Research IndicatorsGraph generated 31 August 2019 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 31 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (5)
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: GAB2 (cancer-related)
Guo L, Li B, Miao M, et al.MicroRNA‑663b targets GAB2 to restrict cell proliferation and invasion in hepatocellular carcinoma.
Mol Med Rep. 2019; 19(4):2913-2920 [PubMed
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Previous studies have demonstrated that numerous tumor‑specific microRNAs (miRNAs) are upregulated or downregulated in hepatocellular carcinoma (HCC), and that their dysregulation is implicated in HCC occurrence and development. Therefore, investigation of crucial miRNAs involved in HCC oncogenesis and progression may provide novel insights into the therapy of patients with this malignant tumor. In the present study, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) assays were performed to detect tissue and cellular expression levels of miRNA‑663b (miR‑663b) in HCC. The effects of miR‑663b overexpression on the proliferation and invasion of HCC cells were examined using Cell Counting Kit‑8 and Transwell invasion assays, respectively. The direct target of miR‑663b in HCC cells was determined by bioinformatics analysis, luciferase reporter assay, RT‑qPCR and western blot analysis. It was observed that miR‑663b was expressed at low levels in HCC tissues and cell lines. miR‑663b upregulation suppressed the proliferative and invasive abilities of HCC cells. Additionally, Grb2‑associated binding 2 (GAB2) was regarded as a direct target gene of miR‑663b in HCC cells. Furthermore, GAB2 was overexpressed in HCC tissues, and overexpression of GAB2 was inversely correlated with levels of miR‑663b. GAB2 overexpression was able to rescue the suppressive effects of miR‑663b on HCC cells. These results demonstrated that this newly‑identified miR‑663b/GAB2 axis may be implicated in HCC occurrence and development.
Ganglioglioma is the most common epilepsy-associated neoplasm that accounts for approximately 2% of all primary brain tumors. While a subset of gangliogliomas are known to harbor the activating p.V600E mutation in the BRAF oncogene, the genetic alterations responsible for the remainder are largely unknown, as is the spectrum of any additional cooperating gene mutations or copy number alterations. We performed targeted next-generation sequencing that provides comprehensive assessment of mutations, gene fusions, and copy number alterations on a cohort of 40 gangliogliomas. Thirty-six harbored mutations predicted to activate the MAP kinase signaling pathway, including 18 with BRAF p.V600E mutation, 5 with variant BRAF mutation (including 4 cases with novel in-frame insertions at p.R506 in the β3-αC loop of the kinase domain), 4 with BRAF fusion, 2 with KRAS mutation, 1 with RAF1 fusion, 1 with biallelic NF1 mutation, and 5 with FGFR1/2 alterations. Three gangliogliomas with BRAF p.V600E mutation had concurrent CDKN2A homozygous deletion and one additionally harbored a subclonal mutation in PTEN. Otherwise, no additional pathogenic mutations, fusions, amplifications, or deletions were identified in any of the other tumors. Amongst the 4 gangliogliomas without canonical MAP kinase pathway alterations identified, one epilepsy-associated tumor in the temporal lobe of a young child was found to harbor a novel ABL2-GAB2 gene fusion. The underlying genetic alterations did not show significant association with patient age or disease progression/recurrence in this cohort. Together, this study highlights that ganglioglioma is characterized by genetic alterations that activate the MAP kinase pathway, with only a small subset of cases that harbor additional pathogenic alterations such as CDKN2A deletion.
Li J, Xu J, Yan X, et al.MicroRNA-485 plays tumour-suppressive roles in colorectal cancer by directly targeting GAB2.
Oncol Rep. 2018; 40(1):554-564 [PubMed
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Colorectal cancer (CRC) is reported to be the third most common cancer and the fourth leading cause of cancer-related deaths around the world. MicroRNA-485 (miR-485) has been reported to be aberrantly expressed and play important roles in several types of human malignancy. However, the expression level, biological functions and underlying molecular mechanisms of miR-485 in CRC remain unclear. Therefore, the aim of the present study was to determine miR-485 expression levels and their clinical significance in CRC and to explore the functions and underlying mechanisms of miR-485 in this disease. In the present study, miR-485 was lowly expressed in CRC tissues and cell lines. Decreased miR-485 expression was associated with tumour size, lymph node metastasis, distant metastasis and TNM stage. Functional assays indicated that upregulation of miR-485 impaired CRC cell proliferation, invasion and induced cell apoptosis. Grb2-associated binding 2 (GAB2) was identified as a direct target of miR-485 in CRC. GAB2 was upregulated in CRC tissues and was negatively correlated with the miR-485 expression level. Furthermore, GAB2 knockdown simulated the tumour-suppressing roles of miR-485 overexpression in CRC cells. Moreover, restored GAB2 expression reversed the effects of miR-485 overexpression in CRC cells. In addition, miR-485 suppressed the AKT and ERK signalling pathways in CRC by directly targeting GAB2. Collectively, these findings demonstrate that miR-485 may play tumour suppressive roles in CRC by directly targeting GAB2 and indirectly regulating AKT and ERK signalling pathways, suggesting that miR-485 may be a potential therapeutic target for patients with this disease.
