Gene Summary

Gene:DAB2; DAB adaptor protein 2
Aliases: DOC2, DOC-2
Summary:This gene encodes a mitogen-responsive phosphoprotein. It is expressed in normal ovarian epithelial cells, but is down-regulated or absent from ovarian carcinoma cell lines, suggesting its role as a tumor suppressor. This protein binds to the SH3 domains of GRB2, an adaptor protein that couples tyrosine kinase receptors to SOS (a guanine nucleotide exchange factor for Ras), via its C-terminal proline-rich sequences, and may thus modulate growth factor/Ras pathways by competing with SOS for binding to GRB2. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:disabled homolog 2
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (37)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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

  • Neoplasm Invasiveness
  • Western Blotting
  • Breast Cancer
  • Immunohistochemistry
  • Prostate Cancer
  • Apoptosis
  • Promoter Regions
  • Signal Transducing Adaptor Proteins
  • DAB2
  • Cancer DNA
  • Cell Movement
  • Tumor Suppressor Gene
  • Uterine Cancer
  • Neoplasm Metastasis
  • Molecular Sequence Data
  • Oligonucleotide Array Sequence Analysis
  • Neoplastic Cell Transformation
  • Serine Endopeptidases
  • Adenocarcinoma
  • Adaptor Proteins, Vesicular Transport
  • beta Catenin
  • Gene Expression Profiling
  • Cell Proliferation
  • DNA Methylation
  • Carcinoma
  • RNA Interference
  • Epithelial Cells
  • Disease Progression
  • Transfection
  • Lung Cancer
  • Chromosome 5
  • Biomarkers, Tumor
  • Messenger RNA
  • Down-Regulation
  • Polymerase Chain Reaction
  • Signal Transduction
  • Cancer Gene Expression Regulation
  • Ovarian Cancer
  • MicroRNAs
  • Epigenetics
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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

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

Latest Publications: DAB2 (cancer-related)

Ma S, Zhang WL, Leckey BD, et al.
X-ray irradiation induced Disabled-2 gene promoter de-methylation enhances radiosensitivity of non-small-cell lung carcinoma cells.
J Exp Clin Cancer Res. 2018; 37(1):315 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Disabled-2 (Dab2) is known as a tumor suppressor as well as a Wnt pathway inhibitor. We previously reported that Dab2 was down-regulated due to gene promoter hypermethylation in lung cancer. Here, we aim to study if X-ray irradiation can induce de-methylation of the Dab2 gene and subsequently up-regulate its expression, and also to attempt to suppress the malignant biological behavior of and enhance the radiosensitivity in lung cancer cells with hypermethylation of the Dab2 gene.
METHODS: Immunostaining was performed to investigate the relationship between Dab2 expression and lung cancer clinicopathological characteristics. Bisulfite sequencing PCR (BSP) was used to evaluate the methylation status of lung cancer cells with or without X-ray treatment. Real-time PCR and western Blot were performed to investigate the expression of Dab2, Wnt pathway factors, DNMTs and methyl CpG binding protein 2 (MeCP2). Colony Formation, matrigel invasion and xenograft experiment were performed to evaluate the malignant biological behavior of lung cancer cells with irradiation.
RESULTS: The result of immunostaining of Dab2 in lung cancer tissues showed that decreased Dab2 expression was positively correlated with poor differentiation, lymph node metastasis, advanced TNM stage and poor prognosis. X-ray treatment significantly up-regulated Dab2 expression and inhibited Wnt factors in LK2 cells (with hypermethylation of the Dab2 gene promoter, P < 0.05), but not in SPC-A-1 cells (with hypomethylation of the Dab2 gene promoter); however, the effect could be reversed by Dab2 or Axin knockdown (P < 0.05). Decreased expression of DNMT1, DNMT3b and MeCP2 could be detected in both LK2 and SPC-A-1 cells compared to non-irradiated cells (P < 0.05). Both in vitro studies and in vivo xenograft tumor growth demonstrated that X-ray could significantly inhibit the proliferation and invasion of LK2 but not SPC-A-1 cells (P < 0.05).
CONCLUSION: In general, X-ray-induced up-regulation of Dab2 and inhibition of the Wnt pathway may be mediated by de-methylation of a hypermethylated Dab2 gene promoter. X-ray treatment significantly inhibits proliferation and invasion of lung cancer cells with hypermethylation of the Dab2 gene promoter, but is less effective in lung cancer cells with hypomethylation of the Dab2 gene promoter. These results indicate that the methylation status of the Dab2 gene promoter might be a potential predictor of the radiosensitivity of lung cancer cells.

Yang K, Li YW, Gao ZY, et al.
MiR-93 functions as a tumor promoter in prostate cancer by targeting disabled homolog 2 (DAB2) and an antitumor polysaccharide from green tea (Camellia sinensis) on their expression.
Int J Biol Macromol. 2019; 125:557-565 [PubMed] Related Publications
Our previous work has demonstrated that the role of miR-93 in prostate cancer (PC) progression. The aim of this study was to determine the downstream gene regulated by miR-93 and the molecular mechanisms underlying its roles in PC. Bioinformatics analysis and luciferase reporter assays predicted disabled homolog 2 (DAB2) as a direct target gene of miR-93. Real time quantitative polymerase chain reaction (qRT-PCR) and Western blot analysis revealed that DAB2 was tumor repressor in PC cells, and its mRNA expression was negatively correlated with miR-93 in PC tissues. Gain and loss of function experiments also indicated DAB2 overexpression significantly suppressed PC cells proliferation, invasion and migration, while knockdown of its expression came to the opposite effect. Furthermore, a rescue experiment indicated miR-93 directly regulated PC cell growth and migration, as well as AKT and ERK activation by targeting DAB2. Additionally, antitumor effect of a Green tea polysaccharide (GTP) on PC-3 cells could be achieved by increasing DAB2 protein expression and inactivating AKT and ERK1/2 signaling. Our study suggests that miR-93 promoted PC progression and metastasis by repressing DAB2 to activate Akt/ERK1/2 pathway, and elevation of DAB2 and inactivation of Akt/ERK1/2 might be a potential therapeutic target for PC by GTP.

