GRB2

Gene Summary

Gene:GRB2; growth factor receptor bound protein 2
Aliases: ASH, Grb3-3, MST084, NCKAP2, MSTP084, EGFRBP-GRB2
Location:17q25.1
Summary:The protein encoded by this gene binds the epidermal growth factor receptor and contains one SH2 domain and two SH3 domains. Its two SH3 domains direct complex formation with proline-rich regions of other proteins, and its SH2 domain binds tyrosine phosphorylated sequences. This gene is similar to the Sem5 gene of C.elegans, which is involved in the signal transduction pathway. Two alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:growth factor receptor-bound protein 2
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
Show (42)
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

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

  • Protein Binding
  • 3T3 Cells
  • Proto-Oncogene Proteins
  • GRB2 Adaptor Protein
  • Transfection
  • Messenger RNA
  • Cell Proliferation
  • Intracellular Signaling Peptides and Proteins
  • Neoplasm Proteins
  • Gene Expression Profiling
  • Fusion Proteins, bcr-abl
  • Signal Transducing Adaptor Proteins
  • Shc Signaling Adaptor Proteins
  • Mutation
  • Western Blotting
  • Recombinant Fusion Proteins
  • Chromosome 17
  • Protein-Tyrosine Kinases
  • Phosphatidylinositol 3-Kinases
  • Breast Cancer
  • Molecular Sequence Data
  • Down-Regulation
  • Cell Line
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Cancer Gene Expression Regulation
  • Chronic Myelogenous Leukemia
  • Enzyme Activation
  • Cell Movement
  • Phosphorylation
  • Antineoplastic Agents
  • AKT1
  • MAP Kinase Signaling System
  • Epidermal Growth Factor Receptor
  • Neoplastic Cell Transformation
  • ras GTPase-Activating Proteins
  • Phosphoproteins
  • Base Sequence
  • Proteins
  • MicroRNAs
  • Amino Acid Sequence
Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

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

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

Latest Publications: GRB2 (cancer-related)

Singh PR, Priya ES, Balakrishnan S, et al.
Nimbolide inhibits androgen independent prostate cancer cells survival and proliferation by modulating multiple pro-survival signaling pathways.
Biomed Pharmacother. 2016; 84:1623-1634 [PubMed] Related Publications
BACKGROUND: Prostate cancer is the most prominent cancer in men, experiencing a relapse in disease often express high serum TNF-α levels. It has been correlated with increased cell survival and proliferation of prostate cancer cells. Previous studies reported that nimbolide, a terpenoid derived from the leaves and flowers of neem tree inhibits cancer growth through selective modulation of cell signaling pathways linked to inflammation, survival, proliferation, angiogenesis and metastasis.
METHODS: The present study aimed to examine the effect of nimbolide at 1 and 2μM concentrations on TNF-α/TNFR1 mediated signaling molecules involved in cell survival and proliferation in PC-3 cell line via NF-κB and MAPK pathways by real time PCR and western blot. Protein and compound interaction were performed by Molecular docking analysis.
RESULTS: Our results indicate that nimbolide treatment suppressed expression of TNF-α, SODD, Grb2, SOS mRNA and modulated TNF-α/TNFR1 regulated NF-κB and MAPK signaling molecules in PC-3 cells. Additional molecular dynamics simulation studies confirmed the stability of nimbolide and signaling molecules binding interactions. Binding pose analysis revealed the significance of hydrogen bond interactions for effective stabilization of virtual ligand protein complexes.
CONCLUSION: Nimbolide inhibited prostate cancer cell survival and proliferation via NF-κB and MAPK pathways.

Piunti A, Shilatifard A
Epigenetic balance of gene expression by Polycomb and COMPASS families.
Science. 2016; 352(6290):aad9780 [PubMed] Related Publications
Epigenetic regulation of gene expression in metazoans is central for establishing cellular diversity, and its deregulation can result in pathological conditions. Although transcription factors are essential for implementing gene expression programs, they do not function in isolation and require the recruitment of various chromatin-modifying and -remodeling machineries. A classic example of developmental chromatin regulation is the balanced activities of the Polycomb group (PcG) proteins within the PRC1 and PRC2 complexes, and the Trithorax group (TrxG) proteins within the COMPASS family, which are highly mutated in a large number of human diseases. In this review, we will discuss the latest findings regarding the properties of the PcG and COMPASS families and the insight they provide into the epigenetic control of transcription under physiological and pathological settings.

Tian LQ, Liu EQ, Zhu XD, et al.
MicroRNA-197 inhibits cell proliferation by targeting GAB2 in glioblastoma.
Mol Med Rep. 2016; 13(5):4279-88 [PubMed] Related Publications
Glioblastoma is the most common type of primary brain tumor in adults, and is usually fatal in a short duration. Acquiring a better understanding of the pathogenic mechanisms of glioblastoma is essential to the design of effective therapeutic strategies. Grb2-associated binding protein 2 (GAB2) is a member of the daughter of sevenless/Gab family of scaffolding adapters, and has been reported to be important in the development and progression of human cancer. Previously, it has been reported that GAB2 is expressed at high levels in glioma, and may serve as a useful prognostic marker for glioma and a novel therapeutic target for glioma invasion intervention. Elucidating why GAB2 is overexpressed in glioma, and investigating how to downregulate it will assist in further understanding the pathogenesis and progression of the disease, and to offer novel targets for therapy. The present study used in situ hybridization to detect microRNA (miR)‑197 expression levels and Targetscan to predict that the 3'-UTR of GAB2 was targeted by miR-197. Northern blotting and reverse transcription‑quantitative polymerase chain reaction were also conducted in the current study. miR-197 is downregulated in glioblastoma tissues, compared with adjacent normal tissues, however it involvement continues to be detected in the disease. The results of the present study demonstrated that miR‑197, as a tumor suppressor gene, inhibited proliferation by regulating GAB2 in glioblastoma cells. Furthermore, GAB2 was not only upregulated in glioma, but its expression levels were also associated with the grades of glioma severity. In addition, overexpression of GAB2 suppressed the expression of miR‑197 in glioblastoma cells. Therefore, restoration of miR‑197 and targeting GAB2 may be used, in conjunction with other therapies, to prevent the progression of glioblastoma.

Saunders EJ, Dadaev T, Leongamornlert DA, et al.
Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array.
Br J Cancer. 2016; 114(8):945-52 [PubMed] Related Publications
BACKGROUND: Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B.
METHODS: Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes.
RESULTS: Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant.
CONCLUSIONS: MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.