Herr R, Halbach S, Heizmann M, et al.BRAF inhibition upregulates a variety of receptor tyrosine kinases and their downstream effector Gab2 in colorectal cancer cell lines.
Oncogene. 2018; 37(12):1576-1593 [PubMed
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BRAF mutations occur in ~10% of colorectal cancer (CRC) and are associated with poor prognosis. Inhibitors selective for the BRAF
Lung squamous cell cancer (SCC) is typically found in smokers and has a very low incidence in non-smokers, indicating differences in the tumor biology of lung SCC in smokers and non-smokers. However, the specific mutations that drive tumor growth in non-smokers have not been identified. To identify mutations in lung SCC of non-smokers, we performed a genetic analysis using arrays comparative genomic hybridization (ArrayCGH). We analyzed 19 patients with lung SCC who underwent surgical treatment between April 2005 and April 2015. Clinical characteristics were reviewed, and DNA was extracted from fresh frozen lung cancer specimens. All of copy number alterations from ArrayCGH were validated using The Cancer Genome Atlas (TCGA) copy number variation (CNV) data of lung SCC. We examined the frequency of copy number changes according to the smoking status (non-smoker [n = 8] or smoker [n = 11]). We identified 16 significantly altered regions from ArrayCGH data, three gain and four loss regions overlapped with the TCGA lung squamous cell carcinoma (LUSC) patients. Within these overlapped significant regions, we detected 15 genes that have been reported in the Cancer Gene census. We also found that the proto-oncogene GAB2 (11q14.1) was significantly amplified in non-smokers patients and vice versa in both ArrayCGH and TCGA data. Immunohistochemical analyses showed that GAB2 protein was relatively upregulated in non-smoker than smoker tissues (37.5% vs. 9.0%, P = 0.007). GAB2 amplification may have an important role in the development of lung SCC in non-smokers. GAB2 may represent a potential biomarker for lung SCC in non-smokers.
Our previous studies have found that Growth factor receptor-bound protein 2-associated binding protein 2 (Gab2)-a docking protein-governs the development of fatty liver disease. Here, we further demonstrate that Gab2 mediates hepatocarcinogenesis. Compared with a faint expression in
Uveal melanoma (UM) is characterized by high metastasis and poor prognosis. A more improved understanding of the metastatic mechanism in UM cells is essential for the design of molecular therapy. Grb2‑associated binder 2 (Gab2) has been reported to serve important roles in the progression of various types of human cancer. However, the role of Gab2 in the migration and invasion of UM remains unclear. The present study sought to further assess the expression of Gab2 in UM and the role of Gab2 in the invasion of UM cells. Clinical UM tissue samples and UM cell lines were analyzed using western blot analysis for the expression of Gab2. RNA interference was used to investigate the effect of Gab2 on the migratory and invasive characteristics of UM cells in vitro. The expression levels of matrix metalloproteinase (MMP)2, MMP9 and fascin in Gab2‑knockdown, and control cells were also detected using western blot analysis. A total of 20 clinical UM samples and a subset of UM cell lines were investigated with uniformly high Gab2 expression. In the in vitro experiment, reduction of Gab2 using small interfering RNA inhibited the migration and invasion of UM cells by mediating MMPs, and fascin expression. These data suggest that Gab2 is a useful prognostic marker for UM and a novel therapeutic target for UM metastasis intervention.
Wang Z, Cheng Y, Abraham JM, et al.RNA sequencing of esophageal adenocarcinomas identifies novel fusion transcripts, including NPC1-MELK, arising from a complex chromosomal rearrangement.
Cancer. 2017; 123(20):3916-3924 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Studies of chromosomal rearrangements and fusion transcripts have elucidated mechanisms of tumorigenesis and led to targeted cancer therapies. This study was aimed at identifying novel fusion transcripts in esophageal adenocarcinoma (EAC).
METHODS: To identify new fusion transcripts associated with EAC, targeted RNA sequencing and polymerase chain reaction (PCR) verification were performed in 40 EACs and matched nonmalignant specimens from the same patients. Genomic PCR and Sanger sequencing were performed to find the breakpoint of fusion genes.