Son HJ, Jo YS, Kim MS, et al.
DAB2IP with tumor-inhibiting activities exhibits frameshift mutations in gastrointestinal cancers.
Pathol Res Pract. 2018; 214(12):2075-2080 [PubMed] Related Publications
A scaffold protein DAB2 and its interaction partner DAB2IP have putative tumor suppressor gene (TSG) functions. Previous studies identified that both DAB2 and DAB2IP genes were inactivated by promoter hypermethylation in human cancers, but their mutational alterations in cancers remain largely unknown. The aim of our study was to find whether DAB2 and DAB2IP were mutated in gastric (GCs) and colorectal cancers (CRCs) by DNA sequencing. Both DAB2 and DAB2IP have mononucleotide repeats in their coding sequence that could be mutation targets in high microsatellite instability (MSI-H) cancers. We analyzed GC and CRC tissues and found that 8 of 34 GCs (23.5%) and 15 of 79 CRCs (20.0%) with MSI-H harbored DAB2IP frameshift mutations. DAB2 frameshift mutations were found in 2 of 79 CRCs (2.5%) with MSI-H. These mutations were not detected in microsatellite stable (MSS) cancers. We also found intratumoral heterogeneity (ITH) of DAB2IP frameshift mutations in 7 of 16 CRCs (43.8%). Loss of DAB2IP protein expression was found in approximately 20% of GCs and CRCs irrespective of MSI and DAB2IP frameshift mutation status. Our study shows that the TSG DAB2IP harbored frameshift mutations and ITH as well as expression loss. Together these tumor alterations might play a role in tumorigenesis of GC and CRC with MSI-H by down-regulating the tumor-inhibiting activities of DAB2IP.

Paluszczak J, Kiwerska K, Mielcarek-Kuchta D
Frequent methylation of DAB2, a Wnt pathway antagonist, in oral and oropharyngeal squamous cell carcinomas.
Pathol Res Pract. 2018; 214(2):314-317 [PubMed] Related Publications
BACKGROUND: Aberrations in Wnt signaling pathway are related to the pathogenesis of head and neck carcinomas and their activation frequently results from epigenetic alterations. This study aimed to assess the frequency of the methylation of DAB2, which acts as a negative regulator of Wnt signaling, and correlate it with clinicopathological features in a group of oral cancer patients.
MATERIAL AND METHODS: Forty nine patients with primary oral squamous cell carcinoma were enrolled in the study. DNA samples were isolated from surgical sections using phenol-chloroform extraction. Methylation-specific PCR was used to detect gene promoter methylation.
RESULTS: The analysis of the occurrence of DAB2 promoter methylation in primary oral carcinomas indicated that the gene is methylated in 70% of cases. However, no correlation was found between its methylation and TNM staging or overall survival.
CONCLUSIONS: Our findings corroborate that DAB2 is a frequent target of epigenetic silencing in oral carcinomas and may be potentially used for tumor detection.

Tian X, Zhang Z
miR-191/DAB2 axis regulates the tumorigenicity of estrogen receptor-positive breast cancer.
IUBMB Life. 2018; 70(1):71-80 [PubMed] Related Publications
Disabled-2 (DAB2) has been shown to be downregulated in a variety of human cancer types including breast tumors. However, the role of DAB2 in estrogen receptor positive (ER+) breast cancer cells has not been reported. In this context, we demonstrated that DAB2 expression was significantly decreased in ER+ breast cancer cell lines and ER+ clinical specimens, compared with ER- breast cancer cell lines and ER- tissues, respectively. Depletion of estrogen significantly elevated DAB2 expression in ER+ MCF7 and T-47D cells. Treatment with estradiol (E2) reduced the expression of DAB2 and administration of tamoxifen upregulated DAB2 expression in a dose-dependent manner. Functionally, silencing of DAB2 in hormone-starved MCF7 and T-47D cells promoted cellular proliferation and enforced expression of DAB2 in normal-cultured or E2-treated cells suppressed cellular proliferation. Mechanistically, estrogen-induced miR-191 was identified as a direct upstream regulator of DAB2 in ER+ cells. Luciferase reporter assay indicated that miR-191 inhibited DAB2 expression by directly targeting the 3'-UTR of DAB2. Importantly, the expression and function of miR-191 showed the opposite tendency with DAB2 in ER+ cells. In vivo, inhibition of miR-191 significantly suppressed the xenograft growth induced by E2, and silencing of DAB2 could restored the growth arrest induced by miR-191 inhibition. Taken together, our data unveil that the miR-191-DAB2 axis seems to be an important pathway associated with estrogen signaling in breast cancer and may serve as a potential diagnostic biomarker and a powerful therapeutic target for ER+ breast cancer patients. © 2017 IUBMB Life, 70(1):71-80, 2018.

Cai W, Jiang H, Yu Y, et al.
miR-367 regulation of DOC-2/DAB2 interactive protein promotes proliferation, migration and invasion of osteosarcoma cells.
Biomed Pharmacother. 2017; 95:120-128 [PubMed] Related Publications
Recently, miR-367 is reported to exert either oncogenic or tumor suppressive effects in human malignancies. Recent study reports that miR-367 is up-regulated in OS tissues and cell lines, and abrogates adriamycin-induced apoptosis. The clinical significance of miR-367 and its function in OS need further investigation. In our study, miR-367 expression in OS was markedly elevated compared with corresponding non-tumor tissues. High miR-367 expression was associated with malignant clinical features and poor prognosis of OS patients. In accordance, the levels of miR-367 were dramatically up-regulated in OS cells. Loss of miR-367 expression in Saos-2 cells obviously inhibited the proliferation, migration and invasion of cancer cells in vitro. Meanwhile, miR-367 restoration promoted these malignant behaviors of MG-63 cells. Mechanistically, miR-367 negatively regulated DOC-2/DAB2 interactive protein (DAB2IP) abundance in OS cells. Hereby, DAB2IP was recognized as a direct target gene of miR-367 in OS. DAB2IP mRNA level was down-regulated and inversely correlated with miR-367 expression in OS specimens. DAB2IP overexpression prohibited proliferation, migration and invasion in Saos-2 cells, while DAB2IP knockdown showed promoting effects on proliferation, migration and invasion of MG-63 cells. Furthermore, the role of miR-367 might be mediated by DAB2IP-regulated phosphorylation of ERK and AKT in OS cells. To conclude, miR-367 may function as a biomarker for prediction of prognosis and a target for OS therapy.

