DOC-2/hDab2, a candidate tumor suppressor gene involved in the development of gestational trophoblastic diseases

Fülöp, Vilmos; Colitti, Cristiano V.; Genest, David R.; Berkowitz, Ross S.; Yiu, Gary K.; Ng, Sook Kien; Szepesi, János; Mok, Samuel C.

doi:10.1038/sj.onc.1201955

Cited by 95 publications

(61 citation statements)

References 14 publications

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“…Because this complex is important for the activation of K-ras, the dissociation of Sos/Grb2 may lead to decreased activation of K-ras. Transfection of a full-length DOC-2 cDNA construct into ovarian cancer and choriocarcinoma cell lines significantly reduces their growth rate, both in vitro and in vivo, suggesting a potential function of DOC-2 as a tumor suppressor (Fulop et al, 1998;Mok et al, 1998). However, the importance of DOC-2 in pancreatic cancer, which exhibits a high rate of K-ras Received February 14, 2001.…”

Section: Doc-2/hdab2mentioning

confidence: 99%

“…Western blot analysis demonstrated a 105-kd protein band (Fulop et al, 1998) that was moderately-to-strongly present in seven of eight (88%) cancer samples (Fig. 1B) and absent in the normal pancreatic tissue samples (Fig.…”

Section: Western Blot Analysis In Pancreatic Tissuesmentioning

confidence: 99%

“…Antiserum (␣M2) raised against a synthetic peptide (IDEKTGVI EHEH PVNKIS) was used as a primary antibody (polyclonal rabbit anti-DOC-2 antibody, dilution of 1:1000). The specificity of the anti-DOC-2 antibody was described previously in detail (Fulop et al, 1998;Mok et al, 1998). Briefly, consecutive 4-m paraffin-embedded tissue sections were deparaffinized and dehydrated.…”

Section: Immunohistochemistrymentioning

confidence: 99%

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DOC-2/hDab2 Expression Is Up-Regulated in Primary Pancreatic Cancer but Reduced in Metastasis

Huang

Friess

Kleeff

et al. 2001

Laboratory Investigation

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SUMMARY:DOC-2/hDab2 (DOC-2) has tumor suppressive functions in ovarian cancer and choriocarcinoma. In these tumors, it negatively influences mitogenic signal transduction of growth factors and blocks ras activity. Pancreatic cancer exhibits a high frequency of K-ras gene mutations; however, it is not known whether DOC-2 expression is altered in these tumors. Therefore, we investigated DOC-2 expression in 22 pancreatic adenocarcinomas and in 6 pancreatic cancer cell lines. Findings in human tumors were compared with normal controls and correlated with clinicopathological data. Additionally, the influence of K-ras on DOC-2 transcription was investigated. Northern blot and Western blot analyses both demonstrated an increase of DOC-2 mRNA and protein levels in primary pancreatic cancers in comparison with normal controls. In situ hybridization showed DOC-2 mRNA expression in the majority of cancer cells of primary tumors, as well as in chronic pancreatitis-like lesions surrounding the cancer mass. Immunohistochemistry mirrored the in situ hybridization findings. In contrast, levels of expression of DOC-2 in lymph node metastases were markedly decreased in comparison with levels in primary tumors. In addition, in 5 metastatic pancreatic cancer cell lines, DOC-2 mRNA and protein levels were low, whereas quantitative RT-PCR demonstrated relatively higher levels in a nonmetastatic pancreatic cancer cell line. In conclusion, DOC-2 is overexpressed in primary pancreatic adenocarcinoma but down-regulated in metastatic disease, suggesting a tumor suppressor function of DOC-2 in the late steps of pancreatic carcinogenesis. (Lab Invest 2001, 81:863-873).P ancreatic adenocarcinomas are the fourth or fifth leading cause of cancer-related death in developed countries, with an average 5-year survival rate of less than 0.5% (Gudjonsson, 1995). The poor prognosis of pancreatic cancer manifests itself by low resection rates, nonresponsiveness to adjuvant or palliative therapy, and a high incidence of recurrence and early metastasis formation following potentially curative resection.It is known that various genetic and epigenetic alterations are involved in the pathogenesis of pancreatic cancer, including overexpression of mitogenic growth factors and growth factor receptors (Friess et al, 1993;Korc et al, 1992), as well as mutations of the K-ras proto-oncogene and p53 and Smad4 tumor suppressor genes (Friess et al, 1998). A better understanding of the underlying molecular mechanisms, including those related to metastasis in this malignancy, will hopefully contribute to improvement of early diagnosis and effective therapy in the future. DOC-2/hDab2(DOC-2) is a candidate tumor suppressor gene that was first isolated by differential RNA display techniques (Liang and Pardee, 1992;Mok et al, 1994). In 1995, Albertsen and coworkers (Albertsen et al, 1996) reported the complete gene sequence of the 3.2-kb DOC-2 transcript and its localization at chromosome 5p13. It was shown that DOC-2 is the human homolog of mouse Dab2, which was cloned f...