RESULTS: Five novel in-frame fusion transcripts were identified and verified in 40 EACs and in a validation cohort of 15 additional EACs (55 patients in all): fibroblast growth factor receptor 2 (FGFR2)-GRB2-associated binding protein 2 (GAB2) in 2 of 55 or 3.6%, Niemann-Pick C1 (NPC1)-maternal embryonic leucine zipper kinase (MELK) in 2 of 55 or 3.6%, ubiquitin-specific peptidase 54 (USP54)-calcium/calmodulin dependent protein kinase II γ (CAMK2G) in 2 of 55 or 3.6%, megakaryoblastic leukemia (translocation) 1 (MKL1)-fibulin 1 (FBLN1) in 1 of 55 or 1.8%, and CCR4-NOT transcription complex subunit 2 (CNOT2)-chromosome 12 open reading frame 49 (C12orf49) in 1 of 55 or 1.8%. A genomic analysis indicated that NPC1-MELK arose from a complex interchromosomal translocation event involving chromosomes 18, 3, and 9 with 3 rearrangement points, and this was consistent with chromoplexy.
CONCLUSIONS: These data indicate that fusion transcripts occur at a stable frequency in EAC. Furthermore, our results indicate that chromoplexy is an underlying mechanism that generates fusion transcripts in EAC. These and other fusion transcripts merit further study as diagnostic markers and potential therapeutic targets in EAC. Cancer 2017;123:3916-24. © 2017 American Cancer Society.
BACKGROUND: Grb2-associated binder 2 (Gab2) is a scaffolding protein that serves as a critical signaling amplifier downstream of tyrosine kinase receptors. Our previous study has shown that Gab2 induces epithelial-to-mesenchymal transition (EMT) and promotes metastasis in colorectal cancer (CRC). However, the role of Gab2 in CRC growth and angiogenesis remains unclear.
METHODS: The expression of vascular endothelial growth factor (VEGF) in different colorectal tissues was detected by immunohistochemistry and qRT-PCR to evaluate its correlation with Gab2. Lentiviral vectors bearing Gab2 gene and its small interfering RNAs were constructed and transfected into CRC cell lines. The effects of Gab2 on the cell proliferation in vitro and tumorigenesis in vivo, were examined via CCK‑8 assay, colony formation assay as well as tumorigenicity assay respectively. Moreover, to assess its potential role in tumor growth and angiogenesis, the expression of Ki67, CD34 and vascular endothelial growth factor receptor-2 (VEGFR2) were detected by immunohistochemistry in CRC cells tumors. Finally, we evaluated the impact of Gab2 on the expression of c-Myc and VEGF, and the probable effect of mechanistic targeted extracellular signal-regulated kinase (ERK) pathway in suppressing tumor growth and angiogenesis.
RESULTS: Up-regulation of Gab2 expression was found to be positively correlated with VEGF in CRC tissues. Exogenous expression of Gab2 obviously promoted, whereas silencing of Gab2 inhibited, proliferation and clone formation of human CRC cells in vitro. Of note, Gab2 enhanced tumorigenesis and tumor growth in mouse xenografts with high Ki67 expression, and led to an increased vessel density with strong CD34 and VEGFR2 activity. In addition, elevated Gab2 expression obviously up-regulated the expression of VEGF, and stimulated the activation of its downstream genes, ERK1/2 and c-Myc in CRC cells. Instead, down-regulated Gab2 expression significantly reduced the levels of VEGF, and inhibited the transduction of ERK/c-Myc pathway. Finally, we revealed that mechanistic target of mitogen-activated protein kinase (MEK) could attenuate Gab2-induced tumor growth and angiogenesis via altering VEGF and c-Myc levels.
CONCLUSIONS: The results from our study suggest that Gab2 promotes intestinal tumor growth and angiogenesis through upregulation of VEGF expression mediated by the MEK/ERK/c-Myc pathway.
The expression and biological function of Grb2-associated binding 2 (Gab2) in renal cell carcinoma (RCC) cells was tested here. We showed that Gab2 expression was significantly elevated in human RCC tissues and RCC cells. It was correlated with over-activation of Akt and downregulation of microRNA-302c-3p ("miR-302c-3p"), a putative Gab2-targeting microRNA. Knockdown of Gab2 inhibited Akt activation and 786-O RCC cell proliferation. Reversely, forced over-expression of Gab2 led to Akt hyper-activation to facilitate 786-O cell proliferation. Exogenous expression of miR-302c caused Gab2 downregulation, Akt inhibition and 786-O cell proliferation inhibition. On the other hand, miR-302c-3p depletion by expressing its anti-sense ("antagomiR-302c") led to Gab2 upregulation, Akt activation and increased 786-O cell proliferation. Significantly, miR-302c-3p failed to affect the proliferation of 786-O cells with shRNA-depleted Gab2. Together, we suggest that miR-302c-3p depletion in human RCC cells leads to Gab2 over-expression, Akt hyper-activation and cell proliferation.