Ding C, Luo J, Li L, et al.
Gab2 facilitates epithelial-to-mesenchymal transition via the MEK/ERK/MMP signaling in colorectal cancer.
J Exp Clin Cancer Res. 2016; 35:5 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Grb2-associated binder 2 (Gab2), a scaffolding adaptor protein, has recently been implicated in cancer progression. However, the role of Gab2 in the progression and metastasis of colorectal cancer (CRC) remains unclear.
METHODS: Gab2 expression was assessed in CRC patient specimens as well as in CRC cell lines. Recombinant lentivirus vector containing Gab2 gene and its small interfering RNAs were constructed and introduced into CRC cells. Cell migration and invasion ability were evaluated by transwell assays in vitro, and in vivo metastasis was performed on nude mice model. Moreover, the expression of Gab2 and epithelial-to-mesenchymal transition (EMT)-associated proteins (E-cadherin and vimentin) were assessed by western blot and qRT-PCR in CRC cells to evaluate the correlation between Gab2 and EMT. Finally, we evaluated the impact of Gab2 on the activation of its downstream signaling effectors, and furthermore the effects of these pathways on Gab2 induced-EMT were also detected.
RESULTS: We confirmed that increased Gab2 expression correlated with higher tumor node metastasis stage and highly invasive CRC cell lines. Ectopic expression of Gab2 promoted metastasis of CRC cells, whereas silencing of Gab2 resulted in inhibited metastasis both in vitro and in vivo. Overexpression of Gab2 in CRC cells induced EMT, whereas knockdown of Gab2 had the opposite effect. Furthermore, upregulation of Gab2 expression obviously stimulated the activation of extracellular signal-regulated kinase-1/2 (ERK1/2), and increased the expression of matrix metalloproteinase-7 (MMP7) and matrix metalloproteinase-9 (MMP9) in CRC cells. Conversely, downregulation of Gab2 expression significantly decreased the activation of ERK1/2, and inhibited MMP7 and MMP9 expression. U0126, an inhibitor of mitogen-activated protein kinase (MEK), can reverse the effects of Gab2 on EMT.
CONCLUSIONS: Our work highlights that Gab2 induces EMT through the MEK/ERK/MMP pathway, which in turn promotes intestinal tumor metastasis.

Pathak HB, Zhou Y, Sethi G, et al.
A Synthetic Lethality Screen Using a Focused siRNA Library to Identify Sensitizers to Dasatinib Therapy for the Treatment of Epithelial Ovarian Cancer.
PLoS One. 2015; 10(12):e0144126 [PubMed] Free Access to Full Article Related Publications
Molecular targeted therapies have been the focus of recent clinical trials for the treatment of patients with recurrent epithelial ovarian cancer (EOC). The majority have not fared well as monotherapies for improving survival of these patients. Poor bioavailability, lack of predictive biomarkers, and the presence of multiple survival pathways can all diminish the success of a targeted agent. Dasatinib is a tyrosine kinase inhibitor of the Src-family kinases (SFK) and in preclinical studies shown to have substantial activity in EOC. However, when evaluated in a phase 2 clinical trial for patients with recurrent or persistent EOC, it was found to have minimal activity. We hypothesized that synthetic lethality screens performed using a cogently designed siRNA library would identify second-site molecular targets that could synergize with SFK inhibition and improve dasatinib efficacy. Using a systematic approach, we performed primary siRNA screening using a library focused on 638 genes corresponding to a network centered on EGFR, HER2, and the SFK-scaffolding proteins BCAR1, NEDD9, and EFS to screen EOC cells in combination with dasatinib. We followed up with validation studies including deconvolution screening, quantitative PCR to confirm effective gene silencing, correlation of gene expression with dasatinib sensitivity, and assessment of the clinical relevance of hits using TCGA ovarian cancer data. A refined list of five candidates (CSNK2A1, DAG1, GRB2, PRKCE, and VAV1) was identified as showing the greatest potential for improving sensitivity to dasatinib in EOC. Of these, CSNK2A1, which codes for the catalytic alpha subunit of protein kinase CK2, was selected for additional evaluation. Synergistic activity of the clinically relevant inhibitor of CK2, CX-4945, with dasatinib in reducing cell proliferation and increasing apoptosis was observed across multiple EOC cell lines. This overall approach to improving drug efficacy can be applied to other targeted agents that have similarly shown poor clinical activity.

Wang WJ, Mou K, Wu XF, et al.
Grb2-associated binder 2 silencing impairs growth and migration of H1975 cells via modulation of PI3K-Akt signaling.
Int J Clin Exp Pathol. 2015; 8(9):10575-84 [PubMed] Free Access to Full Article Related Publications
Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death and often has a poor prognosis. Investigation of NSCLC cancer cell migration, invasion and development of strategies to block this process is essential to improve the disease prognosis. In this study, we tested our hypothesis that Grb2-associated binder 2 (Gab2) regulate NSCLC cancer cell H1975 malignant biological behaviors, and silencing Gab2 reduced H1975 cellular colony forming ability, migration and invasion. Moreover, silenced cells present defects in phosphatidylinositol 3-kinase (PI3K)-serine/threonine kinase (Akt) signaling, and reduced expression/activity of matrix metallopeptidase (MMP)-2/9. Furthermore, in Gab2 siRNA-transfected cells, we detected a decrease in signal transducer and activator of transcription 3 (STAT3) phosphorylation and nuclear translocation. In vivo, Gab2 siRNA cells inoculated subcutaneously in nude mice demonstrated decreased tumor growth and PI3K-Akt signaling inhibition. These results indicate that Gab2 is a key factor in H1975 tumor migration, invasion, suggesting that Gab2 can be a novel therapeutic target in NSCLC.

van Jaarsveld MT, van Kuijk PF, Boersma AW, et al.
miR-634 restores drug sensitivity in resistant ovarian cancer cells by targeting the Ras-MAPK pathway.
Mol Cancer. 2015; 14:196 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Drug resistance hampers the efficient treatment of malignancies, including advanced stage ovarian cancer, which has a 5-year survival rate of only 30 %. The molecular processes underlying resistance have been extensively studied, however, not much is known about the involvement of microRNAs.
METHODS: Differentially expressed microRNAs between cisplatin sensitive and resistant cancer cell line pairs were determined using microarrays. Mimics were used to study the role of microRNAs in drug sensitivity of ovarian cancer cell lines and patient derived tumor cells. Luciferase reporter constructs were used to establish regulation of target genes by microRNAs.
RESULTS: MiR-634 downregulation was associated with cisplatin resistance. Overexpression of miR-634 affected cell cycle progression and enhanced apoptosis in ovarian cancer cells. miR-634 resensitized resistant ovarian cancer cell lines and patient derived drug resistant tumor cells to cisplatin. Similarly, miR-634 enhanced the response to carboplatin and doxorubicin, but not to paclitaxel. The cell cycle regulator CCND1, and Ras-MAPK pathway components GRB2, ERK2 and RSK2 were directly repressed by miR-634 overexpression. Repression of the Ras-MAPK pathway using a MEK inhibitor phenocopied the miR-634 effects on viability and chemosensitivity.
CONCLUSION: miR-634 levels determine chemosensitivity in ovarian cancer cells. We identify miR-634 as a therapeutic candidate to resensitize chemotherapy resistant ovarian tumors.

