Research IndicatorsGraph generated 11 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. 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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: VAV1 (cancer-related)
Grassilli S, Nika E, Lambertini E, et al.A network including PU.1, Vav1 and miR-142-3p sustains ATRA-induced differentiation of acute promyelocytic leukemia cells - a short report.
Cell Oncol (Dordr). 2016; 39(5):483-489 [PubMed
] Related Publications
PURPOSE: Reduced expression of miR-142-3p has been found to be associated with the development of various subtypes of myeloid leukemia, including acute promyelocytic leukemia (APL). In APL-derived cells, miR-142-3p expression can be restored by all-trans retinoic acid (ATRA), which induces the completion of their maturation program. Here, we aimed to assess whether PU.1, essential for ATRA-induced gene transcription, regulates the expression of miR-142-3p in APL-derived cells and, based on the established cooperation between PU.1 and Vav1 in modulating gene expression, to evaluate the role of Vav1 in restoring the expression of miR-142-3p.
METHODS: ATRA-induced increases in PU.1 and Vav1 expression in APL-derived NB4 cells were counteracted with specific siRNAs, and the expression of miR-142-3p was measured by quantitative real-time PCR (qRT-PCR). The recruitment of PU.1 and/or Vav1 to the regulatory region of miR-142 was assessed by quantitative chromatin immunoprecipitation (Q-ChIP). Synthetic inhibitors or mimics for miR-142-3p were used to assess whether this miRNA plays a role in regulating the expression of PU.1 and/or Vav1.
RESULTS: We found that the expression of miR-142-3p in differentiating APL-derived NB4 cells is dependent on PU.1, and that Vav1 is essential for the recruitment of this transcription factor to its cis-binding element on the miR-142 promoter. In addition, we found that in ATRA-treated NB4 cells miR-142-3p sustains agonist-induced increases in both PU.1 and Vav1.
CONCLUSIONS: Our results suggest the existence of a Vav1/PU.1/miR-142-3p network that supports ATRA-induced differentiation in APL-derived cells. Since selective regulation of miRNAs may play a role in the future treatment of hematopoietic malignancies, our results may provide a basis for the development of new therapeutic strategies to restore the expression of miR-142-3p.
Liu M, Miao N, Zhu Y, et al.[Association between polymorphism in Vav3 genes and risk of primary prostatic cancer in Chinese Han population].
Zhonghua Bing Li Xue Za Zhi. 2016; 45(7):451-6 [PubMed
] Related Publications
OBJECTIVE: To study the associations between genetic variations of Vav3 gene and prostate cancer susceptibility.
METHODS: Data were collected in a hospital-based and case-control study of 1 015 prostate cancer cases and 1 068 cancer-free controls collecting from a period of time between 2008 and 2012. Based on the online database, NCBI dbSNP (http: //www.ncbi.nlm.nih.gov/projects/SNP) and SNPinfo (http: //snpinfo.niehs.nih.gov/snpfunc.htm). Functional single nucleotide polymorphisms (SNPs) of Vav3 were screened and genotyped, and assessed their associations with risk of prostate cancer by using logistic regression analysis. Furthermore, the associations between SNPs of Vav3 and some clinicopathological parameters were evaluated.
RESULTS: Among the two SNPs investigated, only Vav3 rs12410676 G>A was associated with decreased prostate cancer risk [additive model, OR=0.80 (0.69-0.93), P=0.003; dominant model, OR=0.81 (0.68-0.97), P=0.022; recessive model, OR=0.54 (0.36-0.82), P=0.004]. The combined effect of Vav3 rs8676 G>A and rs12410676 G>A was found as a decreased prostate cancer risk along with the increased variant alleles (P<0.05). Specifically, participants carrying Vav3 rs12410676 AA/AG genotypes were more likely to be at lower prostate cancer risk, compared with participants carrying GG genotypes, in groups of BMI≤25 kg/m(2,) smoking, Gleason>7(4+ 3), and higher invasive prostate cancer. Finally, some positive findings were evidently significant with false positive report probability values at different prior probability levels (0.25, 0.1 and 0.01).
CONCLUSION: Vav3 SNPs may contribute to the risk of prostate cancer in Eastern Chinese men, but the effect is weak and needs further validation by larger, multicenter and ethnic-based studies.
Kataoka K, Ogawa S[Genetic landscape of adult T-cell leukemia/lymphoma].
Rinsho Ketsueki. 2016; 57(4):417-24 [PubMed
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Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy associated with HTLV-1 infection. To decipher the genetic landscape of ATL, we performed an integrated molecular analysis, which included whole-genome, whole-exome, transcriptome and targeted sequencing, as well as array-based copy number and methylation analyses. The somatic alterations are highly enriched for T-cell receptor/NF-κB signaling, the G-protein coupled receptor associated with T-cell migration, and other T-cell-related pathways as well as immune surveillance related genes. Among these, PLCG1, PRKCB, CARD11, VAV1, IRF4, CCR4, and CCR7 activating mutations and CTLA4-CD28 and ICOS-CD28 fusion genes have been identified. In addition, these genes significantly overlap with HTLV-1 Tax interactome. These results provide an important basis for the development of new ATL diagnostics and therapeuticsregimens.
AIM: This study was to evaluate the diagnostic value of OSR2, VAV3, and PPFIA3 hypermethylation in gastric cancer (GC) patients.
PATIENTS AND METHODS: By using methylation-specific polymerase chain reaction (MSP), we detected the methylation status in tissue and serum samples from 48 gastric cancer (GC) patients and 25 normal individuals.