Growing evidence suggests a major role for Src-homology-2-domain-containing phosphatase 2 (SHP2/PTPN11) in MYCN-driven high-risk neuroblastoma, although biologic confirmation and a plausible mechanism for this contribution are lacking. Using a zebrafish model of MYCN-overexpressing neuroblastoma, we demonstrate that mutant ptpn11 expression in the adrenal gland analog of MYCN transgenic fish promotes the proliferation of hyperplastic neuroblasts, accelerates neuroblastomagenesis, and increases tumor penetrance. We identify a similar mechanism in tumors with wild-type ptpn11 and dysregulated Gab2, which encodes a Shp2 activator that is overexpressed in human neuroblastomas. In MYCN transgenic fish, Gab2 overexpression activated the Shp2-Ras-Erk pathway, enhanced neuroblastoma induction, and increased tumor penetrance. We conclude that MYCN cooperates with either GAB2-activated or mutant SHP2 in human neuroblastomagenesis. Our findings further suggest that combined inhibition of MYCN and the SHP2-RAS-ERK pathway could provide effective targeted therapy for high-risk neuroblastoma patients with MYCN amplification and aberrant SHP2 activation.
Marcotte EL, Pankratz N, Amatruda JF, et al.Variants in BAK1, SPRY4, and GAB2 are associated with pediatric germ cell tumors: A report from the children's oncology group.
Genes Chromosomes Cancer. 2017; 56(7):548-558 [PubMed
] Free Access to Full Article Related Publications
Germ cell tumors (GCT) are a rare form of childhood cancer that originate from the primordial germ cell. Recent genome-wide association studies (GWAS) have identified susceptibility alleles for adult testicular GCT (TGCT). We test whether these SNPs are associated with GCT in pediatric and adolescent populations. This case-parent triad study includes individuals with GCT diagnosed between ages 0 and 19. We evaluated 26 SNPs from GWAS of adult TGCT and estimated main effects for pediatric GCT within complete trios (N = 366) using the transmission disequilibrium test. We used Estimation of Maternal, Imprinting and interaction effects using Multinomial modelling to evaluate maternal effects in non-Hispanic white trios and dyads (N = 244). We accounted for multiple comparisons using a Bonferroni correction. A variant in SPRY4 (rs4624820) was associated with reduced risk of GCT (OR [95% CI]: 0.70 [0.57, 0.86]). A variant in BAK1 (rs210138) was positively associated with GCT (OR [95% CI]: 1.70 [1.32, 2.18]), with a strong estimated effect for testis tumors (OR [95% CI]: 3.31 [1.89, 5.79]). Finally, a SNP in GAB2 (rs948662) was associated with increased risk for GCT (OR [95% CI]: 1.56 [1.20, 2.03]). Nominal associations (P < 0.05) were noted for eight additional loci. A maternal effect was observed for KITLG SNP rs4474514 (OR [95% CI]: 1.66 [1.21, 2.28]) and a paternal parent-of-origin effect was observed for rs7221274 (P = 0.00007), near TEX14, RAD51C, and PPM1E. We observed associations between SNPs in SPRY4, BAK1, and GAB2 and GCTs. This analysis suggests there may be common genetic risk factors for GCT in all age groups.
Ma J, Yu J, Liu J, et al.MicroRNA-302a targets GAB2 to suppress cell proliferation, migration and invasion of glioma.
Oncol Rep. 2017; 37(2):1159-1167 [PubMed
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Glioma is the most frequent and aggressive primary tumor of the brain in humans. Over the last few decades, significant progress has been made in early detection and multi-mode treatments, but the prognosis of gliomas is still extremely poor. MicroRNAs are endogenously expressed non-coding, single strand and short RNA molecules. Increasing number of studies demonstrated that microRNAs are dysregulated in a variety of human cancers, and play significant roles in tumorigenesis and tumor development, including glioma. In the present study, we for the first time found that microRNA-302a (miR-302a) was significantly downregulated in both glioma tissues and cell lines. In glioma patients, low miR-302a expression was correlated with KPS score and WHO grade. Restoration of miR-302a expression inhibited cell proliferation, migration and invasion of glioma in vitro. In addition, GAB2 was identified as a direct target of miR-320a. In clinical glioma tissues, GAB2 was upregulated and in-versely correlated with miR-302a expression. GAB2 underexpression had similar biological roles with miR-302a overexpression in glio-ma cells, further confirming that GAB2 was a functional downstream target of miR-302a. Moreover, rescue experiments showed that upregulation of GAB2 effectively reversed the inhibition effects of miR-302a on glioma cells proliferation, migration and invasion. These findings suggested that miR-302a is an important tumor suppressor of glioma progression by directly targeting GAB2, thus providing new insight into the molecular mechanisms underlying glioma occurrence, development and evolution of glioma.
Hu X, He B, Zhou L, et al.Expression Pattern and Clinical Significance of Gab2 Protein in Hepatocellular Carcinoma.