Haddad SA, Lunetta KL, Ruiz-Narváez EA, et al.
Hormone-related pathways and risk of breast cancer subtypes in African American women.
Breast Cancer Res Treat. 2015; 154(1):145-54 [PubMed] Free Access to Full Article Related Publications
We sought to investigate genetic variation in hormone pathways in relation to risk of overall and subtype-specific breast cancer in women of African ancestry (AA). Genotyping and imputation yielded data on 143,934 SNPs in 308 hormone-related genes for 3663 breast cancer cases (1098 ER-, 1983 ER+, 582 ER unknown) and 4687 controls from the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. AMBER includes data from four large studies of AA women: the Carolina Breast Cancer Study, the Women's Circle of Health Study, the Black Women's Health Study, and the Multiethnic Cohort Study. Pathway- and gene-based analyses were conducted, and single-SNP tests were run for the top genes. There were no strong associations at the pathway level. The most significantly associated genes were GHRH, CALM2, CETP, and AKR1C1 for overall breast cancer (gene-based nominal p ≤ 0.01); NR0B1, IGF2R, CALM2, CYP1B1, and GRB2 for ER+ breast cancer (p ≤ 0.02); and PGR, MAPK3, MAP3K1, and LHCGR for ER- disease (p ≤ 0.02). Single-SNP tests for SNPs with pairwise linkage disequilibrium r (2) < 0.8 in the top genes identified 12 common SNPs (in CALM2, CETP, NR0B1, IGF2R, CYP1B1, PGR, MAPK3, and MAP3K1) associated with overall or subtype-specific breast cancer after gene-level correction for multiple testing. Rs11571215 in PGR (progesterone receptor) was the SNP most strongly associated with ER- disease. We identified eight genes in hormone pathways that contain common variants associated with breast cancer in AA women after gene-level correction for multiple testing.

Wu SH, Hsiao YT, Kuo CL, et al.
Bufalin Inhibits NCI-H460 Human Lung Cancer Cell Metastasis In Vitro by Inhibiting MAPKs, MMPs, and NF-κB Pathways.
Am J Chin Med. 2015; 43(6):1247-64 [PubMed] Related Publications
Bufalin, a component of Chan Su (a traditional Chinese medicine), has been known to have antitumor effects for thousands of years. In this study, we investigated its anti-metastasis effects on NCI-H460 lung cancer cells. Under sub-lethal concentrations (from 25 up to 100 nM), bufalin significantly inhibits the invasion and migration nature of NCI-H460 cells that were measured by Matrigel Cell Migration Assay and Invasion System. Bufalin also suppressed the enzymatic activity of matrix metalloproteinase (MMP)-9, which was examined by gelatin zymography methods. Western blotting revealed that bufalin depressed several key metastasis-related proteins, such as NF-κB, MMP-2, MMP-9, protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3-K), phosphorylated Akt, growth factor receptor-bound protein 2 (GRB2), phosphorylated extracellular signal-regulated kinase (ERK), phosphorylated p38, and phosphorylated c-Jun NH2-terminal kinase (JNK). As evidenced by immunostaining and the electrophoretic mobility shift assay (EMSA), bufalin induced not only a decreased cytoplasmic NF-κB production, but also decreased its nuclear translocation. Several metastasis-related genes, including Rho-associated (Rho A), coiled-coil-containing protein kinase 1 (ROCK1), and focal adhesion kinase (FAK), were down-regulated after bufalin treatment. In conclusion, bufalin is effective in inhibiting the metastatic nature of NCI-H460 cells in low, sub-lethal concentrations. Such an effect involves many mechanisms including MMPs, mitogen-activated protein kinases (MAPKs) and NF-κB systems. Bufalin has a potential to evolve into an anti-metastasis drug for human lung cancer in the future.

Yan JF, Kim H, Jeong SK, et al.
Integrated Proteomic and Genomic Analysis of Gastric Cancer Patient Tissues.
J Proteome Res. 2015; 14(12):4995-5006 [PubMed] Related Publications
V-erb-b2 erythroblastic leukemia viral oncogene homologue 2, known as ERBB2, is an important oncogene in the development of certain cancers. It can form a heterodimer with other epidermal growth factor receptor family members and activate kinase-mediated downstream signaling pathways. ERBB2 gene is located on chromosome 17 and is amplified in a subset of cancers, such as breast, gastric, and colon cancer. Of particular interest to the Chromosome-Centric Human Proteome Project (C-HPP) initiative is the amplification mechanism that typically results in overexpression of a set of genes adjacent to ERBB2, which provides evidence of a linkage between gene location and expression. In this report we studied patient samples from ERBB2-positive together with adjacent control nontumor tissues. In addition, non-ERBB2-expressing patient samples were selected as comparison to study the effect of expression of this oncogene. We detected 196 proteins in ERBB2-positive patient tumor samples that had minimal overlap (29 proteins) with the non-ERBB2 tumor samples. Interaction and pathway analysis identified extracellular signal regulated kinase (ERK) cascade and actin polymerization and actinmyosin assembly contraction as pathways of importance in ERBB2+ and ERBB2- gastric cancer samples, respectively. The raw data files are deposited at ProteomeXchange (identifier: PXD002674) as well as GPMDB.