Zhao YH, Zhang XF, Zhao YQ, et al.
Time-series analysis in imatinib-resistant chronic myeloid leukemia K562-cells under different drug treatments.
J Huazhong Univ Sci Technolog Med Sci. 2017; 37(4):621-627 [PubMed] Related Publications
Chronic myeloid leukemia (CML) is characterized by the accumulation of active BCR-ABL protein. Imatinib is the first-line treatment of CML; however, many patients are resistant to this drug. In this study, we aimed to compare the differences in expression patterns and functions of time-series genes in imatinib-resistant CML cells under different drug treatments. GSE24946 was downloaded from the GEO database, which included 17 samples of K562-r cells with (n=12) or without drug administration (n=5). Three drug treatment groups were considered for this study: arsenic trioxide (ATO), AMN107, and ATO+AMN107. Each group had one sample at each time point (3, 12, 24, and 48 h). Time-series genes with a ratio of standard deviation/average (coefficient of variation) >0.15 were screened, and their expression patterns were revealed based on Short Time-series Expression Miner (STEM). Then, the functional enrichment analysis of time-series genes in each group was performed using DAVID, and the genes enriched in the top ten functional categories were extracted to detect their expression patterns. Different time-series genes were identified in the three groups, and most of them were enriched in the ribosome and oxidative phosphorylation pathways. Time-series genes in the three treatment groups had different expression patterns and functions. Time-series genes in the ATO group (e.g. CCNA2 and DAB2) were significantly associated with cell adhesion, those in the AMN107 group were related to cellular carbohydrate metabolic process, while those in the ATO+AMN107 group (e.g. AP2M1) were significantly related to cell proliferation and antigen processing. In imatinib-resistant CML cells, ATO could influence genes related to cell adhesion, AMN107 might affect genes involved in cellular carbohydrate metabolism, and the combination therapy might regulate genes involved in cell proliferation.

Tao Y, Sun C, Zhang T, Song Y
SMURF1 promotes the proliferation, migration and invasion of gastric cancer cells.
Oncol Rep. 2017; 38(3):1806-1814 [PubMed] Related Publications
Smad ubiquitin regulatory factor 1 (SMURF1), a well-known E3 ubiquitin ligase, targets substrate proteins for ubiquitination and proteasomal degradation. Accumulating studies have shown that SMURF1 acts as an oncogenic factor in human malignancies. However, the clinical significance of SMURF1 and its role in gastric cancer (GC) remain unclear. The expression of SMURF1 was detected in 68 cases of GC and corresponding tumor-adjacent specimens. Our results revealed that SMURF1 was prominently overexpressed in GC specimens compared to corresponding tumor-adjacent tissues. Furthermore, increased levels of SMURF1 mRNA were also observed in GC cell lines. Clinicopathological detection ascertained that SMURF1-positive expression was associated with large tumor size, more lymph nodes and distant metastasis as well as advanced tumor-node-metastasis (TNM) stage of GC. Notably, GC patients with SMURF1 positive‑expressing tumors exhibited a significant decreased survival. Further experiments illustrated that SMURF1 knockdown significantly inhibited proliferation, migration and invasion of MGC-803 cells, while SMURF1 overexpression prominently promoted these behaviors in SGC-7901 cells. In vivo studies revealed that SMURF1 knockdown markedly inhibited tumor growth and liver metastasis of GC. Mechanically, SMURF1 inversely regulated the expression of DOC-2/DAB2 interactive protein (DAB2IP) in GC tissues and cells. Furthermore, DAB2IP restoration revealed similar effects to SMURF1 knockdown on MGC-803 cells with decreased proliferation, migration and invasion. In addition, the PI3K/Akt pathway and its downstream targets including c-Myc and ZEB1 were potentially involved in the oncogenic role of the SMURF1/DABIP axis. Collectively, the present study revealed the first evidence that SMURF1 can be potentially used as a clinical biomarker and target for novel treatment of human GC.

Li P, Zhang M, Ma JQ, et al.
Expression and Histopathological Significance of Disabled-2 in Aldosterone-Producing Adenoma.
Horm Metab Res. 2017; 49(7):520-526 [PubMed] Related Publications
The current pathological diagnosis of aldosterone-producing adenoma (APA) is challenging because no histological markers of aldosterone production are available in routine practice. A previous study demonstrated that Disabled-2 (DAB2) is a specific marker of the

Piao J, You K, Guo Y, et al.
Substrate stiffness affects epithelial-mesenchymal transition of cervical cancer cells through miR-106b and its target protein DAB2.
Int J Oncol. 2017; 50(6):2033-2042 [PubMed] Related Publications
The effects of different substrate stiffness were investigated on epithelial-mesenchymal transition (EMT) of cervical cancer cell lines and the role of miR-106b and its target protein DAB2 therein. Cervical cancer cell lines HeLa and SiHa were cultured on artificial substrates with different stiffness prepared using different ratios of acrylamide and bis-acrylamide. Changes of microRNA profiles were detected using microRNA chip analysis, and the expression levels of EMT-related markers E-cadherin and vimentin were detected using western blotting and real-time PCR. In addition, the effects of miR-106b overexpression as well as miR-106b and DAB2 knockdown on expression of E-cadherin and vimentin were also examined using western blotting and real-time PCR. The results showed that i) cervical cancer cell lines SiHa and HeLa cultured on substrate with stiffness of 20 kPa had the strongest EMT ability, showed the highest levels of vimentin and lowest levels of E-cadherin, compared with cells cultured on substrate with stiffness of 1 kPa; ii) miR-106b knockdown reversed the effects of substrate stiffness on EMT of cervical cancer cells, while miR-106 overexpression and DAB2 knockdown induced EMT of cervical cancer cells cultured on substrate with stiffness of 20 kPa. Overall, the results indicated that substrate stiffness could regulate EMT of cervical cancer cell lines HeLa and SiHa at least partially through miR-106b and its downstream target DAB2.