RESULTS: We found that OSR2, VAV3, and PPFIA3 were methylated in 70.8% (34/48), 54.2% (26/48), and 60.4% (29/48) of GC tissue, respectively. On the contrary, those genes were barely methylated in their paired paracancerous histological normal tissues (PCHNTs) (all P values < 0.01). We next analyzed the methylated OSR2, VAV3, and PPFIA3 in serum DNA. Compared with 25 normal individuals, those three genes were significantly hypermethylated in GC patients serum samples (all P values < 0.01). Regarding their diagnostic value in serum samples, the combined sensitivity of at least one positive among the three markers in serum was 83.3%, with a specificity of 88%.
CONCLUSION: Our test suggested that methylation of OSR2, VAV3, and PPFIA3 genes in serum sample may offer a good alternative in a simple, promising, and noninvasive detection of GC.
Dysregulation of miRNAs is reported to be involved in the invasion and metastasis of lung cancer. Previous studies showed that low serum miR-499 expression was associated with advanced TNM stage and poor prognosis. The present study is carried out to evaluate the biological functions of miR-499-5p in lung cancer. We demonstrated that miR-499-5p was significantly reduced in NSCLC tissues and correlated with poor clinical outcomes. Overexpression of miR-499-5p inhibited cell proliferation and induced apoptosis in vitro and in vivo. Furthermore, miR-499-5p overexpression also inhibited NSCLC metastasis in vitro and in vivo. Using bioinformatics tools, we identified VAV3 as a candidate target of miR-499-5p, and demonstrated that restoration of miR-499-5p expression in NSCLC cells downregulated VAV3 expression while inhibition of miR-499-5p upregulated VAV3 expression. Luciferase reporter assays showed that miR-499-5p targeted 3'-UTR of VAV3. Moreover, cancer growth, proliferation and metastasis were decreased and apoptosis was increased after VAV3 blockage induced by miR-499-5p overexpression. We conclude that miR-499-5p functions as a tumor suppressor by targeting VAV3. This finding may provide a therapeutic approach for future treatment of NSCLC.
Tan BB, Zhang MM, Li Y, et al.Inhibition of Vav3 gene can promote apoptosis of human gastric cancer cell line MGC803 by regulating ERK pathway.
Tumour Biol. 2016; 37(6):7823-33 [PubMed
] Related Publications
Previous studies proved that Vav3 gene was overexpressed in cancers. However, the molecular mechanism of Vav3 in apoptosis still keeps unclear; therefore, the relationship between Vav3 gene and apoptosis of gastric cancer (GC) was explored in the present study. Vav3-siRNA was transfected into MGC803 cells, and then cell activity and apoptosis rate were tested with MTT and FCM; apoptosis-related genes and proteins in MAPK signaling pathway were also tested. Results showed that Vav3 was overexpressed in GC than in adjacent normal tissues (all P < 0.05), and expression of Vav3 was related to degree of histological differentiation, cancer invasion depth, and lymphatic metastasis (Χ (2) = 7.185, P = 0.007; Χ (2) = 18.654, P < 0.001; Χ (2) = 5.058, P = 0.025). Vav3 silencing inhibited activity of MGC803 cells, and apoptosis rate of cells was affected. Vav3-siRNA transfection led to changes of apoptosis-related genes such as Survivin, xIAP, Bcl-2, caspase-3, and Bax (all P < 0.01). After transfection, ratio of phosphorylation of ERK significantly reduced. We concluded that Vav3 inhibition can suppress cell activity and promote apoptosis by regulating the apoptosis-related genes through the ERK pathway.
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.
Kataoka K, Nagata Y, Kitanaka A, et al.Integrated molecular analysis of adult T cell leukemia/lymphoma.
Nat Genet. 2015; 47(11):1304-15 [PubMed
] Related Publications
Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV-1) infection. Here we describe an integrated molecular study in which we performed whole-genome, exome, transcriptome and targeted resequencing, as well as array-based copy number and methylation analyses, in a total of 426 ATL cases. The identified alterations overlap significantly with the HTLV-1 Tax interactome and are highly enriched for T cell receptor-NF-κB signaling, T cell trafficking and other T cell-related pathways as well as immunosurveillance. Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). We also discovered frequent intragenic deletions involving IKZF2, CARD11 and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B and CSNK1A1. Our findings not only provide unique insights into key molecules in T cell signaling but will also guide the development of new diagnostics and therapeutics in this intractable tumor.
Many deregulated signal transducer proteins are involved in various cancers at numerous stages of tumor development. One of these, Vav1, is normally expressed exclusively in the hematopoietic system, where it functions as a specific GDP/GTP nucleotide exchange factor (GEF), strictly regulated by tyrosine phosphorylation. Vav was first identified in an NIH3T3 screen for oncogenes. Although the oncogenic form of Vav1 identified in the screen has not been detected in clinical human tumors, its wild-type form has recently been implicated in mammalian malignancies, including neuroblastoma, melanoma, pancreatic, lung and breast cancers, and B-cell chronic lymphocytic leukemia. In addition, it was recently identified as a mutated gene in human cancers of various origins. However, the activity and contribution to cancer of these Vav1 mutants is still unclear. This review addresses the physiological function of wild-type Vav1 and its activity as an oncogene in human cancer. It also discusses the novel mutations identified in Vav1 in various cancers and their potential contribution to cancer development as oncogenes or tumor suppressor genes.