Clin Lab. 2016; 62(6):1087-92 [PubMed
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BACKGROUND: To investigate the expression pattern of Gab2 in hepatocellular carcinoma (HCC) and explore the correlation between Gab2 expression and clinicopathological features of HCC patients. The prognostic significance of Gab2 expression is evaluated to determine the possible role in the progression of HCC.
METHODS: Gab2 expression was detected by immunohistochemistry in 90 HCC samples and matched adjacent noncancerous liver tissues. The mRNA and protein of Gab2 in HCC and normal liver cell lines were examined by quantitative RT-PCR and western blot, respectively. The correlation between Gab2 expression of tumor tissues and clinicopathological parameters was analyzed by Chi-squared test or Fisher's exact test. The association between Gab2 expression and overall survival percentage after surgery was evaluated by Kaplan-Meier method.
RESULTS: Gab2 expression was elevated in HCC tissues compared with matched normal liver tissues (p < 0.001). Gab2 was upregulated in a subset of HCC cell lines. Among the clinical and pathological features, Gab2 expression was correlated to the histologic grade of HCC tissues (p < 0.05). Kaplan-Meier analysis of the cumulative survival rate after surgery indicated that no statistical difference existed between high-Gab2 and low-Gab2 expression group (p = 0.8297).
CONCLUSIONS: Gab2 may be involved in the onset and progression of HCC. Gab2 expression is unable to serve as an independent prognosis factor in HCC patients.
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
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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.
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.
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.
Signal transduction pathways activated by receptor tyrosine kinases (RTK) play a critical role in many aspects of cell function. Adaptor proteins serve an important scaffolding function that facilitates key signaling transduction events downstream of RTKs. Recent work integrating both structural and functional genomic approaches has identified several adaptor proteins as new oncogenes. In this review, we focus on the discovery, structure and function, and therapeutic implication of three of these adaptor oncogenes, CRKL, GAB2, and FRS2. Each of the three genes is recurrently amplified in lung adenocarcinoma or ovarian cancer, and is essential to cancer cell lines that harbor such amplification. Overexpression of each gene is able to transform immortalized human cell lines in in vitro or in vivo models. These observations identify adaptor protein as a distinct class of oncogenes and potential therapeutic targets.
Proteinase activated-receptor 2 (PAR2) participates in cancer metastasis promoted by serine proteinases. The current study aimed to test the molecular mechanism by which PAR2 promotes cancer cell migration. In different cancer cells, activation of PAR2 by activating peptide (PAR2-AP) dramatically increased cell migration, whereas knock down of PAR2 inhibited cellular motility. The PAR2 activation also repressed miR-125b expression while miR-125b mimic successfully blocked PAR2-induced cell migration. Moreover, Grb associated-binding protein 2 (Gab2) was identified as a novel target gene of miR-125b and it mediated PAR2-induced cell migration. The correlation of PAR2 with miR-125b and Gab2 was further supported by the findings obtained from human colorectal carcinoma specimens. Remarkably, knock down of NOP2/Sun domain family, member 2 (NSun2), a RNA methyltransferase, blocked the reduction in miR-125b induced by PAR2. Furthermore, PAR2 activation increased the level of N(6)-methyladenosine (m(6)A)-containing pre-miR-125b in NSun2-dependent manner. Taken together, our results demonstrated that miR-125b mediates PAR2-induced cancer cell migration by targeting Gab2 and that NSun2-dependent RNA methylation contributes to the down-regulation of miR-125b by PAR2 signaling. These findings suggest a novel epigenetic mechanism by which microenvironment regulates cancer cell migration by altering miRNA expression.
Breast cancer is a highly heterogeneous disease that is clinically classified into several subtypes. Among these subtypes, basal-like breast cancer largely overlaps with triple-negative breast cancer (TNBC), and these two groups are generally studied together as a single entity. Differences in the molecular makeup of breast cancers can result in different treatment strategies and prognoses for patients with different breast cancer subtypes. Compared with other subtypes, basal-like and other ER+ breast cancer subtypes exhibit marked differences in etiologic factors, clinical characteristics and therapeutic potential. Anthracycline drugs are typically used as the first-line clinical treatment for basal-like breast cancer subtypes. However, certain patients develop drug resistance following chemotherapy, which can lead to disease relapse and death. Even among patients with basal-like breast cancer, there can be significant molecular differences, and it is difficult to identify specific drug resistance proteins in any given patient using conventional variance testing methods. Therefore, we designed a new method for identifying drug resistance genes. Subgroups, personalized biomarkers, and therapy targets were identified using cluster analysis of differentially expressed genes. We found that basal-like breast cancer could be further divided into at least four distinct subgroups, including two groups at risk for drug resistance and two groups characterized by sensitivity to pharmacotherapy. Based on functional differences among these subgroups, we identified nine biomarkers related to drug resistance: SYK, LCK, GAB2, PAWR, PPARG, MDFI, ZAP70, CIITA and ACTA1. Finally, based on the deviation scores of the examined pathways, 16 pathways were shown to exhibit varying degrees of abnormality in the various subgroups, indicating that patients with different subtypes of basal-like breast cancer can be characterized by differences in the functional status of these pathways. Therefore, these nine differentially expressed genes and their associated functional pathways should provide the basis for novel personalized clinical treatments of basal-like breast cancer.
