPN11 mutations in NFNS have been reported. Knowledge about possible involvement of additional RASopathy-associated genes in NFNS is, however, very limited. We present a comprehensive clinical and molecular analysis of eight affected individuals from three unrelated families displaying features of NF1 and NFNS. The genetic etiology of the clinical phenotypes was investigated by mutation analysis, including NF1, PTPN11, SOS1, KRAS, NRAS, BRAF, RAF1, SHOC2, SPRED1, MAP2K1, MAP2K2, and CBL. All three families harbored a heterozygous NF1 variant, where the first family had a missense variant, c.5425C>T;p.R1809C, the second family a recurrent 4bp-deletion, c.6789_6792delTTAC;p.Y2264Tfs*6, and the third family a splice-site variant, c.2991-1G>A, resulting in skipping of exon 18 and an in-frame deletion of 41 amino acids. These NF1 variants have all previously been reported in NF1 patients. Surprisingly, both c.6789_6792delTTAC and c.2991-1G>A are frequently associated with NF1, but association to NFNS has, to our knowledge, not previously been reported. Our results support the notion that NFNS represents a variant of NF1, genetically distinct from NS, and is caused by mutations in NF1, some of which also cause classical NF1. Due to phenotypic overlap between NFNS and NS, we propose screening for NF1 mutations in NS patients, preferentially when café-au-lait spots are present.

Related: Neurofibromatosis Noonan Syndrome

Capovilla M
[Cellular and molecular mechanisms of carcinogenic side effects and resistance to BRAF inhibitors in metastatic melanoma with BRAFV600 mutation: state of the knowledge].
Ann Pathol. 2013; 33(6):375-85 [PubMed] Related Publications
Cutaneous melanoma is a malignant tumor with a high metastatic potential. If an early treatment is associated with a favorable outcome, the prognosis of metastatic melanoma remains poor. Advances in molecular characterization of cancers, notably the discovery of BRAF gene mutations in metastatic melanoma, allowed to the recent development of targeted therapies against mutated BRAF protein. Despite high tumor response rates observed in clinical trials, these new drugs are associated with frequent secondary tumor resistance occurrence and paradoxical carcinogenic side effects. The cellular and molecular mechanisms of these carcinogenic side effects and secondary resistance are not yet fully elucidated and are actually intensely studied. This review of the literature focus on the mechanisms of these carcinogenic side effects and on the tumor resistance associated with anti-BRAF targeted therapies.

Related: Leukemia BRAF Skin Cancer Vemurafenib (Zelboraf)

Del Vescovo V, Meier T, Inga A, et al.
A cross-platform comparison of affymetrix and Agilent microarrays reveals discordant miRNA expression in lung tumors of c-Raf transgenic mice.
PLoS One. 2013; 8(11):e78870 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Non-coding RNAs play major roles in the translational control of gene expression. In order to identify disease-associated miRNAs in precursor lesions of lung cancer, RNA extracts from lungs of either c-Raf transgenic or wild-type (WT) mice were hybridized to the Agilent and Affymetrix miRNA microarray platforms, respectively. This resulted in the detection of a range of miRNAs varying between 111 and 267, depending on the presence or absence of the transgene, on the gender, and on the platform used. Importantly, when the two platforms were compared, only 11-16% of the 586 overlapping genes were commonly detected. With the Agilent microarray, seven miRNAs were identified as significantly regulated, of which three were selectively up-regulated in male transgenic mice. Much to our surprise, when the same samples were analyzed with the Affymetrix platform, only two miRNAs were identified as significantly regulated. Quantitative PCR performed with lung RNA extracts from WT and transgenic mice confirmed only partially the differential expression of significant regulated miRNAs and established that the Agilent platform failed to detect miR-433. Finally, bioinformatic analyses predicted a total of 152 mouse genes as targets of the regulated miRNAs of which 4 and 11 genes were significantly regulated at the mRNA level, respectively in laser micro-dissected lung dysplasia and lung adenocarcinomas of c-Raf transgenic mice. Furthermore, for many of the predicted mouse target genes expression of the coded protein was also repressed in human lung cancer when the publically available database of the Human Protein Atlas was analyzed, thus supporting the clinical significance of our findings. In conclusion, a significant difference in a cross-platform comparison was observed that will have important implications for research into miRNAs.