Kuraoka M, Amatya VJ, Kushitani K, et al.
Identification of DAB2 and Intelectin-1 as Novel Positive Immunohistochemical Markers of Epithelioid Mesothelioma by Transcriptome Microarray Analysis for Its Differentiation From Pulmonary Adenocarcinoma.
Am J Surg Pathol. 2017; 41(8):1045-1052 [PubMed] Related Publications
As there are currently no absolute immunohistochemical positive markers for the definite diagnosis of malignant epithelioid mesothelioma, the identification of additional "positive" markers that may facilitate this diagnosis becomes of clinical importance. Therefore, the aim of this study was to identify novel positive markers of malignant mesothelioma. Whole genome gene expression analysis was performed using RNA extracted from formalin-fixed paraffin-embedded tissue sections of epithelioid mesothelioma and pulmonary adenocarcinoma. Gene expression analysis revealed that disabled homolog 2 (DAB2) and Intelectin-1 had significantly higher expression in epithelioid mesothelioma compared with that in pulmonary adenocarcinoma. The increased mRNA expression of DAB2 and Intelectin-1 was validated by reverse transcriptase polymerase chain reaction of RNA from tumor tissue and protein expression was validated by Western blotting of 5 mesothelioma cell lines. The utility of DAB2 and Intelectin-1 in the differential diagnosis of epithelioid mesothelioma and pulmonary adenocarcinoma was examined by an immunohistochemical study of 75 cases of epithelioid mesothelioma and 67 cases of pulmonary adenocarcinoma. The positive rates of DAB2 and Intelectin-1 expression in epithelioid mesothelioma were 80.0% and 76.0%, respectively, and 3.0% and 0%, respectively, in pulmonary adenocarcinoma. Immunohistochemically, the sensitivity and specificity of DAB2 was 80% and 97% and those of Intelectin-1 were 76% and 100% for differentiation of epithelioid mesothelioma from pulmonary adenocarcinoma. In conclusion, DAB2 and Intelectin-1 are newly identified positive markers of mesothelioma and have potential to be included in future immunohistochemical marker panels for differentiation of epithelioid mesothelioma from pulmonary adenocarcinoma.

Zhu XH, Wang JM, Yang SS, et al.
Down-regulation of DAB2IP promotes colorectal cancer invasion and metastasis by translocating hnRNPK into nucleus to enhance the transcription of MMP2.
Int J Cancer. 2017; 141(1):172-183 [PubMed] Related Publications
DOC-2/DAB2 interacting protein (DAB2IP) is a RasGAP protein that shows a suppressive effect on cancer progression. Our previous study showed the involvement of transcription regulation of DAB2IP in metastasis of colorectal cancer (CRC). However, the molecular mechanisms of DAB2IP in regulating the progression of CRC need to be further explored. Here, we identified heterogeneous nuclear ribonucleoprotein K (hnRNPK) and matrix metalloproteinase 2 (MMP2) as vital downstream targets of DAB2IP in CRC cells by two-dimensional fluorescence difference gel electrophoresis and cDNA microassay, respectively. Mechanistically, down-regulation of DAB2IP increased the level of hnRNPK through MAPK/ERK signaling pathway. Subsequently, translocation of hnRNPK into nucleus enhanced the transcription activity of MMP2, and therefore promoted invasion and metastasis of CRC. Down-regulation of DAB2IP correlated negatively with hnRNPK and MMP2 expressions in CRC tissues. In conclusion, our study elucidates a novel mechanism of the DAB2IP/hnRNPK/MMP2 axis in the regulation of CRC invasion and metastasis, which may be a potential therapeutic target.

van der Heijden AG, Mengual L, Lozano JJ, et al.
A five-gene expression signature to predict progression in T1G3 bladder cancer.
Eur J Cancer. 2016; 64:127-36 [PubMed] Related Publications
OBJECTIVE: The aim of this study was to analyze tumour gene expression profiles of progressive and non-progressive T1G3 bladder cancer (BC) patients to develop a gene expression signature to predict tumour progression.
METHODS: Retrospective, multicenter study of 96 T1G3 BC patients without carcinoma in situ (CIS) who underwent a transurethral resection. Formalin-fixed paraffin-embedded tissue samples were collected. Global gene expression patterns were analyzed in 21 selected samples from progressive and non-progressive T1G3 BC patients using Illumina microarrays. Expression levels of 94 genes selected based on microarray data and based on literature were studied by quantitative polymerase chain reaction (qPCR) in an independent series of 75 progressive and non-progressive T1G3 BC patients. Univariate logistic regression was used to identify individual predictors. A variable selection method was used to develop a multiplex biomarker model. Discrimination of the model was measured by area under the receiver-operating characteristic curve. Interaction networks between the genes of the model were built by GeneMANIA Cytoscape plugin.
RESULTS: A total of 1294 genes were found differentially expressed between progressive and non-progressive patients. Differential expression of 15 genes was validated by qPCR in an additional set of samples. A five-gene expression signature (ANXA10, DAB2, HYAL2, SPOCD1, and MAP4K1) discriminated progressive from non-progressive T1G3 BC patients with a sensitivity of 79% and a specificity of 86% (AUC = 0.83). Direct interactions between the five genes of the model were not found.
CONCLUSIONS: Progressive and non-progressive T1G3 bladder tumours have shown different gene expression patterns. To identify T1G3 BC patients with a high risk of progression, a five-gene expression signature has been developed.