Despite being an attractive molecular target for both lymphoid and myeloid leukemias characterized by activated tyrosine kinases, the molecular and physiological consequences of reduced signal transducer and activator of transcription-5 (Stat5) during leukemogenesis are not well known. Stat5 is a critical regulator of mouse hematopoietic stem cell (HSC) self-renewal and is essential for normal lymphocyte development. We report that pan-hematopoietic deletion in viable adult Vav1-Cre conditional knockout mice as well as Stat5ab(null/null) fetal liver transplant chimeras generated HSCs with reduced expression of quiescence regulating genes (Tie2, Mpl, Slamf1, Spi1, Cited2) and increased expression of B-cell development genes (Satb1, Dntt, Btla, Flk2). Using a classical murine B-cell acute lymphoblastic leukemia (B-ALL) model, we demonstrate that these HSCs were also poised to produce a burst of B-cell precursors upon expression of Bcl-2 combined with oncogenic Myc. This strong selective advantage for leukemic transformation in the background of Stat5 deficient hematopoiesis was permissive for faster initiation of Myc-induced transformation to B-ALL. However, once established, the B-ALL progression in secondary transplant recipients was Stat5-independent. Overall, these studies suggest that Stat5 can play multiple important roles that not only preserve the HSC compartment but can limit accumulation of potential pre-leukemic lymphoid populations.
Bunaciu RP, Jensen HA, MacDonald RJ, et al.6-Formylindolo(3,2-b)Carbazole (FICZ) Modulates the Signalsome Responsible for RA-Induced Differentiation of HL-60 Myeloblastic Leukemia Cells.
PLoS One. 2015; 10(8):e0135668 [PubMed
] Free Access to Full Article Related Publications
6-Formylindolo(3,2-b)carbazole (FICZ) is a photoproduct of tryptophan and an endogenous high affinity ligand for aryl hydrocarbon receptor (AhR). It was previously reported that, in patient-derived HL-60 myeloblastic leukemia cells, retinoic acid (RA)-induced differentiation is driven by a signalsome containing c-Cbl and AhR. FICZ enhances RA-induced differentiation, assessed by expression of the membrane differentiation markers CD38 and CD11b, cell cycle arrest and the functional differentiation marker, inducible oxidative metabolism. Moreover, FICZ augments the expression of a number of the members of the RA-induced signalsome, such as c-Cbl, Vav1, Slp76, PI3K, and the Src family kinases Fgr and Lyn. Pursuing the molecular signaling responsible for RA-induced differentiation, we characterized, using FRET and clustering analysis, associations of key molecules thought to drive differentiation. Here we report that, assayed by FRET, AhR interacts with c-Cbl upon FICZ plus RA-induced differentiation, whereas AhR constitutively interacts with Cbl-b. Moreover, correlation analysis based on the flow cytometric assessment of differentiation markers and western blot detection of signaling factors reveal that Cbl-b, p-p38α and pT390-GSK3β, are not correlated with other known RA-induced signaling components or with a phenotypic outcome. We note that FICZ plus RA elicited signaling responses that were not typical of RA alone, but may represent alternative differentiation-driving pathways. In clusters of signaling molecules seminal to cell differentiation, FICZ co-administered with RA augments type and intensity of the dynamic changes induced by RA. Our data suggest relevance for FICZ in differentiation-induction therapy. The mechanism of action includes modulation of a SFK and MAPK centered signalsome and c-Cbl-AhR association.
Capuano C, Romanelli M, Pighi C, et al.Anti-CD20 Therapy Acts via FcγRIIIA to Diminish Responsiveness of Human Natural Killer Cells.
Cancer Res. 2015; 75(19):4097-108 [PubMed
] Related Publications
Natural killer (NK) immune cells mediate antibody-dependent cellular cytotoxicity (ADCC) by aggregating FcγRIIIA/CD16, contributing significantly to the therapeutic effect of CD20 monoclonal antibodies (mAb). In this study, we show that CD16 ligation on primary human NK cells by the anti-CD20 mAb rituximab or ofatumumab stably impairs the spontaneous cytotoxic response attributable to cross-tolerance of several unrelated NK-activating receptors (including NKG2D, DNAM-1, NKp46, and 2B4). Similar effects were obtained from NK cells isolated from patients with chronic lymphocytic leukemia in an autologous setting. NK cells rendered hyporesponsive in this manner were deficient in the ability of these cross-tolerized receptors to phosphorylate effector signaling molecules critical for NK cytotoxicity, including SLP-76, PLCγ2, and Vav1. These effects were associated with long-lasting recruitment of the tyrosine phosphatase SHP-1 to the CD16 receptor complex. Notably, pharmacologic inhibition of SHP-1 with sodium stibogluconate counteracted CD20 mAb-induced NK hyporesponsiveness, unveiling an unrecognized role for CD16 as a bifunctional receptor capable of engendering long-lasting NK cell inhibitory signals. Our work defines a novel mechanism of immune exhaustion induced by CD20 mAb in human NK cells, with potentially negative implications in CD20 mAb-treated patients where NK cells are partly responsible for clinical efficacy.