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Section: Doc-2/hdab2mentioning

confidence: 99%

Section: Western Blot Analysis In Pancreatic Tissuesmentioning

confidence: 99%

Section: Immunohistochemistrymentioning

confidence: 99%

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DOC-2/hDab2 Expression Is Up-Regulated in Primary Pancreatic Cancer but Reduced in Metastasis

Huang

Friess

Kleeff

et al. 2001

Laboratory Investigation

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“…The mitogen-responsive phosphoprotein DOC2/DAB2, it has been suggested, is an essential component of the TGFbeta signalling pathway (Hocevar et al, 2001). Silencing of the gene has been described in ovarian, choriocarcinoma, pancreatic, prostate, and mammary carcinomas (Fulop et al, 1998;Huang et al, 2001;Mok et al, 1998;Tseng et al, 1999).…”

Section: Down-regulated Genesmentioning

confidence: 99%

Identification of differentially expressed genes in pulmonary adenocarcinoma by using cDNA array

et al. 2002

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No clear patterns in molecular changes underlying the malignant processes in lung cancer of different histological types have been found so far. To identify critical genes in lung cancer progression we compared the expression profile of cancer related genes in 14 pulmonary adenocarcinoma patients with normal lung tissue by using the cDNA array technique. Principal component analyses (PCA) and permutation test were used to detect the differentially expressed genes. The expression profiles of 10 genes were confirmed by semiquantitative real-time RT -PCR. In tumour samples, as compared to normal lung tissue, the up-regulated genes included such known tumour markers as CCNB1, PLK, tenascin, KRT8, KRT19 and TOP2A. The downregulated genes included caveolin 1 and 2, and TIMP3. We also describe, for the first time, down-regulation of the interesting SOCS2 and 3, DOC2 and gravin. We show that silencing of SOCS2 is not caused by methylation of exon 1 of the gene. In conclusion, by using the cDNA array technique we were able to reveal marked differences in the gene expression level between normal lung and tumour tissue and find possible new tumour markers for pulmonary adenocarcinoma.

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“…Similar to other human cancers, neoplastic transformation of trophoblast is likely to be a multistep process and involves multiple genetic alterations including activation of oncogenes and inactivation of tumor suppressor genes. 3,4 Potential biological markers related to malignant transformation of trophoblast include c-erbB-2, 5 cyclin E, 6 DOC-2/hDab2, 7 Ras GTPase activating protein, 8 telomerase activity, 9 apoptotic index, 10,11 and matrix metalloproteinases, 12 but no molecular parameter can currently replace serial serum human chorionic gonadotrophin (hCG) titers as the mainstay for predicting gestational trophoblastic neoplasia.…”

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confidence: 99%

Promoter Hypermethylation of Multiple Genes in Hydatidiform Mole and Choriocarcinoma

Xue

Chan

Feng

et al. 2004

The Journal of Molecular Diagnostics

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The methylation status of genes in hydatidiform mole and choriocarcinoma and its significance is relatively unexplored. We investigated the methylation status of the promoter regions of six genes, p16, HIC-1, TIMP3, GSTP1, death-associated protein kinase (DAPK), and E-cadherin in 54 hydatidiform moles, five choriocarcinomas, and 10 first trimester placenta by methylation-specific polymerase chain reaction (PCR). Immunohistochemical expression of p16, TIMP3, and E-cadherin, and quantitative real-time RT-PCR of p16 was also performed. Among the six genes examined, the promoter region of four genes (E-cadherin, HIC-1, p16, TIMP3) in choriocarcinoma and three genes (E-cadherin, HIC-1, p16) in hydatidiform mole exhibited aberrant methylation whereas none was hypermethylated in normal placenta. There was a significant correlation between methylation and reduced expression of p16, E-cadherin, and TIMP3 (P < 0.001). Fifteen of the 54 patients with hydatidiform mole developed gestational trophoblastic neoplasia requiring chemotherapy. Promoter hypermethylation of p16 alone, or combined with E-cadherin, was significantly correlated to such development (P ‫؍‬ 0.001, 0.0005, respectively). Hypermethylation of multiple genes, especially p16, might be related to the subsequent development of gestational trophoblastic neoplasia. (J Mol Diagn 2004, 6:326 -334)

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DOC-2/hDab2, a candidate tumor suppressor gene involved in the development of gestational trophoblastic diseases

Cited by 95 publications

References 14 publications

DOC-2/hDab2 Expression Is Up-Regulated in Primary Pancreatic Cancer but Reduced in Metastasis

DOC-2/hDab2 Expression Is Up-Regulated in Primary Pancreatic Cancer but Reduced in Metastasis

Identification of differentially expressed genes in pulmonary adenocarcinoma by using cDNA array

Promoter Hypermethylation of Multiple Genes in Hydatidiform Mole and Choriocarcinoma

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