Zhao N, Liu Y, Chang Z, et al.
Identification of Biomarker and Co-Regulatory Motifs in Lung Adenocarcinoma Based on Differential Interactions.
PLoS One. 2015; 10(9):e0139165 [PubMed] Free Access to Full Article Related Publications
Changes in intermolecular interactions (differential interactions) may influence the progression of cancer. Specific genes and their regulatory networks may be more closely associated with cancer when taking their transcriptional and post-transcriptional levels and dynamic and static interactions into account simultaneously. In this paper, a differential interaction analysis was performed to detect lung adenocarcinoma-related genes. Furthermore, a miRNA-TF (transcription factor) synergistic regulation network was constructed to identify three kinds of co-regulated motifs, namely, triplet, crosstalk and joint. Not only were the known cancer-related miRNAs and TFs (let-7, miR-15a, miR-17, TP53, ETS1, and so on) were detected in the motifs, but also the miR-15, let-7 and miR-17 families showed a tendency to regulate the triplet, crosstalk and joint motifs, respectively. Moreover, several biological functions (i.e., cell cycle, signaling pathways and hemopoiesis) associated with the three motifs were found to be frequently targeted by the drugs for lung adenocarcinoma. Specifically, the two 4-node motifs (crosstalk and joint) based on co-expression and interaction had a closer relationship to lung adenocarcinoma, and so further research was performed on them. A 10-gene biomarker (UBC, SRC, SP1, MYC, STAT3, JUN, NR3C1, RB1, GRB2 and MAPK1) was selected from the joint motif, and a survival analysis indicated its significant association with survival. Among the ten genes, JUN, NR3C1 and GRB2 are our newly detected candidate lung adenocarcinoma-related genes. The genes, regulators and regulatory motifs detected in this work will provide potential drug targets and new strategies for individual therapy.

Park YH, Shin HT, Jung HH, et al.
Role of HER2 mutations in refractory metastatic breast cancers: targeted sequencing results in patients with refractory breast cancer.
Oncotarget. 2015; 6(31):32027-38 [PubMed] Free Access to Full Article Related Publications
In women with metastatic breast cancer (MBC), introduction of the anti-HER2 (human epidermal growth factor receptor-2) directed therapies including trastuzumab, pertuzumab, lapatinib, and/or trastuzumab-DM1 has markedly improved overall survival. However, not all cases of HER2-positive breast tumours derive similar benefit from HER2-directed therapy, and a significant number of patients experience disease progression because of primary or acquired resistance to anti-HER2-directed therapies. We integrated genomic and clinicopathological analyses in a cohort of patients with refractory breast cancer to anti-HER2 therapies to identify the molecular basis for clinical heterogeneity. To study the molecular basis underlying refractory MBC, we obtained 36 MBC tumours tissues and used next-generation sequencing to investigate the mutational and transcriptional profiles of 83 genes. We focused on HER2 mutational sites and HER2 pathways to identify the roles of HER2 mutations and the HER2 pathway in the refractoriness to anti-HER2 therapies. Analysis using massively parallel sequencing platform, CancerSCAN™, revealed that HER2 mutations were found in six of 36 patients (16.7%). One patient was ER (estrogen receptor)-positive and HER2-negative and the other five HER2 mutated patients were HER2-positive and HR (hormone receptor)-negative. Most importantly, four of these five patients did not show any durable clinical response to HER2-directed therapies. The HER2 pathway score obtained through transcriptional analyses identified that Growth Receptor Biding protein 2 (GRB2) was the most significantly down regulated gene in the HER2 mutated samples. Detection of HER2 mutations using higher deep DNA sequencing may identify a predictive biomarker of resistance to HER2-directed therapy. Functional validation is warranted.

Hameiri-Grossman M, Porat-Klein A, Yaniv I, et al.
The association between let-7, RAS and HIF-1α in Ewing Sarcoma tumor growth.
Oncotarget. 2015; 6(32):33834-48 [PubMed] Free Access to Full Article Related Publications
Ewing Sarcoma (ES) is the second most common primary malignant bone tumor in children and adolescents. microRNAs (miRNAs) are involved in cancer as tumor suppressors or oncogenes. We studied the involvement of miRNAs located on chromosomes 11q and 22q that participate in the most common translocation in ES. Of these, we focused on 3 that belong to the let-7 family.We studied the expression levels of let-7a, and let-7b and detected a significant correlation between low expression of let-7b and increased risk of relapse. let-7 is known to be a negative regulator of the RAS oncogene. Indeed, we detected an inverse association between the expression of let-7 and RAS protein levels and its downstream target p-ERK, following transfection of let-7 mimics and inhibitors. Furthermore, we identified let-7 as a negative regulator of HIF-1α and EWS-FLI-1. Moreover, we were able to show that HIF-1α directly binds to the EWS-FLI-1 promoter. Salirasib treatment in-vitro resulted in the reduction of cell viability, migration ability, and in the decrease of cells in S-phase. A significant reduction in tumor burden and in the expression levels of both HIF-1α and EWS-FLI-1 proteins were observed in mice after treatment.Our results support the hypothesis that let-7 is a tumor suppressor that negatively regulates RAS, also in ES, and that HIF-1α may contribute to the aggressive metastatic behavior of ES. Moreover, the reduction in the tumor burden in a mouse model of ES following Salirasib treatment, suggests therapeutic potential for this RAS inhibitor in ES.

Chou YC, Chang MY, Wang MJ, et al.
PEITC inhibits human brain glioblastoma GBM 8401 cell migration and invasion through the inhibition of uPA, Rho A, and Ras with inhibition of MMP-2, -7 and -9 gene expression.
Oncol Rep. 2015; 34(5):2489-96 [PubMed] Related Publications
Glioblastoma is the most aggressive primary brain malignancy, and the efficacy of multimodality treatments remains unsatisfactory. Phenethyl isothiocyanate (PEITC), one member of the isothiocyanate family, was found to inhibit the migration and invasion of many types of human cancer cells. In our previous study, PEITC induced the apoptosis of human brain glioblastoma GBM 8401 cells through the extrinsic and intrinsic signaling pathways. In the present study, we first investigated the effects of PEITC on the migration and invasion of GBM 8401 cells. PEITC decreased the migration of GBM 8401 cells in a dose-dependent manner as determined from scratch wound healing and Transwell migration assays. The percentage of inhibition ranged from 46.89 to 15.75%, and from 27.80 to 7.31% after a 48-h treatment of PEITC as determined from the Transwell migration assay and invasion assay, respectively. The western blot analysis indicated that PEITC decreased the levels of proteins associated with migration and invasion, Ras, uPA, RhoA, GRB2, p-p38, p-JNK, p-ERK, p65, SOS1, MMP-2, MMP-9 and MMP-13, in a dose-dependent manner. Real-time PCR analyses revealed that PEITC reduced the mRNA levels of MMP-2, MMP-7, MMP-9 and RhoA in a dose- and time-dependent manner. PEITC exhibited potent anticancer activities through the inhibition of migration and invasion in the GBM 8401 cells. Our findings elucidate the possible molecular mechanisms and signaling pathways of the anti-metastatic effects of PEITC on human brain glioblastoma cells, and PEITC may be considered as a therapeutic agent.