Lung adenocarcinoma possesses distinct patterns of EGFR/KRAS mutations between East Asian and Western, male and female patients. However, beyond the well-known EGFR/KRAS distinction, gender and ethnic specific molecular aberrations and their effects on prognosis remain largely unexplored. Association modules capture the dependency of an effector molecular aberration and target gene expressions. We established association modules from the copy number variation (CNV), DNA methylation and mRNA expression data of a Taiwanese female cohort. The inferred modules were validated in four external datasets of East Asian and Caucasian patients by examining the coherence of the target gene expressions and their associations with prognostic outcomes. Modules 1 (cis-acting effects with chromosome 7 CNV) and 3 (DNA methylations of UBIAD1 and VAV1) possessed significantly negative associations with survival times among two East Asian patient cohorts. Module 2 (cis-acting effects with chromosome 18 CNV) possessed significantly negative associations with survival times among the East Asian female subpopulation alone. By examining the genomic locations and functions of the target genes, we identified several putative effectors of the two cis-acting CNV modules: RAC1, EGFR, CDK5 and RALBP1. Furthermore, module 3 targets were enriched with genes involved in cell proliferation and division and hence were consistent with the negative associations with survival times. We demonstrated that association modules in lung adenocarcinoma with significant links of prognostic outcomes were ethnic and/or gender specific. This discovery has profound implications in diagnosis and treatment of lung adenocarcinoma and echoes the fundamental principles of the personalized medicine paradigm.
Pancreatic cancer, one of the most lethal forms of human cancer, is largely resistant to many conventional chemotherapeutic agents. Although many therapeutic approaches focus on tumor growth, metastasis is a primary factor contributing to lethality. Therefore, novel therapies to target metastatic invasion could prevent tumor spread and recurrence resulting from local and distant metastasis. The protein Vav1 is aberrantly expressed in more than half of pancreatic cancers. Its expression promotes activation of Rac and Cdc42 and leads to enhanced invasion and migration, as well as increased tumor cell survival and proliferation, suggesting that Vav1 could be a potent therapeutic target for pancreatic cancer. The purine analogue azathioprine, well known for its function as an anti-inflammatory compound, was recently shown to function by inhibiting Vav1 signaling in immune cells. We therefore hypothesized that azathioprine could also inhibit Vav1 in pancreatic tumor cells to reduce its proinvasive functions. Indeed, we have found that treatment of cultured pancreatic tumor cells with azathioprine inhibited Vav1-dependent invasive cell migration and matrix degradation, through inhibition of Rac and Cdc42 signaling. Furthermore, azathioprine treatment decreased metastasis in both xenograft and genetic mouse models of pancreatic cancer. Strikingly, metastasis was dramatically reduced in Vav1-expressing tumors arising from p48(Cre/+), Kras(G12D/+), p53(F/+) mice. These inhibitory effects were mediated through Vav1, as Vav1-negative cell lines and tumors were largely resistant to azathioprine treatment. These findings demonstrate that azathioprine and related compounds could be potent antimetastatic agents for Vav1-positive pancreatic tumors.
Tan B, Li Y, Fan L, et al.[Effect and mechanism of Vav3 on the proliferation of human gastric cancer SGC7901 cells].
Zhonghua Zhong Liu Za Zhi. 2015; 37(3):175-80 [PubMed
] Related Publications
OBJECTIVE: The purpose of this study was to investigate the effect and mechanism of Vav3 gene on the proliferation of human gastric cancer cell line SGC7901.
METHODS: The expressions of Vav3 proten in gastric cancer tissue, tumor-adjacent tissue, human gastric cancer cell line SGC7901 and gastric epithelial cell line GES-1 cells were tested by Western blot. Vav3-siRNA was transfected into the SGC7901 cells. The proliferation of SGC7901 cells in vitro was measured by MTT assay. Cell cycle of SGC7901 cells was determined by flow cytometry.The expressions of proliferation-related genes PCNA, p16, cyclin D1, Rb were determined by qPCR and Western blot assay. Orthotopic transplantation nude mouse models of gastric cancer were prepared, and the tumor growth and expressions of PCNA, P16, cyclin D1, and Rb proteins were examined.
RESULTS: The relative expressions of Vav3 in the gastric cancer and peritumoral tissue were 0.910±0.242 and 0.243±0.045, respectively; the relative expressions of Vav3 in SGC7901 and GSE-1 cells were 0.925±0.127 and 0.277±0.038, respevtively (both P<0.05). The expression of Vav3 protein in SGC7901 cells was effectively inhibited by Vav3-siRNA. Proliferation of SGC7901 cells was inhibited by (83.43±10.17)% after 80 nmol/L Vav3-siRNA transfection (P<0.05). The ratio of SGC7901 cells in G0/G1 phase was increased, and in S phase decreased after Vav3-siRNA transfection (both P<0.05). The expressions of PCNA and cyclin D1 were decreased in cells after Vav3-siRNA transfection, and expressions of p16 and Rb were increased after Vav3-siRNA transfection (P<0.05 for all). The tumor growth in the Vav3-siRNA group was much slower than that in the other 2 control groups of nude mouse models. Compared with the two control groups, expressions of PCNA and cyclin D1 were significantly lower in the Vav3-siRNA group, while expressions of p16 and Rb were increased (P<0.05 for all).
CONCLUSION: Vav3 can promote the proliferation of gastric cancer cells by regulating proliferation-related genes.
Trenkle T, Hakim SG, Jacobsen HC, Sieg PDifferential Gene Expression of the Proto-oncogene VAV3 and the Transcript Variant VAV3.1 in Oral Squamous Cell Carcinoma.