Wang P, Henning SM, Magyar CE, et al.
Green tea and quercetin sensitize PC-3 xenograft prostate tumors to docetaxel chemotherapy.
J Exp Clin Cancer Res. 2016; 35:73 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Chemotherapy with docetaxel (Doc) remains the standard treatment for metastatic and castration-resistance prostate cancer (CRPC). However, the clinical success of Doc is limited by its chemoresistance and side effects. This study investigated whether natural products green tea (GT) and quercetin (Q) enhance the therapeutic efficacy of Doc in CRPC in mouse models.
METHODS: Male severe combined immunodeficiency (SCID) mice (n = 10 per group) were inoculated with androgen-independent prostate cancer PC-3 cells subcutaneously. When tumors were established the intervention started. Mice were administered with GT + Q, Doc 5 mg/kg (LD), GT + Q + LD Doc, Doc 10 mg/kg (HD) or control. The concentration of GT polyphenols in brewed tea administered as drinking water was 0.07% and Q was supplemented in diet at 0.4%. Doc was intravenously injected weekly for 4 weeks, GT and Q given throughout the study.
RESULTS: GT + Q or LD Doc slightly inhibited tumor growth compared to control. However, the combination of GT and Q with LD Doc significantly enhanced the potency of Doc 2-fold and reduced tumor growth by 62% compared to LD Doc in 7-weeks intervention. A decrease of Ki67 and increase of cleaved caspase 7 were observed in tumors by the mixture, along with lowered blood concentrations of growth factors like VEGF and EGF. The mixture significantly elevated the levels of tumor suppressor mir15a and mir330 in tumor tissues. An increased risk of liver toxicity was only observed with HD Doc treatment.
CONCLUSIONS: These results provide a promising regimen to enhance the therapeutic effect of Doc in a less toxic manner.

Li X, Dai X, Wan L, et al.
Smurf1 regulation of DAB2IP controls cell proliferation and migration.
Oncotarget. 2016; 7(18):26057-69 [PubMed] Free Access to Full Article Related Publications
Tumor cell proliferation, survival and migration are regulated by the deletion of ovarian carcinoma 2/disabled homolog 2 (DOC-2/DAB2) interacting protein (DAB2IP), a tumor suppressor that serves as a scaffold protein for H-Ras and TRAF2. Importantly, the oncogenic histone methyl-transferase EZH2 epigenetically down-regulates DAB2IP in a variety of tumors. Recently, we demonstrated that DAB2IP is negatively regulated by Akt-dependent phosphorylation and SCFFbw7-mediated degradation. Here, we further identify the oncoprotein Smurf1, an E3-ubiquitin ligase, as a novel negative regulator of DAB2IP. Smurf1-mediated cellular proliferation and migration are largely dependent on the presence of DAB2IP, suggesting that DAB2IP is a key effector molecule of Smurf1 oncogenic function. Additionally, we identify that similar to DAB2IP, Smurf1 is also a target of phosphorylation by both Akt1 and Akt2 kinases, which enhances Smurf1 abundance, leading to a reduction in DAB2IP. Given the role of DAB2IP in tumorigenesis and metastasis, our data identify Smurf1 as an upstream oncogenic factor that negatively regulates DAB2IP to govern aberrant cell growth and migration.

Zhao X, Cai H, Wang X, Ma L
Discovery of signature genes in gastric cancer associated with prognosis.
Neoplasma. 2016; 63(2):239-45 [PubMed] Related Publications
Gene expression profiles of gastric cancer (GC) were analyzed with bioinformatics tools to identify signature genes associated with prognosis. Four gene expression data sets (accession number: GSE2685, GSE30727, GSE38932 and GSE26253) were downloaded from Gene Expression Omnibus. Differentially expressed genes (DEGs) were screened out using significance analysis of microarrays (SAM) algorithm. P-value 1 were set as the threshold. A co-expression network was constructed for the GC-related genes with package WGCNA of R. Modules were disclosed with WGCNA algorithm. Survival-related signature genes were screened out via COX single-variable regression.A total of 3210 GC-related genes were identified from the 3 data sets. Significantly enriched GO biological process terms included cell death, cell proliferation, apoptosis, response to hormone and phosphorylation. Pathways like viral carcinogenesis, metabolism, EBV viral infection, and PI3K-AKT signaling pathway were significantly over-represented in the DEGs. A gene co-expression network including 2414 genes was constructed, from which 7 modules were revealed. A total of 17 genes were identified as signature genes, such as DAB2, ALDH2, CD58, CITED2, BNIP3L, SLC43A2, FAU and COL5A1.Many signature genes associated with prognosis of GC were identified in present study, some of which have been implicated in the pathogenesis of GC. These findings could not only improve the knowledge about GC, but also provide clues for clinical treatments.