Chiang CY, Pan CC, Chang HY, et al.
SH3BGRL3 Protein as a Potential Prognostic Biomarker for Urothelial Carcinoma: A Novel Binding Partner of Epidermal Growth Factor Receptor.
Clin Cancer Res. 2015; 21(24):5601-11 [PubMed] Related Publications
PURPOSE: Mass spectrometry-based biomarker discovery has clinical benefit. To identify novel biomarkers for urothelial carcinoma, we performed quantitative proteomics on pooled urine pairs from patients with and without urothelial carcinoma.
EXPERIMENTAL DESIGN: Shot-gun proteomics using liquid chromatography-tandem mass spectrometry and stable isotope dimethyl labeling identified 219 candidate proteins. The potential implication of SH3 domain binding glutamic acid-rich protein like 3 (SH3BGRL3) was examined by immunoblotting of the urine (n = 13) and urothelial tumors (n = 32). Additional immunohistochemistry was performed on bladder cancer array (n = 1145) and correlated with tumor aggressiveness. Then, biologic functions and signaling pathways of SH3BGRL3 were explored using stable cell lines.
RESULTS: The detectable urine SH3BGRL3 in patients with urothelial carcinoma was positively associated with higher histologic grading and muscle invasiveness of urothelial carcinoma. SH3BGRL3 is expressed in 13.9% (159/1145) of bladder cancer cohort and is positively associated with muscle invasion (P = 0.0028). SH3BGRL3 expression is associated with increased risk of progression in patients with nonmuscle-invasive bladder cancer (P = 0.032). SH3BGRL3 expression is significantly associated with a high level of epidermal growth factor receptor (EGFR) in bladder cancer (P < 0.0001). SH3BGRL3 promotes the epithelial-mesenchymal transition, cell migration, and proliferation of urothelial carcinoma in vitro. SH3BGRL3 interacts with phosphor-EGFR at Y1068, Y1086, and Y1173 through Grb2 by its proline-rich motif, and activates the Akt-associated signaling pathway.
CONCLUSIONS: Evaluation of SH3BGRL3 expression status or urine content may identify a subset of patients with bladder cancer who may require more intensive treatment. SH3BGRL3 deserves further investigation as a cotargeting candidate for designing EGFR-based cancer therapies. Clin Cancer Res; 21(24); 5601-11. ©2015 AACR.

Liu S, Song L, Zeng S, Zhang L
MALAT1-miR-124-RBG2 axis is involved in growth and invasion of HR-HPV-positive cervical cancer cells.
Tumour Biol. 2016; 37(1):633-40 [PubMed] Related Publications
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT 1) is a large, infrequently spliced non-coding RNA aberrantly expressed in cervical cancer. But the molecular mechanisms of its oncogenic role are still not quite clear. The present study explored whether there is a competing endogenous RNAs (ceRNAs) mechanism involved in the oncogenic effect of MALAT1. MALAT1 expression was firstly verified in high-risk human papillomavirus (HR-HPV)-positive tumor tissues and cell lines. Its regulation over miR-124 and the downstream target of miR-124 in regulation of growth, invasion, and apoptosis of the cancer cells are also studied. Findings of this study confirmed higher MALAT1 expression in HR-HPV (+) cervical cancer. Knockdown of endogenous MALAT1 significantly reduced cell growth rate and invasion and increased cell apoptosis of Hela and siHa cells. Besides, knockdown of MALAT1 increased the expression of miRNA-124, while ectopic expression of miR-124 decreased MALAT1 expression. In addition, we also verified a direct interaction between miR-124 and 3'UTR of GRB2. MALAT1 can indirectly modulate GRB2 expression via competing miR-124. Knockdown of GRB2 reduced cell invasion and increased cell apoptosis. In conclusion, MALAT1 can promote HR-HPV (+) cancer cell growth and invasion at least partially through the MALAT1-miR-124-RBG2 axis. This finding might provide some useful evidence about the lncRNA interaction regulatory network in tumorigenesis cervical cancer.

Ding C, Luo J, Yu W, et al.
Gab2 is a novel prognostic factor for colorectal cancer patients.
Int J Clin Exp Pathol. 2015; 8(3):2779-86 [PubMed] Free Access to Full Article Related Publications
Gab2 (Grb2-associated binder 2), a member of the DOS/Gab family of scaffolding adapters, serves as a critical signal amplifier downstream of various growth factor receptors. Recent studies have identified that Gab2 is overexpressed in several cancer types and that increased Gab2 expression promotes cell proliferation, cell transformation, and tumor progression. Here, we show for the first time that Gab2 protein is overexpressed in clinical colorectal cancer (CRC) specimens. Elevated mRNA (P=0.014) expression and protein (P=0.003) expression of Gab2 were found in most CRC tissues compared with the matched adjacent non-tumor tissues using real-time quantitative reverse transcription PCR (qRT-PCR) and western blotting, respectively. Immunohistochemical analyses showed that Gab2 protein was upregulated in CRC tissues relative to adjacent normal tissues (P<0.001), and this overexpression was significantly correlated with lymph node metastasis (P=0.007), distant metastasis (P<0.001) and TNM stage (P=0.002). According to Kaplan-Meier model, CRC patients with Gab2-positive had a significantly poorer prognosis compared to those with Gab2-negative (P=0.007). Multivariate analysis suggested that the positive expression of Gab2 protein was an independent prognostic factor for CRC patients. In conclusion, our data demonstrated that Gab2 expression may play an important role in the progression of CRC, and underscored that Gab2 has the potential value as a prognostic predictor for CRC patients.