Anticancer Res. 2015; 35(5):2593-600 [PubMed
] Related Publications
The VAV proteins VAV1, VAV2 and VAV3 have been identified as important molecules in tumorigenesis, tumor growth and cell migration. In addition to the full-length isoforms, a much shorter family member, VAV3.1, also known as VAV3 isoform 2, is known to be differentially expressed in a broad variety of tissues. Furthermore, VAV3.1 was shown to be down-regulated in cultured keratinocytes by the growth factors epidermal growth factor (EGF) EGF and transforming growth factor beta (TGFβ) TGFβ which in turn play important roles in the pathogenesis of oral squamous cell carcinoma (OSCC). Herein we showed that VAV3.1 is underexpressed in OSCC tissue samples compared to corresponding normal mucosa. We further demonstrated a trend of distinctive down-regulation of mRNA for VAV3.1 in tissues of locally advanced OSCC that have already metastasized to regional lymph nodes, indicating an increased malignant potential of tumors with low VAV3.1 mRNA expression. Moreover, in other studies a correlation between increased VAV3 expression and cancer progression was shown. In the present study, the analyzed OSCC tissue samples showed no significant change of VAV3 mRNA expression. Taken together, our data support the hypothesis that molecular interactions and signaling cascades of VAV3 can be regulated or directed by the competing molecule VAV3.1. Additionally, discrete and different functions of VAV3.1 in metastasis and tumorigenesis are conceivable.
Although colorectal cancer (CRC) is one of the most common malignancies worldwide, the current therapeutic approaches for advanced CRC are ineffective. In this study, we investigated the involvement of the VAV3 oncogene in tumor progression and in the prognosis of human CRC. The two patient cohorts in this study comprised 354 CRC cases from 1998 to 2005 with documented pathologic and clinical factors and clinical outcomes. VAV3 protein levels were significantly correlated with the depth of invasion (P = 0.0259), the nodal status (P < 0.0001), distant metastasis (P = 0.0354), the stage (P < 0.0001), and poor disease-free survival (P = 0.003). Multivariate Cox regression analysis showed that VAV3 overexpression is an independent prognostic marker for CRC (P = 0.041). In vitro experiments indicated that VAV3 knockdown inhibited CRC cell growth, spread, and xenograft proliferation. Mechanistic studies further revealed that VAV3 overexpression could dysregulate the expression of cell cycle control- and metastasis-related molecules by activating the PI3K-AKT signaling pathway in both CRC cells and xenografts. This study suggests that VAV3 overexpression could be a useful marker for predicting the outcomes of CRC patients and that VAV3 targeting represents a potential modality for treating CRC.
Ovarian carcinoma is a highly lethal malignancy due to frequent relapse and drug resistance. Cancer stem cells (CSCs) are thought to contribute significantly to disease relapse and drug resistance. In this study, a subpopulation of CSCs of ovarian carcinoma was isolated and the genes differentially expressed in these cells were identified to characterize CSCs and to find candidate biomarkers. Ovarian carcinoma cells from patients were primarily cultured, and spheroid-forming cells (SFCs) were isolated. The characteristic genes of SFCs were identified through cDNA microarray and validation by quantitative real-time polymerase chain reaction and immunohistochemistry, and the association of their expression with clinicopathologic parameters was analyzed. GSC (4.26-fold), VAV3 (7.05-fold), FOXA2 (12.06-fold), LEF1 (17.26-fold), COMP (21.33-fold), GRIN2A (9.36-fold), CD86 (23.14-fold), PYY (4.18-fold), NKX3-2 (10.35-fold), and PDK4 (74.26-fold) were significantly upregulated in SFCs compared with parental cancer cells. With validation for human ovarian carcinomas, LEF1, PYY, NKX3-2, and WNT3A were significantly upregulated in chemoresistant cancers compared with chemosensitive cancers. Overexpression of LEF1, VAV3, and NKX3-2 was significantly associated with distant metastasis by immunohistochemistry. VAV3 overexpression was an independent poor survival indicator (hazard ratio=15.27, P<0.05) by multivariate Cox analysis. The further functional assay revealed that VAV3 knockdown regulated CSC activation and ovarian cancer cell proliferation and sensitized paclitaxel (PTX)-resistant cancer cells to PTX treatment. Taken together, we identified by high-throughput analysis of CSCs that VAV3 overexpression is a novel biomarker for poor prognosis and survival in ovarian carcinoma.
Zong L, Hattori N, Yoda Y, et al.Establishment of a DNA methylation marker to evaluate cancer cell fraction in gastric cancer.
Gastric Cancer. 2016; 19(2):361-9 [PubMed
] Related Publications
BACKGROUND: Tumor samples are unavoidably contaminated with coexisting normal cells. Here, we aimed to establish a DNA methylation marker to estimate the fraction of gastric cancer (GC) cells in any DNA sample by isolating genomic regions specifically methylated in GC cells.
METHODS: Genome-wide and gene-specific methylation analyses were conducted with an Infinium HumanMethylation450 BeadChip array and by quantitative methylation-specific PCR, respectively. Purified cancer and noncancer cells were prepared by laser-capture microdissection. TP53 mutation data were obtained from our previous study using next-generation target sequencing.
RESULTS: Genome-wide DNA methylation analysis of 12 GC cell lines, 30 GCs, six normal gastric mucosae, one sample of peripheral leukocytes, and four noncancerous gastric mucosae identified OSR2, PPFIA3, and VAV3 as barely methylated in normal cells and highly methylated in cancer cells. Quantitative methylation-specific PCR using 26 independent GCs validated that one or more of them was highly methylated in all of the GCs. Using four pairs of purified cells, we confirmed the three genes were highly methylated (85 % or more) in cancer cells and barely methylated (5 % or less) in noncancer cells. The cancer cell fraction assessed by the panel of the three genes showed good correlation with that assessed by the TP53 mutant allele frequency in 13 GCs (r = 0.77). After correction of the GC cell fraction, unsupervised clustering analysis of the genome-wide DNA methylation profiles yielded clearer clustering.