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.
Davis SJ, Sheppard KE, Anglesio MS, et al.Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition.
Mol Cancer Ther. 2015; 14(6):1495-503 [PubMed
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Identification of genomic alterations defining ovarian carcinoma subtypes may aid the stratification of patients to receive targeted therapies. We characterized high-grade serous ovarian carcinoma (HGSC) for the association of amplified and overexpressed genes with clinical outcome using gene expression data from 499 HGSC patients in the Ovarian Tumor Tissue Analysis cohort for 11 copy number amplified genes: ATP13A4, BMP8B, CACNA1C, CCNE1, DYRK1B, GAB2, PAK4, RAD21, TPX2, ZFP36, and URI. The Australian Ovarian Cancer Study and The Cancer Genome Atlas datasets were also used to assess the correlation between gene expression, patient survival, and tumor classification. In a multivariate analysis, high GAB2 expression was associated with improved overall and progression-free survival (P = 0.03 and 0.02), whereas high BMP8B and ATP13A4 were associated with improved progression-free survival (P = 0.004 and P = 0.02). GAB2 overexpression and copy number gain were enriched in the AOCS C4 subgroup. High GAB2 expression correlated with enhanced sensitivity in vitro to the dual PI3K/mTOR inhibitor PF-04691502 and could be used as a genomic marker for identifying patients who will respond to treatments inhibiting PI3K signaling.
Sun L, Zhang B, Liu Y, et al.MiR125a-5p acting as a novel Gab2 suppressor inhibits invasion of glioma.
Mol Carcinog. 2016; 55(1):40-51 [PubMed
] Related Publications
Poor prognosis of glioma is due to the characteristics of high invasiveness. Recently, it was demonstrated that Gab2 was over-expressed and related to cellular migration and invasion in glioma, however, the mechanisms of regulation are still unknown. A better understanding of molecular events key to the carcinogenesis and tumor progression may facilitate development of new therapeutic targets and anti-glioma strategies. This study is the first to focus on miR125a-5p, which was predicted to regulate Gab2 with directly targeting the 3' un-translated region (3'UTR) of Gab2 and could inhibit migration and invasion of glioma cells by mediating Gab2 to affect cytoskeleton rearrangement and matrix metalloproteinases expression. Interestingly, further evaluation revealed that the miR125a-5p promoter was hypermethylated and that attenuating promoter methylation was sufficient to up-regulate miR125a-5p expression in glioma cells. Additionally, we reported that miR125a-5p was down-regulated in glioma as well as statistical analysis suggested that its expression level correlated with the World Health Organization grades of glioma (P < 0.05) and that patients with a low miR125a-5p level exhibited shorter survival time (P < 0.05). Taken together, these results reveal that miR125a-5p represents potential therapeutic targets in glioma by modulating Gab2.
Matsumura T, Sugimachi K, Takahashi Y, et al.Clinical significance of GAB2, a scaffolding/docking protein acting downstream of EGFR in human colorectal cancer.
Ann Surg Oncol. 2014; 21 Suppl 4:S743-9 [PubMed
] Related Publications
PURPOSE: Recent studies indicated that the scaffolding adaptor protein GAB2 (GRB2-associated binding protein 2) plays a critical role in the proliferation and migration of various cancers. This study aimed to determine the role of aberrant GAB2 expression in human colorectal cancer (CRC).
METHODS: Quantitative real-time reverse transcription polymerase chain reaction was used to evaluate GAB2 mRNA expression in 152 CRC tissues samples to determine the clinicopathological significance of GAB2 expression. We also performed in vitro proliferation assays using siGAB2-transfected CRC cells.
RESULTS: GAB2 expression in tumor colorectal tissues was significantly higher than in normal colorectal tissues (p = 0.0212). High GAB2 expression levels were associated with malignant clinicopathologic potential factors, including lymphatic invasion (p = 0.0003), venous invasion (p = 0.0170), and liver metastasis (p = 0.0144). The survival rate of patients with high GAB2 expression levels was significantly lower than that of patients with low GAB2 expression (p = 0.0074). Multivariate analysis indicated that GAB2 expression was a factor affecting lymph node metastasis. Cell proliferation was significantly suppressed by siGAB2 expression in CRC cells in vitro.