Zhao YG, Shi BY, Qian YY, et al.
Dynamic expression changes between non-muscle-invasive bladder cancer and muscle-invasive bladder cancer.
Tumori. 2014 Nov-Dec; 100(6):e273-81 [PubMed] Related Publications
AIMS AND BACKGROUND: Despite elaborate characterization of the risk factors, bladder cancer is still a major epidemiological problem whose incidence continues to rise each year. We aim to investigate the dynamic expression changes between non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC).
METHODS: The gene expression profile GSE13507 was obtained from the Gene Expression Omnibus, and the R package was used to identify gene expression signatures (GESs) between NMIBC and MIBC. Gene ontology enrichment analysis was performed for GES function analysis. We used miRTarBase and TargetScan to identify the differentially regulated microRNAs, and TfactS to identify transcription factors between NMIBC and MIBC. Bionet was used to identify the differentially expressed subnetwork.
RESULTS: A total of 802 upregulated NMIBC GESs and 668 downregulated MIBC GESs were identified. Functional enrichment analysis revealed that the MIBC GESs were majorly involved in cell cycle and inflammatory response. miR-29c and miR-9 were regarded as key microRNAs in MIBC. SMAD3 in MIBC and SMAD5 and SMAD7 in NMIBC were potential activated transcription factors. In addition, a subnetwork that was considered to capture the differences between MIBC and NMIBC was identified, of which GRB2 and UBC were the hub nodes.
CONCLUSIONS: Some key microRNAs, activated transcription factors and hub nodes have been identified in this study, which may be used as potential biomarkers or targets for the diagnosis, treatment and detection of bladder cancer at different stages.

Li LY, Zhang K, Jiang H, et al.
Quantitative proteomics reveals the downregulation of GRB2 as a prominent node of F806-targeted cell proliferation network.
J Proteomics. 2015; 117:145-55 [PubMed] Related Publications
UNLABELLED: High-throughput proteomics has successfully identified thousands of proteins as potential therapeutic targets during investigations into mechanisms of drug action. A novel macrolide analog, denoted F806, is a potential antitumor drug. Here, using the quantitative proteomic approach of stable isotope labeling with amino acids in cell culture (SILAC) coupled to high-resolution mass spectrometry (MS), we characterize the F806-regulating protein profiles and identify the potential target molecules or pathways of F806 in esophageal squamous cell carcinoma (ESCC) cells. From a total of 1931 quantified proteins, 181 proteins were found to be down-regulated (FDR p-value<0.1, H/L ratio<0.738), and 119 proteins were up-regulated (FDR p-value<0.1, H/L ratio>1.156). Among the down-regulated proteins, we uncovered the over- and under-represented protein clusters in biological process and molecular function respectively by Gene Ontology analysis. Furthermore, down-regulated and up-regulated proteins were significantly enriched in 37 pathways and 60 sub-pathways by bioinformatic analysis (FDR p-value<0.1), while a down-regulated molecule growth factor receptor-bound protein 2 (GRB2) was a prominent node in fourteen cell proliferation-related sub-pathways. We concluded that GRB2 downregulation would be a potential target of F806 in ESCC cells.
BIOLOGICAL SIGNIFICANCE: This study used SILAC-based quantitative proteomics screen to systematically characterize molecular changes induced by a novel macrolide analog F806 in esophageal squamous cell carcinoma (ESCC) cells. Followed by bioinformatic analyses, signal pathway networks generated from the quantified proteins, would facilitate future investigation into the further mechanisms of F806 in ESCC cells. Notably, it provided information that growth factor receptor-bound protein 2 (GRB2) would be a prominent node in the F806-targeted cell proliferation network.

Onuki-Nagasaki R, Nagasaki A, Hakamada K, et al.
Identification of kinases and regulatory proteins required for cell migration using a transfected cell-microarray system.
BMC Genet. 2015; 16:9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cell migration plays a major role in a variety of normal biological processes, and a detailed understanding of the associated mechanisms should lead to advances in the medical sciences in areas such as cancer therapy. Previously, we developed a simple chip, based on transfected-cell microarray (TCM) technology, for the identification of genes related to cell migration. In the present study, we used the TCM chip for high-throughput screening (HTS) of a kinome siRNA library to identify genes involved in the motility of highly invasive NBT-L2b cells.
RESULTS: We performed HTS using TCM coupled with a programmed image tracer to capture time-lapse fluorescence images of siRNA-transfected cells and calculated speeds of cell movement. This first screening allowed us to identify 52 genes. After quantitative PCR (qPCR) and a second screening by a conventional transfection method, we confirmed that 32 of these genes were associated with the migration of NBT-L2b cells. We investigated the subcellular localization of proteins and levels of expression of these 32 genes, and then we used our results and databases of protein-protein interactions (PPIs) to construct a hypothetic but comprehensive signal network for cell migration.
CONCLUSIONS: The genes that we identified belonged to several functional categories, and our pathway analysis suggested that some of the encoded proteins functioned as the hubs of networks required for cell migration. Our signal pathways suggest that epidermal growth factor receptor (EGFR) is an upstream regulator in the network, while Src and GRB2 seem to represent nodes for control of respective the downstream proteins that are required to coordinate the many cellular events that are involved in migration. Our microarray appears to be a useful tool for the analysis of protein networks and signal pathways related to cancer metastasis.

Paff M, Alexandru-Abrams D, Hsu FP, Bota DA
The evolution of the EGFRvIII (rindopepimut) immunotherapy for glioblastoma multiforme patients.
Hum Vaccin Immunother. 2014; 10(11):3322-31 [PubMed] Free Access to Full Article Related Publications
Glioblastoma Multiforme (GBM) is the most common type of brain tumor and it is uniformly fatal. The community standard of treatment for this disease is gross or subtotal resection of the tumor, followed by radiation and temozolomide. At recurrence bevacizumab can be added for increased progression free survival. Many challenges are encountered while trying to devise new drugs to treat GBM, such as the presence of the blood brain barrier which is impermeable to most drugs. Therefore in the past few years attention was turned to immunological means for the treatment of this devastating disease. EGFRvIII targeting has proven a good way to attack glioblastoma cells by using the immune system. Although in still in development, this approach holds the promise as a great first step toward immune-tailored drugs for the treatment of brain cancers.

