Grb7 signal transduction protein mediates metastatic progression of esophageal carcinoma

Tanaka, Shinji; Kawaguchi, Hidetoshi; Saeki, Hiroshi; Ohno, Shinji; Wands, Jack R.; Sugimachi, Keizō

doi:10.1002/(sici)1097-4652(200006)183:3<411::aid-jcp14>3.0.co;2-z

Cited by 47 publications

(52 citation statements)

References 22 publications

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“…The importance of Grb7 in tumour progression has been suggested by several studies (Tanaka et al, 1997(Tanaka et al, , 1998(Tanaka et al, , 2000Han and Guan, 1999). Downregulating Grb7 either by anti-sense or siRNA technology has shown to inhibit the invasive (Tanaka et al, Figure 3 Effects of combined treatment with G7-18NATE-P and Doxorubicin on SK-BR-3 breast cancer cells.…”

Section: Discussionmentioning

confidence: 96%

Combination treatment with Grb7 peptide and Doxorubicin or Trastuzumab (Herceptin) results in cooperative cell growth inhibition in breast cancer cells

et al. 2007

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Grb7 has potential importance in the progression of cancer. We have previously identified a novel peptide that binds to the SH2 domain of Grb7 and inhibits its association with several different receptor tyrosine kinases. We have synthesised the Grb7 peptide, G7-18NATE, with two different cell penetrating peptides, Penetratin and Tat. In this study, we have shown that both Penetratin-and Tat-conjugated G7-18NATE peptides are able to inhibit the proliferation of SK-BR-3, ZR-75-30, MDA-MB-361 and MDA-MB-231 breast cancer cells. There was no significant effects on breast cancer MCF-7cells, non-malignant MCF 10A or 3T3 cells. In addition, there was no significant inhibition of proliferation by Penetratin or Tat alone or by their conjugates with arbitrary peptide sequence in any of the cell lines tested. We determined the EC 50 of G7-18NATE-P peptide for SK-BR-3 cell proliferation to be 7.663 Â 10 À6 M. Co-treatment of G7-18NATE-P peptide plus Doxorubicin in SK-BR-3 breast cancer cells resulted in an additional inhibition of proliferation, resulting in 56 and 84% decreases in the Doxorubicin EC 50 value in the presence of 5 Â 10 À6 and 1.0 Â 10 À5 M G7-18NATE-P peptide, respectively. Importantly, the co-treatment with Doxorubicin and the delivery peptide did not change the Doxorubicin EC 50 . Since Grb7 associates with ErbB2, we assessed whether the peptide inhibitor would have a combined effect with a molecule that targets ErbB2, Herceptin. Co-treatment of Herceptin plus 1.0 Â 10 À5 M G7-18NATE-P peptide in SK-BR-3 cells resulted in a 46% decrease in the Herceptin EC 50 value and no decrease following the co-treatment with Herceptin and penetratin alone. This Grb7 peptide has potential to be developed as a therapeutic agent alone, in combination with traditional chemotherapy, or in combination with other targeting molecules.

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Section: Discussionmentioning

confidence: 96%

Combination treatment with Grb7 peptide and Doxorubicin or Trastuzumab (Herceptin) results in cooperative cell growth inhibition in breast cancer cells

et al. 2007

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“…16 GRB7/FAK (focal adhesion kinase) complex formation and its correlation with increased invasion were also reported in esophageal squamous cell carcinomas. 17 Conversely, expression of an antisense GRB7 RNA lowers endogenous grb7 protein levels and suppresses the in vitro invasive phenotype of these cells. 18 It is noteworthy to stress that we found GRB7 and ERBB2 coamplified and coexpressed in invasive adenocarcinoma and high grade intraepithelial neoplasia in Barrett's esophagus.…”

Section: Fish Analysismentioning

confidence: 99%

Coamplification and coexpression of GRB7 and ERBB2 is found in high grade intraepithelial neoplasia and in invasive Barrett's carcinoma