Related: Lung Cancer MicroRNAs

Chen Y, Xin X, Li J, et al.
RTK/ERK pathway under natural selection associated with prostate cancer.
PLoS One. 2013; 8(11):e78254 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Prostate cancer (PCa) is a global disease causing large numbers of deaths every year. Recent studies have indicated the RTK/ERK pathway might be a key pathway in the development of PCa. However, the exact association and evolution-based mechanism remain unclear. This study was conducted by combining genotypic and phenotypic data from the Chinese Consortium for Prostate Cancer Genetics (ChinaPCa) with related databases such as the HapMap Project and Genevar. In this analysis, expression of quantitative trait loci (eQTLs) analysis, natural selection and gene-based pathway analysis were involved. The pathway analysis confirmed the positive relationship between PCa risk and several key genes. In addition, combined with the natural selection, it seems that 4 genes (EGFR, ERBB2, PTK2, and RAF1) with five SNPs (rs11238349, rs17172438, rs984654, rs11773818, and rs17172432) especially rs17172432, might be pivotal factors in the development of PCa. The results indicate that the RTK/ERK pathway under natural selection is a key link in PCa risk. The joint effect of the genes and loci with positive selection might be one reason for the development of PCa. Dealing with all the factors simultaneously might give insight into prevention and aid in predicting the success of potential therapies for PCa.

Related: Prostate Cancer EGFR

Chen Y, Li T, Yu X, et al.
The RTK/ERK pathway is associated with prostate cancer risk on the SNP level: a pooled analysis of 41 sets of data from case-control studies.
Gene. 2014; 534(2):286-97 [PubMed] Related Publications
Prostate cancer (PCa) is a malignant disease influencing numerous men worldwide every year. However, the exact pathogenesis and the genes, environment, and other factors involved have not been explained clearly. Some studies have proposed that cell signaling pathways might play a key role in the development and progression of PCa. According to our previous study, the RTK/ERK pathway containing nearly 40 genes was associated with PCa risk. On the basis of these genes, we conducted a meta-analysis with our own Chinese Consortium for Prostate Cancer Genetics (ChinaPCa) study and available studies in the databases to describe the association between the pathway and PCa on the SNP level. The results suggested that rs4764695/IGF1 (recessive model: pooled OR=0.92, 95%CI=0.852-0.994, P=0.034; I(2)=0%, P=0.042; allele analysis: pooled OR=0.915, 95%CI=0.874-0.958, P=0; I(2)=0%, P=0.424; codominant model: OR=0.835, 95%CI=0.762-0.916, P=0; I(2)=0%, P=0.684) and rs1570360/VEGF (recessive model: OR=0.596, 95%CI=0.421-0.843, P=0.003; I(2)=23.9%, P=0.269; codominant model: OR=0.576, 95%CI=0.404-0.820, P=0.002; I(2)=49.1%, P=0.140) were significantly associated with PCa. In subgroup analysis, the relationship was also found in Caucasians for IGF1 (dominant model: OR=0.834, 95%CI=0.769-0.904, P=0; allele analysis: OR=0.908, 95%CI=0.863-0.955, P=0; AA vs CC: OR=0.829, 95%CI=0.750-0.916, P=0; AC vs CC: OR=0.837, 95%CI=0.768-0.912, P=0). In addition, in Asians (allele analysis: OR=0.21, 95%CI=0.168-0.262, P=0) and Caucasians (recessive model: OR=0.453, 95%CI: 0.240-0.855, P=0.015; codominant model: OR=0.464, 95%CI=0.240-0.898, P=0.023) for VEGF, the association was significant. The results indicated that rs4764695/IGF1 and rs1570360/VEGF might play a key role in the development and progression of PCa. On the SNP level, we suggest that the study gives us a new view of gene-pathway analysis and targeted therapy for PCa.