CONCLUSIONS: GAB2 expression was associated with lymph node metastasis and may play a role in the growth and metastasis of CRC. These results suggest that GAB2 is a potential therapeutic target in CRC.
Bozok Cetintas V, Tezcanli Kaymaz B, Aktug H, et al.Capsaicin induced apoptosis and gene expression dysregulation of human acute lymphoblastic leukemia CCRF-CEM cells.
J BUON. 2014 Jan-Mar; 19(1):183-90 [PubMed
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PURPOSE: Capsaicin, an ingredient of red chili pepper, has possible tumorigenicity/genotoxicity properties. We aimed to determine the effects of capsaicin on the proliferation and gene expression profiles of acute lymphoblastic leukemia (ALL) CCRF-CEM cell line.
METHODS: Cell viability and IC50 dose was determined by WST cytotoxicity assay. qRT-PCR, immunohistochemical staining and western blot methods were used to determine target genes' expression levels. Apoptosis was evaluated by measuring the caspase-3 activity.
RESULTS: Capsaicin inhibited the proliferation of CCRFCEM cells in a dose-dependent manner. Increased mRNA expressions of caspase gene family members, activated caspase-3 and decreased mRNA and protein expression of BCL-2 gene indicated apoptotic response to capsaicin. Moreover capsaicin treatment suppressed significantly the expression of the key cell signaling pathways of KRAS, AKT, GAB2, PTPN11, BRAF, INPP5D, MAPK7.
CONCLUSION: Capsaicin induces apoptosis in CCRF-CEM cells and this response is associated with downregulation of cell signaling pathways.
High-grade serous ovarian cancers are characterized by widespread recurrent copy number alterations. Although some regions of copy number change harbor known oncogenes and tumor suppressor genes, the genes targeted by the majority of amplified or deleted regions in ovarian cancer remain undefined. Here we systematically tested amplified genes for their ability to promote tumor formation using an in vivo multiplexed transformation assay. We identified the GRB2-associated binding protein 2 (GAB2) as a recurrently amplified gene that potently transforms immortalized ovarian and fallopian tube secretory epithelial cells. Cancer cell lines overexpressing GAB2 require GAB2 for survival and show evidence of phosphatidylinositol 3-kinase (PI3K) pathway activation, which was required for GAB2-induced transformation. Cell lines overexpressing GAB2 were as sensitive to PI3K inhibition as cell lines harboring mutant PIK3CA. Together, these observations nominate GAB2 as an ovarian cancer oncogene, identify an alternative mechanism to activate PI3K signaling, and underscore the importance of PI3K signaling in this cancer.
Chronic myeloid leukemia (CML) is a cytogenetic disorder resulting from formation of the Philadelphia chromosome (Ph), that is, the t(9;22) chromosomal translocation and the formation of the BCR-ABL1 fusion protein. Tyrosine kinase inhibitors (TKI), such as imatinib and nilotinib, have emerged as leading compounds with which to treat CML. t(9;22) is not restricted to CML, 20-30% of acute lymphoblastic leukemia (ALL) cases also carry the Ph. However, TKIs are not as effective in the treatment of Ph+ ALL as in CML. In this study, the Ph+ cell lines JURL-MK2 and SUP-B15 were used to investigate TKI resistance mechanisms and the sensitization of Ph+ tumor cells to TKI treatment. The annexin V/PI (propidium iodide) assay revealed that nilotinib induced apoptosis in JURL-MK2 cells, but not in SUP-B15 cells. Since there was no mutation in the tyrosine kinase domain of BCR-ABL1 in cell line SUP-B15, the cells were not generally unresponsive to TKI, as evidenced by dephosphorylation of the BCR-ABL1 downstream targets, Crk-like protein (CrkL) and Grb-associated binder-2 (GAB2). Resistance to apoptosis after nilotinib treatment was accompanied by the constitutive and nilotinib unresponsive activation of the phosphoinositide 3-kinase (PI3K) pathway. Treatment of SUP-B15 cells with the dual PI3K/mammalian target of rapamycin (mTOR) inhibitor BEZ235 alone induced apoptosis in a low percentage of cells, while combining nilotinib and BEZ235 led to a synergistic effect. The main role of PI3K/mTOR inhibitor BEZ235 and the reason for apoptosis in the nilotinib-resistant cells was the block of the translational machinery, leading to the rapid downregulation of the anti-apoptotic protein MDM2 (human homolog of the murine double minute-2). These findings highlight MDM2 as a potential therapeutic target to increase TKI-mediated apoptosis and imply that the combination of PI3K/mTOR inhibitor and TKI might form a novel strategy to combat TKI-resistant BCR-ABL1 positive leukemia.
Chang X, Shi L, Gao F, et al.Genomic and transcriptome analysis revealing an oncogenic functional module in meningiomas.