CONCLUSIONS: A DNA methylation marker-namely, the panel of the three genes-is useful to estimate the cancer cell fraction in GCs.
The identification of key tumorigenic events in Sonic Hedgehog (SHH) subgroup medulloblastomas (MBSHH) will be essential for the development of individualized therapies and improved outcomes. However, beyond confirmation of characteristic SHH pathway mutations, recent genome-wide sequencing studies have not revealed commonly mutated genes with widespread relevance as potential therapeutic targets. We therefore examined any role for epigenetic DNA methylation events in MBSHH using a cross-species approach to candidate identification, prioritization and validation. MBSHH-associated DNA methylation events were first identified in 216 subgrouped human medulloblastomas (50 MBSHH, 28 Wnt/Wingless, 44 Group 3 and 94 Group 4) and their conservation then assessed in tumors arising from four independent murine models of Shh medulloblastoma, alongside any role in tumorigenesis using functional assessments in mouse and human models. This strategy identified widespread regional CpG hypo-methylation of VAV1, leading to its elevated expression, as a conserved aberrant epigenetic event, which characterizes the majority of MBSHH tumors in both species, and is associated with a poor outcome in MBSHH patients. Moreover, direct modulation of VAV1 in mouse and human models revealed a critical role in tumor maintenance, and its abrogation markedly reduced medulloblastoma growth. Further, Vav1 activity regulated granule neuron precursor germinal zone exit and migration initiation in an ex vivo model of early postnatal cerebellar development. These findings establish VAV1 as a critical epigenetically regulated oncogene with a key role in MBSHH maintenance, and highlight its potential as a validated therapeutic target and prognostic biomarker for the improved therapy of medulloblastoma.
Tan B, Li Y, Zhao Q, et al.Inhibition of Vav3 could reverse the drug resistance of gastric cancer cells by downregulating JNK signaling pathway.
Cancer Gene Ther. 2014; 21(12):526-31 [PubMed
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This study aims to investigate the effect and mechanism of Vav3 on the multidrug resistance of gastric cancer. Fluorescence quantitative RT-PCR and western blot assay were used to detect Vav3 and drug resistance genes in gastric cancer tissues as well as gastric cell lines such as SGC7901, SGC7901/adriamycin (ADR) and GES-1. Besides, Vav3-specific small interfering RNA (Vav3-siRNA) was applied to inhibit Vav3 in SGC7901/ADR, and SRB assay was used to determine chemosensitivity. After that, drug resistance genes and proteins in MAPK and PI3K/AKT signaling pathway were detected after Vav3-siRNA transfection. The results showed that overexpressed Vav3 was found in gastric cancer tissues and SGC7901 and SGC7901/ADR cells. Activity of SGC7901/ADR cells transfected with Vav3-siRNA combined with 5-fluorouracil/oxaliplatin was much lower than that of control groups, and MDR1/P-gp, GST-π and Bcl-2, Bax genes were significantly downregulated in Vav3-siRNA transfection group. AKT, ERK and p38 total protein and their phosphorylation levels showed no significant change in Vav3-siRNA-transfected SGC7901/ADR cells, whereas the ratio of C-Jun phosphorylation levels to total C-Jun protein was significantly downregulated. The results suggested that Vav3 may play a role in drug resistance of gastric cancer by inhibiting drug resistance genes MDR1/P-gp, GST-π and Bcl-2 through regulating the JNK signaling pathway.
Vav family members function as remarkable scaffold proteins that exhibit both GDP/GTP exchange activity for Rho/Rac GTPases and numerous protein-protein interactions via three adaptor Src-homology domains. The exchange activity is under the unique regulation by phosphorylation of tyrosine residues hidden by intra-molecular interactions. Deletion of the autoinhibitory N-terminal region results in an oncogenic protein, onco-Vav, leading to a potent activation of Rac GTPases whereas the proto-oncogene barely leads to transformation. Substitution of conserved residues of the SH2-SH3 adaptor region in onco-Vav reverses oncogenicity. While a unique substitution D797N did not affect transformation induced by onco-Vav, we demonstrate that this single substitution leads to transformation in the Vav1 proto-oncogene highlighting the pivotal role of the adaptor region. Moreover, we identified the cell junction protein β-catenin as a new Vav1 interacting partner. We show that the oncogenicity of activated Vav1 proto-oncogene is associated with a non-degradative phosphorylation of β-catenin at residues important for its functions and its redistribution along the cell membrane in fibroblasts. In addition, a similar interaction is evidenced in epithelial lung cancer cells expressing ectopically Vav1. In these cells, Vav1 is also involved in the modulation of β-catenin phosphorylation. Altogether, our data highlight that only a single mutation in the proto-oncogene Vav1 enhances tumorigenicity.
BACKGROUND: A major player in the process of metastasis is the actin cytoskeleton as it forms key structures in both invasion mechanisms, mesenchymal and amoeboid migration. We tested the actin binding compound Chondramide as potential anti-metastatic agent.
METHODS: In vivo, the effect of Chondramide on metastasis was tested employing a 4T1-Luc BALB/c mouse model. In vitro, Chondramide was tested using the highly invasive cancer cell line MDA-MB-231 in Boyden-chamber assays, fluorescent stainings, Western blot and Pull down assays. Finally, the contractility of MDA-MB-231 cells was monitored in 3D environment and analyzed via PIV analysis.