Walch

Specht

Braselmann³

et al. 2004

Intl Journal of Cancer

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The human growth factor receptor-bound protein 7 gene (GRB7), the founding member of a family of adaptor molecules has been shown to regulate cell migration and has been implicated in tumor progression. GRB7 is localized in close proximity to the ERBB2 gene within an amplicon previously identified in Barrett's adenocarcinoma (BCA). We evaluated gene amplification and mRNA expression of GRB7 and ERBB2 in Barrett's carcinoma and its associated precursor lesions to assess their possible role in Barrett's malignant transformation. Copy number and expression levels were analyzed by Q-PCR (GRB7, ERBB2) and QRT-PCR (GRB7, ERBB2) using TaqMan technology and fluorescence in situ hybridization (ERBB2) in a series of 24 laser-microdissected samples of Barrett's carcinomas and 32 samples of associated premalignant lesions. Parallel analysis of gene copy number changes and expression levels demonstrated that GRB7 and ERBB2 displayed concomitant elevated expression levels and increased copy numbers in 32% of Barrett's carcinomas. There was a correlation between GRB7 and ERBB2 in BCA at the DNA level (r s ‫؍‬ 0.76, p < 0.001) and the mRNA level (r s ‫؍‬ 0.89, p < 0.001). Moreover, coamplification (r s ‫؍‬ 0.97, p < 0.001) and coexpression (r s ‫؍‬ 0.81, p < 0.001) of GRB7 and ERBB2 are shown to be already present in a subset of BCA associated high-grade intraepithelial neoplasia (HGIN), possibly reflecting a role of a concerted expression of GRB7 and ERBB2. No alterations, neither gene amplification nor overexpression were detected in Barrett's carcinoma associated low grade intraepithelial neoplasia (LGIN), intestinal metaplasia (IM) and squamous epithelium, indicating that alterations of GRB7 and ERBB2 are late events in the carcinogenesis of Barrett's esophagus. These findings may be of particular interest because the transition from high grade intraepithelial neoplasia to invasive carcinoma is a crucial step in malignant transformation in Barrett's carcinogenesis and might underline the putative role of GRB7 and ERBB2 in cell migration and tumor invasion.

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“…We previously showed that the overexpression of FAK protein was significantly associated with portal venous invasion (17). It was reported that Grb7 protein interacted with and was phosphorylated by FAK under the regulation of matrix-integrin signaling in esophageal carcinoma cells (16). Using immunoblotting and immunoprecipitation methods, we observe a direct interaction of FAK protein with Grb7 protein in HCC cells (data not shown).…”

Section: Discussionmentioning

confidence: 94%

“…Similar studies have been done on a few other carcinomas. For example, it was shown that the Grb7 protein was overexpressed in 14 of 31 (45%) cases as compared with the adjacent normal mucosa, and this finding was significantly correlated with the presence of lymph node metastases in esophageal carcinoma (16). It was observed that DNA and messenger RNA levels of Grb7 were elevated in 32% of Barrett's adenocarcinomas (18).…”

Section: Discussionmentioning

confidence: 97%

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Role of Growth Factor Receptor–Bound Protein 7 in Hepatocellular Carcinoma

Itoh

Taketomi

Tanaka

et al. 2007

Molecular Cancer Research

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The human growth factor receptor -bound protein 7 (Grb7) is an adaptor molecule and is related to cell invasion. In this present study, we investigated the clinical and biological significance of Grb7 expression in human hepatocellular carcinoma (HCC). We reviewed 64 consecutive patients who had undergone liver resection for HCC, and we investigated the correlation between Grb7 expression and clinical outcome. To analyze the biological behavior of Grb7 in vitro and in vivo, we established Grb7 stable knockdown HCC cells using RNA interference technology. The positive staining of Grb7 protein was correlated with portal venous invasion (P < 0.01), hepatic venous invasion (P < 0.01), and intrahepatic metastasis (P < 0.05). Positive expression of Grb7 was significantly correlated with focal adhesion kinase (FAK) protein levels in HCC (P < 0.01). The Grb7-and FAK-positive group showed a significantly poorer prognosis as compared with the Grb7-and FAK-negative group (P < 0.05). Grb7 knockdown HCC cells exhibited significantly lower levels of invasion potential (P < 0.05) and motility (P < 0.05) than the control cells in vitro; moreover, Grb7 knockdown HCC cells showed delayed onset of the tumors compared with the control cells in vivo. Grb7 expression can modulate the invasive phenotype of HCC. Grb7 plays an important role in HCC progression and is strongly associated with expression of FAK. Grb7 could be a therapeutic target in HCC.

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Grb7 signal transduction protein mediates metastatic progression of esophageal carcinoma

Cited by 47 publications

References 22 publications

Combination treatment with Grb7 peptide and Doxorubicin or Trastuzumab (Herceptin) results in cooperative cell growth inhibition in breast cancer cells

Combination treatment with Grb7 peptide and Doxorubicin or Trastuzumab (Herceptin) results in cooperative cell growth inhibition in breast cancer cells

Coamplification and coexpression of GRB7 and ERBB2 is found in high grade intraepithelial neoplasia and in invasive Barrett's carcinoma

Role of Growth Factor Receptor–Bound Protein 7 in Hepatocellular Carcinoma

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