Related: Prostate Cancer

Zhou J, Chen L, Zhang Y, et al.
Synergistic effect of EMS1-shRNA and sorafenib on proliferation, migration, invasion and endocytosis of SMMC-7721.
J Mol Histol. 2014; 45(2):205-16 [PubMed] Related Publications
To investigate the synergistic effect of EMS1-PSilencer4.1-shRNA (EMS1-shRNA) and sorafenib on biological behaviors of HCC cell line SMMC-7721. EMS1-shRNA was constructed and transfected into SMMC-7721 cells. Decreased levels of EMS1/cortactin were tested in RT-QPCR and Western blot assay. Proliferation, migration, invasion, and endocytosis of SMMC-7721 were tested through CCK8 assay, scratch test, transwell invasion assay and transferrin endocytosis assay, respectively. Raf-1 was detected by Western blot assay. HCC xenograft model was prepared to observe tumor growth. Animals were euthanized and their subcutaneous lesions were weighed. Then the tissues were fixed and paraffin sections were prepared. Cortactin and PCNA (a proliferation marker) were then detected by immunohistochemistry. As compared with untreated group, the levels of EMS1 gene and cortactin protein in EMS1-shRNA-transfected group were significantly reduced; Among EMS1-shRNA-transfected group, sorafenib-treated group and combined group, the levels of proliferation at 48 h were reduced to 83.69, 57.18, 41.94 %; the levels of migration were reduced to 49.69, 60.83, and 21. 67 %; the levels of invasion were reduced to 42.97, 53.65, 18.18 %; the levels of endocytosis were reduced to 37.15, 97.95 % (p > 0.05), 20.68 % (p < 0.05, respectively). Western blot assay showed levels of Raf-1 were reduced to 68.56, 59.09, 21.90 %. The tumor volume and weight of nude mice HCC xenograft tumors were reduced significantly either (p < 0.05, respectively). Immunohistochemistry showed levels of cortactin and PCNA were reduced to 35.69, 93.84, 23.68 and 87.69, 43.84, 33.68 % in each group, respectively. The biological behaviors of SMMC-7721 were inhibited in the presence of EMS1-shRNA and sorafenib both alone and in combination. The combination of the agents improved the curative effect over either single agent, showing synergetic effect.

Related: Sorafenib (Nexavar)

Linch M, Sanz-Garcia M, Rosse C, et al.
Regulation of polarized morphogenesis by protein kinase C iota in oncogenic epithelial spheroids.
Carcinogenesis. 2014; 35(2):396-406 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Protein kinase C iota (PKCι), a serine/threonine kinase required for cell polarity, proliferation and migration, is commonly up- or downregulated in cancer. PKCι is a human oncogene but whether this is related to its role in cell polarity and what repertoire of oncogenes acts in concert with PKCι is not known. We developed a panel of candidate oncogene expressing Madin-Darby canine kidney (MDCK) cells and demonstrated that H-Ras, ErbB2 and phosphatidylinositol 3-kinase transformation led to non-polar spheroid morphogenesis (dysplasia), whereas MDCK spheroids expressing c-Raf or v-Src were largely polarized. We show that small interfering RNA (siRNA)-targeting PKCι decreased the size of all spheroids tested and partially reversed the aberrant polarity phenotype in H-Ras and ErbB2 spheroids only. This indicates distinct requirements for PKCι and moreover that different thresholds of PKCι activity are required for these phenotypes. By manipulating PKCι function using mutant constructs, siRNA depletion or chemical inhibition, we have demonstrated that PKCι is required for polarization of parental MDCK epithelial cysts in a 3D matrix and that there is a threshold of PKCι activity above and below which, disorganized epithelial morphogenesis results. Furthermore, treatment with a novel PKCι inhibitor, CRT0066854, was able to restore polarized morphogenesis in the dysplastic H-Ras spheroids. These results show that tightly regulated PKCι is required for normal-polarized morphogenesis in mammalian cells and that H-Ras and ErbB2 cooperate with PKCι for loss of polarization and dysplasia. The identification of a PKCι inhibitor that can restore polarized morphogenesis has implications for the treatment of Ras and ErbB2 driven malignancies.

Hughes L, Ruth K, Rebbeck TR, Giri VN
Genetic variation in IL-16 miRNA target site and time to prostate cancer diagnosis in African-American men.
Prostate Cancer Prostatic Dis. 2013; 16(4):308-14 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
BACKGROUND: Men with a family history of prostate cancer and African-American men are at high risk for prostate cancer and in need of personalized risk estimates to inform screening decisions. This study evaluated genetic variants in genes encoding microRNA (miRNA) binding sites for informing of time to prostate cancer diagnosis among ethnically diverse, high-risk men undergoing prostate cancer screening.
METHODS: The Prostate Cancer Risk Assessment Program (PRAP) is a longitudinal screening program for high-risk men. The eligibility includes men aged between 35 and 69 years with a family history of prostate cancer or African descent. Participants with 1 follow-up visit were included in the analyses (n=477). Genetic variants in genes encoding miRNA binding sites (ALOX15 (arachidonate 15-lipooxygenase), IL-16, IL-18 and RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1)) previously implicated in prostate cancer development were evaluated. Genotyping methods included Taqman SNP Genotyping Assay or pyrosequencing. Cox models were used to assess time to prostate cancer diagnosis by risk genotype.
RESULTS: Among 256 African Americans with one follow-up visit, the TT genotype at rs1131445 in IL-16 was significantly associated with earlier time to prostate cancer diagnosis vs the CC/CT genotypes (P=0.013), with a suggestive association after correction for false discovery (P=0.065). Hazard ratio after controlling for age and PSA for TT vs CC/CT among African Americans was 3.0 (95% confidence interval: 1.26-7.12). No association with time to diagnosis was detected among Caucasians by IL-16 genotype. No association with time to prostate cancer diagnosis was found for the other miRNA target genotypes.
CONCLUSIONS: Genetic variation in IL-16 encoding miRNA target site may be informative of time to prostate cancer diagnosis among African-American men enrolled in prostate cancer risk assessment, which may inform individualized prostate cancer screening strategies in the future.