Cheng Y, Guo Y, Zhang Y, et al.
MicroRNA-106b is involved in transforming growth factor β1-induced cell migration by targeting disabled homolog 2 in cervical carcinoma.
J Exp Clin Cancer Res. 2016; 35:11 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: MicroRNA-106b (miR-106b) was recently identified as an oncogene participating in cancer progression. Transforming growth factor β1(TGF-β1) is an indispensable cytokine regulating the local microenvironment, thereby promoting cervical cancer progression. However, the roles of miR-106b in cervical carcinoma progression and TGF-β1-involvement in the tumorigenesis of cervical cancer remain unknown.
METHODS: The expression of miR-106b in human cervical specimens was detected by real-time PCR analysis and in situ hybridization assay. The effect of miR-106b on cell migration was analyzed by scratch and transwell assays. TGF-β1 was used to induce cell migration. The expression of the miR-106b target gene DAB2 in human cervical tissues and cell lines were measured by qRT-PCR, western blot and immunohistochemistry. Dual-luciferase reporter assay was used to identify DAB2 as a miR-106b-directed target gene.
RESULTS: miR-106b was frequently up-regulated in human cervical carcinoma specimens and cervical cancer cell lines. Over-expression of miR-106b significantly promoted HeLa and SiHa cells migration. Likewise, inhibition of miR-106b decreased HeLa and SiHa cells migration. The multifunctional cytokine TGF-β facilitates metastasis in cervical carcinoma. miR-106b inhibitor treatment decreased the TGF-β1-stimulated migration of HeLa and SiHa cells. DAB2, a predicted target gene of miR-106b, was inhibited by TGF-β1 partly through miR-106b and was involved in TGF-β1-induced cervical cancer cell migration. The expression of DAB2 was low in cervical cancer tissues, and negatively correlated with miR-106b expression. Finally, DAB2 was identified as a miR-106b-directed target gene by dual-luciferase reporter assay.
CONCLUSION: Our data suggest that the TGF-β1/miR-106b/DAB2 axis may be involved in the pathogenesis of cervical carcinoma.

Liu L, Xu C, Hsieh JT, et al.
DAB2IP in cancer.
Oncotarget. 2016; 7(4):3766-76 [PubMed] Free Access to Full Article Related Publications
DOC-2/DAB2 is a member of the disable gene family that features tumor-inhibiting activity. The DOC-2/DAB2 interactive protein, DAB2IP, is a new member of the Ras GTPase-activating protein family. It interacts directly with DAB2 and has distinct cellular functions such as modulating different signal cascades associated with cell proliferation, survival, apoptosis and metastasis. Recently, DAB2IP has been found significantly down regulated in multiple types of cancer. The aberrant alteration of DAB2IP in cancer is caused by a variety of mechanisms, including the aberrant promoter methylation, histone deacetylation, and others. Reduced expression of DAB2IP in neoplasm may indicate a poor prognosis of many malignant cancers. Moreover, DAB2IP stands for a promising direction for developing targeted therapies due to its capacity to inhibit tumor cell growth in vitro and in vivo. Here, we summarize the present understanding of the tumor suppressive role of DAB2IP in cancer progression; the mechanisms underlying the dysregulation of DAB2IP; the gene functional mechanism and the prospects of DAB2IP in the future cancer research.

Xie Y, Zhang Y, Jiang L, et al.
Disabled homolog 2 is required for migration and invasion of prostate cancer cells.
Front Med. 2015; 9(3):312-21 [PubMed] Related Publications
Disabled homolog 2 (DAB2) is frequently deleted or epigenetically silenced in many human cancer cells. Therefore, DAB2 has always been regarded as a tumor suppressor gene. However, the role of DAB2 in tumor progression and metastasis remains unclear. In this study, DAB2 expression was upregulated along with human prostate cancer (PCa) progression. DAB2 overexpression or knockdown effects in LNCaP and PC3 cell lines were verified to address the biological functions of DAB2 in PCa progression and metastasis. LNCaP and PC3 cell lines were generated from human PCa cells with low and high metastatic potentials, respectively. The results showed that DAB2 shRNA knockdown can inhibit the migratory and invasive abilities of PC3 cells, as well as the tumorigenicity, whereas DAB2 overexpression enhanced LNCaP cell migration and invasion. Further investigation showed that DAB2 regulated the cell migration associated genes in PC3 cells, and the differential DAB2 expression between LNCaP and PC3 cells was partly regulated by histone 4 acetylation. Therefore, DAB2 may play an important role in PCa progression and metastasis.

Xu YF, Mao YP, Li YQ, et al.
MicroRNA-93 promotes cell growth and invasion in nasopharyngeal carcinoma by targeting disabled homolog-2.
Cancer Lett. 2015; 363(2):146-55 [PubMed] Related Publications
Dysregulation of microRNAs (miRNAs) has been demonstrated to contribute to malignant progression in nasopharyngeal carcinoma (NPC). We previously reported that miR-93 was significantly upregulated in NPC based on a microarray analysis. However, the potential role and mechanism of action of miR-93 in the initiation and progression of NPC remain largely unknown. Quantitative RT-PCR demonstrated that miR-93 was significantly upregulated in NPC cell lines and clinical specimens. The MTT assay, colony formation assay, anchorage-independent growth, and Transwell migration and invasion assays showed that depletion of miR-93 inhibited NPC cell growth, invasion and migration in vitro and suppressed tumor growth in vivo. Disabled homolog-2 (Dab2) was verified as a miR-93 target gene using Luciferase reporter assays, quantitative RT-PCR and Western blotting and was involved in miR-93-regulated NPC cell growth, invasion and migration. These results indicated that miR-93 plays an important role in the initiation and progression of NPC by targeting Dab2 and the miR-93/Dab2 pathway may contribute to the development of novel therapeutic strategies for NPC in the future.

Westcott JM, Prechtl AM, Maine EA, et al.
An epigenetically distinct breast cancer cell subpopulation promotes collective invasion.
J Clin Invest. 2015; 125(5):1927-43 [PubMed] Free Access to Full Article Related Publications
Tumor cells can engage in a process called collective invasion, in which cohesive groups of cells invade through interstitial tissue. Here, we identified an epigenetically distinct subpopulation of breast tumor cells that have an enhanced capacity to collectively invade. Analysis of spheroid invasion in an organotypic culture system revealed that these "trailblazer" cells are capable of initiating collective invasion and promote non-trailblazer cell invasion, indicating a commensal relationship among subpopulations within heterogenous tumors. Canonical mesenchymal markers were not sufficient to distinguish trailblazer cells from non-trailblazer cells, suggesting that defining the molecular underpinnings of the trailblazer phenotype could reveal collective invasion-specific mechanisms. Functional analysis determined that DOCK10, ITGA11, DAB2, PDFGRA, VASN, PPAP2B, and LPAR1 are highly expressed in trailblazer cells and required to initiate collective invasion, with DOCK10 essential for metastasis. In patients with triple-negative breast cancer, expression of these 7 genes correlated with poor outcome. Together, our results indicate that spontaneous conversion of the epigenetic state in a subpopulation of cells can promote a transition from in situ to invasive growth through induction of a cooperative form of collective invasion and suggest that therapeutic inhibition of trailblazer cell invasion may help prevent metastasis.