RESULTS: In vivo, Chondramide treatment inhibits metastasis to the lung and the migration and invasion of MDA-MB-231 cells is reduced by Chondramide in vitro. On the signaling level, RhoA activity is decreased by Chondramide accompanied by reduced MLC-2 and the stretch induced guanine nucleotide exchange factor Vav2 activation. At same conditions, EGF-receptor autophosphorylation, Akt and Erk as well as Rac1 are not affected. Finally, Chondramide treatment disrupted the actin cytoskeleton and decreased the ability of cells for contraction.
CONCLUSIONS: Chondramide inhibits cellular contractility and thus represents a potential inhibitor of tumor cell invasion.
Vav1 is a signal transducer that functions as a scaffold protein and a regulator of cytoskeleton organization in the hematopoietic system, where it is exclusively expressed. Recently, Vav1 was shown to be involved in diverse human cancers, including lung cancer. We demonstrate that lung cancer cells that abnormally express Vav1 secrete growth factors in a Vav1-dependent manner. Transcriptome analysis demonstrated that Vav1 depletion results in a marked reduction in the expression of colony-stimulating-factor-1 (CSF1), a hematopoietic growth factor. The association between Vav1 expression and CSF1 was further supported by signal transduction experiments, supporting involvement of Vav1 in regulating lung cancer secretome. Blocking of ERK phosphorylation, led to a decrease in CSF1 transcription, thus suggesting a role for ERK, a downstream effector of Vav1, in CSF1 expression. CSF1-silenced cells exhibited reduced focus formation, proliferation abilities, and growth in NOD/SCID mice. CSF1-silenced H358 cells resulted in significantly smaller tumors, showing increased fibrosis and a decrease in tumor infiltrating macrophages. Finally, immunohistochemical analysis of primary human lung tumors revealed a positive correlation between Vav1 and CSF1 expression, which was associated with tumor grade. Additional results presented herein suggest a potential cross-talk between cancer cells and the microenvironment controlled by CSF1/Vav1 signaling pathways.
INTRODUCTION: The Rac-GEF P-REX1 is a key mediator of ErbB signaling in breast cancer recently implicated in mammary tumorigenesis and metastatic dissemination. Although P-REX1 is essentially undetectable in normal human mammary epithelial tissue, this Rac-GEF is markedly upregulated in human breast carcinomas, particularly of the luminal subtype. The mechanisms underlying P-REX1 upregulation in breast cancer are unknown. Toward the goal of dissecting the mechanistic basis of P-REX1 overexpression in breast cancer, in this study we focused on the analysis of methylation of the PREX1 gene promoter.
METHODS: To determine the methylation status of the PREX1 promoter region, we used bisulfite genomic sequencing and pyrosequencing approaches. Re-expression studies in cell lines were carried out by treatment of breast cancer cells with the demethylating agent 5-aza-2'-deoxycitidine. PREX1 gene methylation in different human breast cancer subtypes was analyzed from the TCGA database.
RESULTS: We found that the human PREX1 gene promoter has a CpG island located between -1.2 kb and +1.4 kb, and that DNA methylation in this region inversely correlates with P-REX1 expression in human breast cancer cell lines. A comprehensive analysis of human breast cancer cell lines and tumors revealed significant hypomethylation of the PREX1 promoter in ER-positive, luminal subtype, whereas hypermethylation occurs in basal-like breast cancer. Treatment of normal MCF-10A or basal-like cancer cells, MDA-MB-231 with the demethylating agent 5-aza-2'-deoxycitidine in combination with the histone deacetylase inhibitor trichostatin A restores P-REX1 levels to those observed in luminal breast cancer cell lines, suggesting that aberrant expression of P-REX1 in luminal breast cancer is a consequence of PREX1 promoter demethylation. Unlike PREX1, the pro-metastatic Rho/Rac-GEF, VAV3, is not regulated by methylation. Notably, PREX1 gene promoter hypomethylation is a prognostic marker of poor patient survival.
CONCLUSIONS: Our study identified for the first time gene promoter hypomethylation as a distinctive subtype-specific mechanism for controlling the expression of a key regulator of Rac-mediated motility and metastasis in breast cancer.
Bartolomé RA, Díaz-Martínez M, Coló GP, et al.A Blk-p190RhoGAP signaling module downstream of activated Gα13 functionally opposes CXCL12-stimulated RhoA activation and cell invasion.
Cell Signal. 2014; 26(11):2551-61 [PubMed
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Activation of the GTPase RhoA linked to cell invasion can be tightly regulated following Gα13 stimulation. We have used a cellular model displaying Gα13-dependent inhibition of RhoA activation associated with defective cell invasion to the chemokine CXCL12 to characterize the molecular players regulating these processes. Using both RNAi transfection approaches and protein overexpression experiments here we show that the Src kinase Blk is involved in Gα13-activated tyrosine phosphorylation of p190RhoGAP, which causes RhoA inactivation and ultimately leads to deficient cell invasion. Characterization of molecular interplays between Gα13, Blk and p190RhoGAP revealed that Blk binds Gα13, and that Blk-mediated p190RhoGAP phosphorylation upon Gα13 activation correlates with weakening of Gα13-Blk association connected to increased Blk-p190RhoGAP assembly. These results place Blk upstream of the p190RhoGAP-RhoA pathway in Gα13-activated cells, overall representing an opposing signaling module during CXCL12-triggered invasion. In addition, analyses with Blk- or Gα13-knockdown cells indicated that Blk can also mediate CXCL12-triggered phosphorylation of p190RhoGAP independently of Gα13. However, even if CXCL12 induces the Blk-mediated GAP phosphorylation, the simultaneous stimulation of the guanine-nucleotide exchange factor Vav1 by the chemokine, as earlier reported, leads to a net increase in RhoA activation. Therefore, when Gα13 is concurrently stimulated with CXCL12 there appears to be sufficient Blk activity to promote adequate levels of p190RhoGAP tyrosine phosphorylation to inactivate RhoA and to impair cell invasiveness.