Related: MicroRNAs Prostate Cancer

Rajput S, Kumar BN, Dey KK, et al.
Molecular targeting of Akt by thymoquinone promotes G(1) arrest through translation inhibition of cyclin D1 and induces apoptosis in breast cancer cells.
Life Sci. 2013; 93(21):783-90 [PubMed] Related Publications
AIM: Thymoquinone (TQ), the predominant bioactive constituent of black seed oil (Nigella Sativa), has been shown to possess antineoplastic activity against multifarious tumors. However, the meticulous mechanism of TQ on Akt mediated survival pathway is still unrevealed in breast cancer. Here, we investigated TQ's mechanism of action against PI3K/Akt signaling and its downstream targets by modulating proteins translational machinery, leading to apoptosis in cancer cells.
MAIN METHODS: MDA-MB-468 and T-47D cells were treated with TQ and evaluated for its anticancer activity through phase distribution and western blot. Modulatory effects of TQ on Akt were affirmed through kinase and drug potential studies.
KEY FINDINGS: Studies revealed G1 phase arrest till 24h incubation with TQ while extended exposure showed phase shift to subG1 indicating apoptosis, supported by suppression of cyclin D1, cyclin E and cyclin dependent kinase inhibitor p27 expression. Immunoblot and membrane potential studies revealed mitochondrial impairment behind apoptotic process with upregulation of Bax, cytoplasmic cytochrome c and procaspase-3, PARP cleavage along with Bcl-2, Bcl-xL and survivin downregulation. Moreover, we construed the rationale behind mitochondrial dysfunction by examining the phosphorylation status of PDK1, PTEN, Akt, c-raf, GSK-3β and Bad in TQ treated cells, thus ratifying the involvement of Akt in apoptosis. Further, the consequential effect of Akt inhibition by TQ is proven by translational repression through deregulated phosphorylation of 4E-BP1, eIF4E, S6R and p70S6K.
SIGNIFICANCE: Our observations for the first time may provide a new insight for the development of novel therapies for Akt overexpressed breast cancer by TQ.

Related: Apoptosis Breast Cancer AKT1 Signal Transduction

Wu CL, Tsai HC, Chen ZW, et al.
Ras activation mediates WISP-1-induced increases in cell motility and matrix metalloproteinase expression in human osteosarcoma.
Cell Signal. 2013; 25(12):2812-22 [PubMed] Related Publications
WISP-1 is a cysteine-rich protein that belongs to the CCN (Cyr61, CTGF, Nov) family of matrix cellular proteins. Osteosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. However, the effect of WISP-1 on migration activity in human osteosarcoma cells is mostly unknown. In this study, we first found that the expression of WISP-1 in osteosarcoma patients was significantly higher than that in normal bone and corrected with tumor stage. Exogenous treatment of osteosarcoma cells with WISP-1 promoted cell motility and matrix metalloproteinase (MMP)-2 and MMP-9 expression. In addition, the Ras and Raf-1 inhibitor or siRNA abolished WISP-1-induced cell migration and MMP expression. On the other hand, activation of the Ras, Raf-1, MEK, ERK, and NF-κB signaling pathway after WISP-1 treatment was demonstrated, and WISP-1-induced expression of MMPs and migration activity were inhibited by the specific inhibitor, and mutant of MEK, ERK, and NF-κB cascades. Taken together, our results indicated that WISP-1 enhances the migration of osteosarcoma cells by increasing MMP-2 and MMP-9 expression through the integrin receptor, Ras, Raf-1, MEK, ERK, and NF-κB signal transduction pathway.

Related: Bone Cancers Osteosarcoma Signal Transduction


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Cite this page: Cotterill SJ. RAF1, Cancer Genetics Web: http://www.cancerindex.org/geneweb/RAF1.htm Accessed: date

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