Li C, Chen J, Chen T, et al.
Aberrant Hypermethylation at Sites -86 to 226 of DAB2 Gene in Non-Small Cell Lung Cancer.
Am J Med Sci. 2015; 349(5):425-31 [PubMed] Related Publications
BACKGROUND: Lung cancer is now the leading cause of malignant tumor-related deaths worldwide and non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases. Human Disabled-2 (DAB2) was reported to act as a tumor suppressor gene and was found downregulated in numerous cancer types. However, the expression of DAB2 in NSCLC and the mechanism of DAB2 expression regulation remain unclear.
METHODS: DAB2 expression was analyzed by quantitative real-time polymerase chain reaction (PCR) and Western blot in 20 paired primary NSCLC tissues and corresponding normal lung tissues. Immunohistochemistry assay was performed in paired NSCLC tissues from another 20 patients. Methylation status of DAB2 promoter was analyzed using bisulfite sequencing polymerase chain reaction.
RESULTS: DAB2 messenger RNA level was significantly lower in NSCLC tissues than normal tissues in 95.0% of the group of patients under investigation. In addition, NSCLC tissues showed a significant reduction in DAB2 protein when compared with normal tissues. Importantly, 85% of NSCLC tissues (17/20) had high methylation in DAB2 promoter when compared with normal tissues.
CONCLUSIONS: DAB2 expression is decreased in NSCLC, and the frequent methylation event at sites -86 to 226 of the DAB2 gene could contribute to the downregulation of DAB2.

Zhang T, Shen Y, Chen Y, et al.
The ATM inhibitor KU55933 sensitizes radioresistant bladder cancer cells with DAB2IP gene defect.
Int J Radiat Biol. 2015; 91(4):368-78 [PubMed] Related Publications
PURPOSE: Our preliminary results showed that differentially expressed in ovarian cancer-2/disabled homolog 2 (DOC-2/DAB2) interactive protein (DAB2IP), a putative tumor suppressor gene, is down-regulated in bladder cancer (BCa) with aggressive phenotypes. In this study, we investigated how DAB2IP knockdown influenced BCa cell response to ionizing radiation (IR) and discussed possible ways to enhance cell radiosensitivity.
METHODS AND MATERIALS: The small interfering RNA (siRNA) system was implemented to inhibit endogenous DAB2IP expression in two human BCa cell lines, T24 and 5637. Cell sensitivity to IR alone or combined treatment was measured by a colony formation assay (CFA). Western blot was used to determine the phosphorylation levels of ataxia-telangiectasia mutated (ATM), catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs) and related DNA damage repair (DDR) proteins. Immunofluorescence as well as a flow cytometry assay were employed to detect DNA double-strand break (DSB) repair and cell cycle distribution, respectively.
RESULTS: DAB2IP-knockdown of BCa cells (i.e., siDAB2IP) exhibit increased clonogenic survival in response to IR compared with control cells (i.e., siCON) expressing an endogenous level of DAB2IP. The mechanism in siDAB2IP cells could be explained by elevated ATM expression and activation, increased S phase cell distribution as well as faster DSB repair kinetics. 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one (KU55933) significantly sensitized siDAB2IP cells to IR due to inhibition of the phosphorylation of ATM and its downstream targets following IR and slower DSB repair kinetics.
CONCLUSIONS: Loss of DAB2IP expression in BCa cells signifies their radioresistance. KU55933, which suppresses ATM phosphorylation upon irradiation, could be applied in the radiotherapy of BCa patients with a DAB2IP gene defect.

Schimmer BP, Cordova M
Corticotropin (ACTH) regulates alternative RNA splicing in Y1 mouse adrenocortical tumor cells.
Mol Cell Endocrinol. 2015; 408:5-11 [PubMed] Related Publications
The stimulatory effect of ACTH on gene expression is well documented and is thought to be a major mechanism by which ACTH maintains the functional and structural integrity of the gland. Previously, we showed that ACTH regulates the accumulation of over 1200 transcripts in Y1 adrenal cells, including a cluster with functions in alternative splicing of RNA. On this basis, we postulated that some of the effects of ACTH on the transcription landscape of Y1 cells are mediated by alternative splicing. In this study, we demonstrate that ACTH regulates the alternative splicing of four transcripts - Gnas, Cd151, Dab2 and Tia1. Inasmuch as alternative splicing potentially affects transcripts from more than two-thirds of the mouse genome, we suggest that these findings are representative of a genome-wide effect of ACTH that impacts on the mRNA and protein composition of the adrenal cortex.

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

Lai CH, Chang CS, Liu HH, et al.
Sensitization of radio-resistant prostate cancer cells with a unique cytolethal distending toxin.
Oncotarget. 2014; 5(14):5523-34 [PubMed] Free Access to Full Article Related Publications
Cytolethal distending toxin (CDT) produced by Campylobacter jejuni is a genotoxin that induces cell-cycle arrest and apoptosis in mammalian cells. Recent studies have demonstrated that prostate cancer (PCa) cells can acquire radio-resistance when DOC-2/DAB2 interactive protein (DAB2IP) is downregulated. In this study, we showed that CDT could induce cell death in DAB2IP-deficient PCa cells. A combination of CDT and radiotherapy significantly elicited cell death in DAB2IP-deficient PCa cells by inhibiting the repair of ionizing radiation (IR)-induced DNA double-strand break (DSB) during G2/M arrest, which is triggered by ataxia telangiectasia mutated (ATM)-dependent DNA damage checkpoint responses. We also found that CDT administration significantly increased the efficacy of radiotherapy in a xenograft mouse model. These results indicate that CDT can be a potent therapeutic agent for radio-resistant PCa.