Mukhopadhyay B, Schuebel K, Mukhopadhyay P, et al.
Cannabinoid receptor 1 promotes hepatocellular carcinoma initiation and progression through multiple mechanisms.
Hepatology. 2015; 61(5):1615-26 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Hepatocellular carcinoma (HCC) has high mortality and no adequate treatment. Endocannabinoids interact with hepatic cannabinoid 1 receptors (CB1Rs) to promote hepatocyte proliferation in liver regeneration by inducing cell cycle proteins involved in mitotic progression, including Forkhead Box M1. Because this protein is highly expressed in HCC and contributes to its genesis and progression, we analyzed the involvement of the endocannabinoid/CB1R system in murine and human HCC. Postnatal diethylnitrosamine treatment induced HCC within 8 months in wild-type mice but fewer and smaller tumors in CB1R(-/-) mice or in wild-type mice treated with the peripheral CB1R antagonist JD5037, as monitored in vivo by serial magnetic resonance imaging. Genome-wide transcriptome analysis revealed CB1R-dependent, tumor-induced up-regulation of the hepatic expression of CB1R, its endogenous ligand anandamide, and a number of tumor-promoting genes, including the GRB2 interactome as well as Forkhead Box M1 and its downstream target, the tryptophan-catalyzing enzyme indoleamine 2,3-dioxygenase. Increased indoleamine 2,3-dioxygenase activity and consequent induction of immunosuppressive T-regulatory cells in tumor tissue promote immune tolerance.
CONCLUSION: The endocannabinoid/CB1R system is up-regulated in chemically induced HCC, resulting in the induction of various tumor-promoting genes, including indoleamine 2,3-dioxygenase; and attenuation of these changes by blockade or genetic ablation of CB1R suppresses the growth of HCC and highlights the therapeutic potential of peripheral CB1R blockade.

Huang C, Sheng Y, Jia J, Chen L
Identification of melanoma biomarkers based on network modules by integrating the human signaling network with microarrays.
J Cancer Res Ther. 2014; 10 Suppl:C114-24 [PubMed] Related Publications
BACKGROUND: Melanoma is a leading cause of cancer death. Thus, accurate prognostic biomarkers that will assist rational treatment planning need to be identified.
METHODS: Microarray analysis of melanoma and normal tissue samples was performed to identify differentially expressed modules (DEMs) from the signaling network and ultimately detect molecular markers to support histological examination. Network motifs were extracted from the human signaling network. Then, significant expression-correlation differential modules were identified by comparing the network module expression-correlation differential scores under normal and disease conditions using the gene expression datasets. Finally, we obtained DEMs by the Wilcoxon rank test and considered the average gene expression level in these modules as the classification features for diagnosing melanoma.
RESULTS: In total, 99 functional DEMs were identified from the signaling network and gene expression profiles. The area under the curve scores for cancer module genes, melanoma module genes, and whole network modules are 92.4%, 90.44%, and 88.45%, respectively. The classification efficiency rates for nonmodule features are 71.04% and 79.38%, which correspond to the features of cancer genes and melanoma cancer genes, respectively. Finally, we acquired six significant molecular biomarkers, namely, module 10 (CALM3, Ca 2+ , PKC, PDGFRA, phospholipase-g, PIB5PA, and phosphatidylinositol-3-kinase), module 14 (SRC, Src homology 2 domain-containing [SHC], SAM68, GIT1, transcription factor-4, CBLB, GRB2, VAV2, LCK, YES, PTCH2, downstream of tyrosine kinase [DOK], and KIT), module 16 (ELK3, p85beta, SHC, ZFYVE9, TGFBR1, TGFBR2, CITED1, SH3KBP1, HCK, DOK, and KIT), module 45 (RB, CCND3, CCNA2, CDK4, and CDK6), module 75 (PCNA, CDK4, and CCND1), and module 114 (PSD93, NMDAR, and FYN).
CONCLUSION: We explored the gene expression profile and signaling network in a global view and identified DEMs that can be used as diagnostic or prognostic markers for melanoma.

Zhong S, Ma T, Zhang X, et al.
MicroRNA expression profiling and bioinformatics analysis of dysregulated microRNAs in vinorelbine-resistant breast cancer cells.
Gene. 2015; 556(2):113-8 [PubMed] Related Publications
Vinorelbine (NVB) is one of the most active cytotoxic agents in breast cancer, especially metastatic breast cancer. However, breast cancer patients who are treated with the drug often develop resistance to it and some other drugs. Recently studies have shown that microRNAs (miRNAs) play an important role in drug resistance. In present study, miRNA expression profiles of breast cancer cells MDA-MB-231/S and its NVB-resistant variant MDA-MB-231/NVB cells were analyzed using microarray and the results were confirmed by real-time quantitative polymerase chain reaction. Bioinformatic analyses were carried out to predict gene targets of the dysregulated miRNAs and to analyze their potential roles in the development of drug resistance. Here, 123 differentially expressed miRNAs were identified in the resistant subline compared to MDA-MB-231/S. Networks of KEGG pathways, Gene Ontology (GO) terms, and protein-protein interaction (PPI) of 17 specific selected dysregulated miRNAs were constructed. The results showed that MAPK, mTOR, Wnt, and TGF-beta signaling pathways and several target genes such as CCND1, GRB2 and NT5E may associate with drug resistance of breast cancer cells to NVB. In summary, this study demonstrates that altered miRNA expression pattern is involved in acquiring resistance to NVB in breast cancer MDA-MB-231 cells. All these analysis results provided us a comprehensive view of the function of differential expression miRNAs related to drug resistance of breast cancer and may be helpful for the further study.

Takayama Y, Nobusawa S, Ochiai I, et al.
Malignant meningioma with adenocarcinoma-like metaplasia: demonstration of intestinal phenotype.
Neuropathology. 2015; 35(2):158-64 [PubMed] Related Publications
Meningiomas show a diverse histopathologic appearance, often referred to as metaplastic changes; however, adenocarcinoma-like metaplasia is an extremely rare condition. Here, we present a novel case. A dura-based bulky mass located in the right frontotemporal region was identified radiologically in an 83-year-old woman. The tumor, yellow to ash-gray in color, was subtotally removed. Histopathological examination revealed robust adenocarcinoma-like structures within a conventional meningothelial neoplasm. Meningioma elements showed a WHO grade I to III histology. Morphological and immunophenotypic transition between meningothelial and columnar epithelial cells was confirmed on detailed observation. It was of note that the adenocarcinomatous components shared an immunophenotype with intestinal epithelium, expressing CDX2, MUC2 and cytokeratin 20. The present case could be differentiated from secretory meningioma based on distinct cellular atypia, lack of intracytoplasmic lumina and pseudosammoma bodies, and the intact status of the KLF4 gene. In addition, the morphological and immunophenotypic transition excluded the possibility of metastatic carcinoma within meningioma. This is the first reported case of meningioma with adenocarcinoma-like metaplasia harboring an intestinal immunophenotype.