Neurosurg Focus. 2013; 35(6):E3 [PubMed
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OBJECT: Meningiomas are among the most common primary adult brain tumors. Although typically benign, roughly 2%-5% display malignant pathological features. The key molecular pathways involved in malignant transformation remain to be determined.
METHODS: Illumina expression microarrays were used to assess gene expression levels, and Illumina single-nucleotide polymorphism arrays were used to identify copy number variants in benign, atypical, and malignant meningiomas (19 tumors, including 4 malignant ones). The authors also reanalyzed 2 expression data sets generated on Affymetrix microarrays (n = 68, including 6 malignant ones; n = 56, including 3 malignant ones). A weighted gene coexpression network approach was used to identify coexpression modules associated with malignancy.
RESULTS: At the genomic level, malignant meningiomas had more chromosomal losses than atypical and benign meningiomas, with average length of 528, 203, and 34 megabases, respectively. Monosomic loss of chromosome 22 was confirmed to be one of the primary chromosomal level abnormalities in all subtypes of meningiomas. At the transcriptome level, the authors identified 23 coexpression modules from the weighted gene coexpression network. Gene functional enrichment analysis highlighted a module with 356 genes that was highly related to tumorigenesis. Four intramodular hubs within the module (GAB2, KLF2, ID1, and CTF1) were oncogenic in other cancers such as leukemia. A putative meningioma tumor suppressor MN1 was also identified in this module with differential expression between malignant and benign meningiomas.
CONCLUSIONS: The authors' genomic and transcriptome analysis of meningiomas provides novel insights into the molecular pathways involved in malignant transformation of meningiomas, with implications for molecular heterogeneity of the disease.
BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer death in the United States. The high mortality rate of patients with pancreatic cancer is primarily due to the difficulty of early diagnosis and a lack of effective therapies. There is an urgent need to discover novel molecular targets for early diagnosis and new therapeutic approaches to improve the clinical outcome of this deadly disease.
AIM: We utilized the reverse-phase protein assay (RPPA) to identify differentially expressed biomarker proteins in tumors and matched adjacent, normal-appearing tissue samples from 15 pancreatic cancer patients.
METHODS: The antibody panel used for the RPPA included 130 key proteins involved in various cancer-related pathways. The paired t test was used to determine the significant differences between matched pairs, and the false discovery rate-adjusted p values were calculated to take into account the effect of multiple comparisons.
RESULTS: After correcting for multiple comparisons, we found 19 proteins that had statistically significant differences in expression between matched pairs. However, only four (AKT, β-catenin, GAB2, and PAI-1) of them met the conservative criteria (both a q value <0.05 and a fold-change of ≥3/2 or ≤2/3) to be considered differentially expressed. Overexpression of AKT, β-catenin, and GAB2 in pancreatic cancer tissues identified by RPPA has also been further confirmed by western blot analysis. Further analysis identified several significantly associated canonical pathways and overrepresented network functions.
CONCLUSION: GAB2, a newly identified protein in pancreatic cancer, may provide additional insight into this cancer's pathogenesis. Future studies in a larger population are warranted to further confirm our results.
Davis SJ, Sheppard KE, Pearson RB, et al.Functional analysis of genes in regions commonly amplified in high-grade serous and endometrioid ovarian cancer.
Clin Cancer Res. 2013; 19(6):1411-21 [PubMed
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PURPOSE: Ovarian cancer has the highest mortality rate of all the gynecologic malignancies and is responsible for approximately 140,000 deaths annually worldwide. Copy number amplification is frequently associated with the activation of oncogenic drivers in this tumor type, but their cytogenetic complexity and heterogeneity has made it difficult to determine which gene(s) within an amplicon represent(s) the genuine oncogenic driver. We sought to identify amplicon targets by conducting a comprehensive functional analysis of genes located in the regions of amplification in high-grade serous and endometrioid ovarian tumors.
EXPERIMENTAL DESIGN: High-throughput siRNA screening technology was used to systematically assess all genes within regions commonly amplified in high-grade serous and endometrioid cancer. We describe the results from a boutique siRNA screen of 272 genes in a panel of 18 ovarian cell lines. Hits identified by the functional viability screen were further interrogated in primary tumor cohorts to determine the clinical outcomes associated with amplification and gene overexpression.
RESULTS: We identified a number of genes as critical for cellular viability when amplified, including URI1, PAK4, GAB2, and DYRK1B. Integration of primary tumor gene expression and outcome data provided further evidence for the therapeutic use of such genes, particularly URI1 and GAB2, which were significantly associated with survival in 2 independent tumor cohorts.
CONCLUSION: By taking this integrative approach to target discovery, we have streamlined the translation of high-resolution genomic data into preclinical in vitro studies, resulting in the identification of a number of genes that may be specifically targeted for the treatment of advanced ovarian tumors.