Dai X, North BJ, Inuzuka H
Negative regulation of DAB2IP by Akt and SCFFbw7 pathways.
Oncotarget. 2014; 5(10):3307-15 [PubMed] Free Access to Full Article Related Publications
Deletion of ovarian carcinoma 2/disabled homolog 2 (DOC-2/DAB2) interacting protein (DAB2IP), is a tumor suppressor that serves as a scaffold protein involved in coordinately regulating cell proliferation, survival and apoptotic pathways. DAB2IP is epigenetically down-regulated in a variety of tumors through the action of the histone methyltransferase EZH2. Although DAB2IP is transcriptionally down-regulated in a variety of tumors, it remains unclear if other mechanisms contribute to functional inactivation of DAB2IP. Here we demonstrate that DAB2IP can be functionally down-regulated by two independent mechanisms. First, we identified that Akt1 can phosphorylate DAB2IP on S847, which regulates the interaction between DAB2IP and its effector molecules H-Ras and TRAF2. Second, we demonstrated that DAB2IP can be degraded in part through ubiquitin-proteasome pathway by SCF(Fbw7). DAB2IP harbors two Fbw7 phosho-degron motifs, which can be regulated by the kinase, CK1δ. Our data hence indicate that in addition to epigenetic down-regulation, two additional pathways can functional inactivate DAB2IP. Given that DAB2IP has previously been identified to possess direct causal role in tumorigenesis and metastasis, our data indicate that a variety of pathways may pass through DAB2IP to govern cancer development, and therefore highlight DAB2IP agonists as potential therapeutic approaches for future anti-cancer drug development.

Eskova A, Knapp B, Matelska D, et al.
An RNAi screen identifies KIF15 as a novel regulator of the endocytic trafficking of integrin.
J Cell Sci. 2014; 127(Pt 11):2433-47 [PubMed] Related Publications
α2β1 integrin is one of the most important collagen-binding receptors, and it has been implicated in numerous thrombotic and immune diseases. α2β1 integrin is a potent tumour suppressor, and its downregulation is associated with increased metastasis and poor prognosis in breast cancer. Currently, very little is known about the mechanism that regulates the cell-surface expression and trafficking of α2β1 integrin. Here, using a quantitative fluorescence-microscopy-based RNAi assay, we investigated the impact of 386 cytoskeleton-associated or -regulatory genes on α2 integrin endocytosis and found that 122 of these affected the intracellular accumulation of α2 integrin. Of these, 83 were found to be putative regulators of α2 integrin trafficking and/or expression, with no observed effect on the internalization of epidermal growth factor (EGF) or transferrin. Further interrogation and validation of the siRNA screen revealed a role for KIF15, a microtubule-based molecular motor, as a significant inhibitor of the endocytic trafficking of α2 integrin. Our data suggest a novel role for KIF15 in mediating plasma membrane localization of the alternative clathrin adaptor Dab2, thus impinging on pathways that regulate α2 integrin internalization.

Xu S, Zhu J, Wu Z
Loss of Dab2 expression in breast cancer cells impairs their ability to deplete TGF-β and induce Tregs development via TGF-β.
PLoS One. 2014; 9(3):e91709 [PubMed] Free Access to Full Article Related Publications
Dab2 is a multifunctional adapter protein which is frequently under-expressed in a variety of cancers. It is implicated in many critical functions, including several signaling pathways, cell arrangement, differentiation of stem cells, and receptor endocytosis. Transforming growth factor-β (TGF-β) is a secreted multifunctional protein that controls several developmental processes and pathogenesis of many diseases. It has been documented that Dab2 played an important role in TGF-β receptors endocytosis. Here, we present evidence that re-expression of Dab2 in SK-BR-3 cell partially restored its ability to deplete TGF-β in surrounding medium by normalizing the trafficking of TGF-β receptors. We also demonstrate that the difference in TGF-β depletions produced by Dab2 expression was sufficient to impact on the conversion of naive CD4+ T cells to regulatory T cells (Tregs), and thus inhibited the proliferation of T cells. This work revealed a critical result that breast cancer cell was deficient in Dab2 expression and related receptor endocytosis-mediated TGF-β depletion, which may contribute to the accumulation of TGF-β in tumor microenvironment and the induction of immune tolerance.

Zhang Z, Chen Y, Xie X, Tang J
The expression of disabled-2 is common reduced in meningiomas.
Neurol India. 2014 Jan-Feb; 62(1):57-61 [PubMed] Related Publications
AIMS: Disabled-2 (Dab2) is frequently down-regulated in several types of cancers. We examined the expression level of Dab2 in human meningiomas and meningioma cells, aimed to investigate its role in the oncogenesis and development of meningiomas.
MATERIALS AND METHODS: Western blot analysis was employed to detect Dab2 expression in 90 fresh tissues of meningiomas, 10 leptomeninges and two kinds of human malignant meningioma cell lines. Independent samples t-test, analysis of variance, Pearson Chi-square test and likelihood ratio test were used to analyze the expression level of Dab2 and its relations to clinic-pathological characteristics of meningiomas.
RESULTS: Dab2 was significantly down-regulated in classic meningiomas than the atypical or anaplastic meningiomas. The reduced or loss of expression of Dab2 were significantly correlated with the lower classification of meningiomas and negatively correlated with the invasive ability of adjacent tissues. Furthermore, it was reduced or lost in malignant meningioma cell lines (IOMM-Lee and KT21-MG1). The lower classification of meningiomas correlated with previous comorbidities; not with the gender, age of patients and smoking.
CONCLUSIONS: Dab2 is expressed at variable level in meningiomas with different grade of malignancy and probably plays a pivotal role in the early stage of oncogenesis of malignant meningiomas.

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