Meng LQ
Essential role of polymorphism of Gab1, EGFR, and EGF for the susceptibility of biliary tract cancer.
Tumour Biol. 2014; 35(12):12497-508 [PubMed] Related Publications
Cholangiocarcinoma is a malignant neoplasm arising from the epithelial cells lining the biliary ducts and its occurrence can be anatomically classified as within the liver (intrahepatic) or outside the liver (extrahepatic). Extrahepatic cholangiocarcinoma, which can be called as biliary tract cancer (BTC), is the most common form of this malignancy, and its etiology is still unclear. In this study, we tried to elucidate the complicated association between receptor tyrosine kinase (RTK) gene polymorphisms and susceptibility of BTC by analyzing frequency distribution of genotypes and alleles of GRB2-associated-binding protein 1 (Gab1), endothelial growth factor receptor (EGFR), and endothelial growth factor (EGF) and identified potential risk of BTC for people carrying specific genotype of Gab1 and EGFR. Two hundred twenty-five and 300 patients with BTC and cholelithiasis (gallstone (GS)), respectively, and 300 controls matched by age, sex, and ethnicity with patients were recruited from Shengjing Hospital of China Medical University from January 2008 to July 2011 with informed consents. Genomic DNA of BTC group was extracted and purified from formalin-fixed, paraffin-embedded tumor tissue sections using QiAamp DNA FFPE Tissue kit. For GS group and controls, DNA was extracted from peripheral blood leukocytes using genomic DNA extraction kit from Aid Lab. Target genes of RTK family were identified from National Center of Biotechnology Information (NCBI) SNP database and Japanese Single Nucleotide Polymorphisms (JSNP) database. Frequency distribution of genotypes and alleles was analyzed using HapMap Project database. All of the statistical analysis was conducted with SPSS 13.0 software. Eight loci were identified for Gab1 (4), EGFR (3), and EGF (1) as the target single-nucleotide polymorphisms (SNPs) for the association of gene polymorphisms and BTC. A/A genotype and A allele of rs3805246 in Gab1 and G/G genotype and G allele of rs2017000 in EGFR were significantly higher in BTC group than in GS group or controls. After controlling for BMI, age, gender, and smoking habit, patients with "A/A + G/A" had 2.154 times odds to have BTC; as for patients with "A/A" only, they still had 1.976 times odds to have BTC. In the rs2017000 of EGFR, patients with "G/G + G/A" had 1.772 times odds to have BTC, and patients with "G/G" only had 1.530 times odds to have BTC. Furthermore, patients with A/A in rs3805246 and G/G in rs2017000 simultaneously had 1.620 times chance to have BTC than people with other genotypes. This study explored the independent potential effect of EGFR signaling transduction pathway and its downstream element Gab1 and the gene-gene interaction on the disease mechanism of BTC in the perspective of genetics and molecular epidemiology.

Gao S, Bajrami I, Verrill C, et al.
Dsh homolog DVL3 mediates resistance to IGFIR inhibition by regulating IGF-RAS signaling.
Cancer Res. 2014; 74(20):5866-77 [PubMed] Related Publications
Drugs that inhibit insulin-like growth factor 1 (IGFI) receptor IGFIR were encouraging in early trials, but predictive biomarkers were lacking and the drugs provided insufficient benefit in unselected patients. In this study, we used genetic screening and downstream validation to identify the WNT pathway element DVL3 as a mediator of resistance to IGFIR inhibition. Sensitivity to IGFIR inhibition was enhanced specifically in vitro and in vivo by genetic or pharmacologic blockade of DVL3. In breast and prostate cancer cells, sensitization tracked with enhanced MEK-ERK activation and relied upon MEK activity and DVL3 expression. Mechanistic investigations showed that DVL3 is present in an adaptor complex that links IGFIR to RAS, which includes Shc, growth factor receptor-bound-2 (Grb2), son-of-sevenless (SOS), and the tumor suppressor DAB2. Dual DVL and DAB2 blockade synergized in activating ERKs and sensitizing cells to IGFIR inhibition, suggesting a nonredundant role for DVL3 in the Shc-Grb2-SOS complex. Clinically, tumors that responded to IGFIR inhibition contained relatively lower levels of DVL3 protein than resistant tumors, and DVL3 levels in tumors correlated inversely with progression-free survival in patients treated with IGFIR antibodies. Because IGFIR does not contain activating mutations analogous to EGFR variants associated with response to EGFR inhibitors, we suggest that IGF signaling achieves an equivalent integration at the postreceptor level through adaptor protein complexes, influencing cellular dependence on the IGF axis and identifying a patient population with potential to benefit from IGFIR inhibition.

Samaan S, Lichner Z, Ding Q, et al.
Kallikreins are involved in an miRNA network that contributes to prostate cancer progression.
Biol Chem. 2014; 395(9):991-1001 [PubMed] Related Publications
MicroRNAs (miRNAs) are short RNA nucleotides that negatively regulate their target genes. They are differentially expressed in prostate cancer. Kallikreins are genes that encode serine proteases and are dysregulated in cancer. We elucidated a miRNA-kallikrein network that can be involved in prostate cancer progression. Target prediction identified 23 miRNAs that are dysregulated between high and low risk biochemical failure and are predicted to target five kallikreins linked to prostate cancer; KLK2, KLK3, KLK4, KLK14 and KLK15. We also identified 14 miRNAs that are differentially expressed between Gleason grades and are predicted to target these kallikreins. This demonstrates that kallikreins are downstream effectors through which miRNAs influence tumor progression. We show, through in-silico and experimental analysis, that miR-378/422a and its gene targets PIK3CG, GRB2, AKT3, KLK4 and KLK14 form an integrated circuit in prostate cancer. Our analysis shows that a minisatellite sequence in the kallikrein locus consists of a number of microsatellite repeats that represent predicted miRNA response elements. A number of kallikrein and non-kallikrein prostate cancer-related genes share these microsatellite repeats. We validated some of these interactions in prostate cancer cell lines. Finally, we provide preliminary evidence on the presence of a miRNA-mediated cross-talk between kallikreins, including a kallikrein pseudogene.

Cao K, Shilatifard A
Inhibit globally, act locally: CDK7 inhibitors in cancer therapy.
Cancer Cell. 2014; 26(2):158-9 [PubMed] Related Publications
Cyclin-dependent kinases (CDKs) are involved in temporal control of the cell cycle and transcription and play central roles in cancer development and metastasis. Recently, Kwiatkowski and colleagues identified a novel CDK7-specific inhibitor, THZ1, that hinders proliferation in cancer cell lines and dampens global transcription in T cell leukemia.

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