Grassilli S, Brugnoli F, Lattanzio R, et al.High nuclear level of Vav1 is a positive prognostic factor in early invasive breast tumors: a role in modulating genes related to the efficiency of metastatic process.
Oncotarget. 2014; 5(12):4320-36 [PubMed
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Vav1 is one of the signalling proteins normally restricted to hematopoietic cells that results ectopically expressed in solid tumors, including breast cancer. By immunohistochemical analysis on TMAs containing invasive breast tumor from patients without lymph node involvement, we have found that Vav1 is expressed in almost all investigated cancers and shows a peculiar localization inside the nucleus of tumor cells. High amounts of nuclear Vav1 are positively correlated with low incidence of relapse, regardless phenotype and molecular subtype of breast neoplasia. In particular, Kaplan-Meier plots showed an elevated risk of distant metastasis in patients with low Vav1 expression compared with patients with high Vav1 expression in their tumors. Experiments performed with breast tumor-derived cells indicated that Vav1 negatively modulates their invasiveness in vitro and their metastatic efficiency in vivo, possibly by affecting the expression of genes involved in invasion and/or metastasis of breast tumors. Since the high heterogeneity of breast tumors makes difficult to predict the evolution of early breast neoplasias, the evaluation of nuclear Vav1 levels may help in the characterization and management of early breast cancer patients. In particular, Vav1 may serve as a prognostic biomarker and a target for new therapies aimed to prevent breast cancer progression.
Vav1, a guanine nucleotide exchange factor (GEF) for Rho family GTPases, is a hematopoietic protein involved in a variety of cellular events. In recent years, aberrant expression of Vav1 has been reported in non-hematopoietic cancers including human breast cancer. It remains to be answered how Vav1 is expressed and what Vav1 does in its non-resident tissues. In this study, we aimed to explore the mechanism for Vav1 expression in breast cancer cells in correlation with estrogen-ER pathway. We not only verified the ectopic expression of Vav1 in human breast cancer cell lines, but also observed that Vav1 expression was induced by 17β-estradiol (E2), a typical estrogen receptor (ER) ligand, in ER-positive cell lines. On the other hand, Tamoxifen, a selective estrogen receptor modulator (SERM), and ICI 182,780, an ER antagonist, suppressed the expression of Vav1. The estrogen receptor modulating Vav1 expression was identified to be α form, not β. Furthermore, treatment of E2 increased the transcription of vav1 gene by enhancing the promoter activity, though there was no recognizable estrogen response element (ERE). Nevertheless, two regions at the vav1 gene promoter were defined to be responsible for E2-induced activation of vav1 promoter. Chromatin immunoprecipitation (ChIP) and co-immunoprecipitation (Co-IP) analyses suggested that ERα might access to the vav1 promoter via interacting with transcription factors, c-Myb and ELF-1. Consequently, the enhanced expression of Vav1 led to the elevation of Cyclin D1 and the progression of cell cycle. The present study implies that estrogen-ER modulates the transcription and expression of Vav1, which may contribute to the proliferation of cancerous cells.
INTRODUCTION: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor α (ERα) are among the most effective systemic treatments for ERα-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERα transcriptional regulatory plasticity. Herein we identify VAV3 as a critical component in this process.
METHODS: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERα was evaluated by molecular docking analyses, an agonist fluoligand assay and short hairpin (sh)RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot analysis of signaling and proliferation markers, and shRNA-mediated protein depletion in viability and clonogenic assays, were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine its association with therapeutic response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression.
RESULTS: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase), but instead was likely a result of binding to ERα. VAV3 was selectively reduced upon exposure to YC-1 or ERα depletion, and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with the response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 × 10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy.
CONCLUSIONS: This study proposes VAV3 as a biomarker and a rationale for its use as a signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.
Wan YJ, Yang Y, Leng QL, et al.Vav1 increases Bcl-2 expression by selective activation of Rac2-Akt in leukemia T cells.
Cell Signal. 2014; 26(10):2202-9 [PubMed
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Vav proteins are guanine nucleotide exchange factors (GEFs) that activate a group of small G proteins (GTPases). Vav1 is predominantly expressed in hematopoietic cells, whereas Vav2 and Vav3 are ubiquitously distributed in almost all human tissues. All three Vav proteins contain conserved structural motifs and associate with a variety of cellular activities including proliferation, migration, and survival. Previous observation with Jurkat leukemia T cells showed that Vav1 possessed anti-apoptotic activity by enhancing Bcl-2 transcription. However the mechanism has not been unveiled. Here, we explored the effectors of Vav1 in promoting Bcl-2 expression in Jurkat cells and revealed that Rac2-Akt was specifically evoked by the expression of Vav1, but not Vav2 or Vav3. Although all three Vav isoforms existed in Jurkat cells, Rac2 was distinguishably activated by Vav1 and that led to enhanced Bcl-2 expression and cell survival. Akt was modulated downstream of Vav1-Rac2, and the activation of Akt was indispensable in the enhanced transcription of Bcl-2. Intriguingly, neither Vav2 nor Vav3 was able to activate Rac2-Akt pathway as determined by gene silencing approach. Our data illustrated a unique role of Vav1 in T leukemia survival by selectively triggering Rac2-Akt axis and elevating the expression of anti-apoptotic Bcl-2.