Skip to main content
Top
Published in: BMC Cancer 1/2023

Open Access 01-12-2023 | Gastric Cancer | Research

GRB7 plays a promoting role in the progression of gastric cancer

Authors: Guomin Zhu, Hu Cai, Qiang Xiao, Shukun Zeng, Xiaohua Jiang, Donglan Liu

Published in: BMC Cancer | Issue 1/2023

Login to get access

Abstract

Background

Gastric cancer is a clinically common tumor, showing an upward trend of both incidence and mortality. GRB7 has been identified as a vital regulator in tumor progression. This study aims to uncover the biological function of GRB7 in gastric cancer process.

Methods

immunohistochemical (IHC) staining using a tissue microarray (TMA), quantitative reverse transcription PCR (qRT-PCR) and Western blotting were performed to detect the expression of genes. Furthermore, gastric cancer cell lines AGS and MGC-803 were transfected with short hairpin RNAs against GRB7. The biological function of GRB7 in gastric cancer cells were examined by CCK-8, flow cytometry, wound healing and Transwell assays. Then, in vivo tumor formation assay was conducted to explore the effects of GRB7 on tumor growth. Finally, expression levels of proteins related to cell functions were determined by Western blotting. Coimmunoprecipitation (CoIP) assay was performed to assess the protein-protein interaction.

Results

GRB7 was up-regulated in gastric cancer tissues and cell lines, and its expression was inversely proportional to survival of gastric cancer patients. Moreover, GRB7 knockdown inhibited proliferative, migratory abilities, as well as promoted cell apoptosis in gastric cancer cells. Further study suggested that GRB7 silencing could suppress gastric cancer tumor growth in vivo. Furthermore, our study uncovered an important interaction between GRB7 and MyD88. Silencing MyD88 was observed to alleviate the malignant phenotypes promoted by GRB7 in gastric cancer cells.

Conclusions

Together, this study provided evidence that GRB7 may be an effective molecular targets for the treatment of gastric cancer.
Appendix
Available only for authorised users
Literature
1.
go back to reference Shan C, Zhang Y, Hao X, Gao J, Chen X, Wang K. Biogenesis, functions and clinical significance of circRNAs in gastric cancer. Mol Cancer. 2019;18(1):136.CrossRefPubMedPubMedCentral Shan C, Zhang Y, Hao X, Gao J, Chen X, Wang K. Biogenesis, functions and clinical significance of circRNAs in gastric cancer. Mol Cancer. 2019;18(1):136.CrossRefPubMedPubMedCentral
2.
go back to reference Tani H, Saito N, Kobayashi M, Kameoka S. Clinical significance of keratinocyte growth factor and K-sam gene expression in gastric cancer. Mol Med Rep. 2013;7(5):1381–6.CrossRefPubMedPubMedCentral Tani H, Saito N, Kobayashi M, Kameoka S. Clinical significance of keratinocyte growth factor and K-sam gene expression in gastric cancer. Mol Med Rep. 2013;7(5):1381–6.CrossRefPubMedPubMedCentral
3.
go back to reference Wang X, Zhu G, Yang H, Gao R, Wu Z, Zhang Y, Zhu X, Zhang X, Li J. Radix Rhei Et RhizomeAn Investigation of the Antigastric Cancer Effect in Tumor Microenvironment of: A Network Pharmacology Study. Evid based complement altern med: eCAM. 2021;2021:9913952. Wang X, Zhu G, Yang H, Gao R, Wu Z, Zhang Y, Zhu X, Zhang X, Li J. Radix Rhei Et RhizomeAn Investigation of the Antigastric Cancer Effect in Tumor Microenvironment of: A Network Pharmacology Study. Evid based complement altern med: eCAM. 2021;2021:9913952.
4.
go back to reference Gong X, Zhang H. Diagnostic and prognostic values of anti-helicobacter pylori antibody combined with serum CA724, CA19-9, and CEA for young patients with early gastric cancer. J Clin Lab Anal. 2020;34(7):e23268.CrossRefPubMedPubMedCentral Gong X, Zhang H. Diagnostic and prognostic values of anti-helicobacter pylori antibody combined with serum CA724, CA19-9, and CEA for young patients with early gastric cancer. J Clin Lab Anal. 2020;34(7):e23268.CrossRefPubMedPubMedCentral
5.
go back to reference Abozeid M, Rosato A, Sommaggio R. Immunotherapeutic strategies for gastric carcinoma: a review of preclinical and clinical recent development. Biomed Res Int 2017, 2017:5791262. Abozeid M, Rosato A, Sommaggio R. Immunotherapeutic strategies for gastric carcinoma: a review of preclinical and clinical recent development. Biomed Res Int 2017, 2017:5791262.
6.
go back to reference Sun J, Long Y, Peng X, Xiao D, Zhou J, Tao Y, Liu S. The survival analysis and oncogenic effects of CFP1 and 14-3-3 expression on gastric cancer. Cancer Cell Int. 2019;19:225.CrossRefPubMedPubMedCentral Sun J, Long Y, Peng X, Xiao D, Zhou J, Tao Y, Liu S. The survival analysis and oncogenic effects of CFP1 and 14-3-3 expression on gastric cancer. Cancer Cell Int. 2019;19:225.CrossRefPubMedPubMedCentral
7.
go back to reference Patel T, Cecchini M. Targeted therapies in Advanced Gastric Cancer. Curr Treat Options Oncol. 2020;21(9):70.CrossRefPubMed Patel T, Cecchini M. Targeted therapies in Advanced Gastric Cancer. Curr Treat Options Oncol. 2020;21(9):70.CrossRefPubMed
8.
go back to reference Zhou F, Li N, Jiang W, Hua Z, Xia L, Wei Q, Wang L. Prognosis significance of HER-2/neu overexpression/amplification in Chinese patients with curatively resected gastric cancer after the ToGA clinical trial. World J Surg Oncol. 2012;10:274.CrossRefPubMedPubMedCentral Zhou F, Li N, Jiang W, Hua Z, Xia L, Wei Q, Wang L. Prognosis significance of HER-2/neu overexpression/amplification in Chinese patients with curatively resected gastric cancer after the ToGA clinical trial. World J Surg Oncol. 2012;10:274.CrossRefPubMedPubMedCentral
9.
go back to reference Alcalde J, González-Muñoz M, Villalobo A. Grb7-derived calmodulin-binding peptides inhibit proliferation, migration and invasiveness of Tumor cells while they enhance attachment to the substrate. Heliyon. 2020;6(5):e03922.CrossRefPubMedPubMedCentral Alcalde J, González-Muñoz M, Villalobo A. Grb7-derived calmodulin-binding peptides inhibit proliferation, migration and invasiveness of Tumor cells while they enhance attachment to the substrate. Heliyon. 2020;6(5):e03922.CrossRefPubMedPubMedCentral
10.
go back to reference Zheng Y, Pei Y, Yang L, Zeng Z, Wang J, Xie G, Wang L, Yuan J. Upregulated GRB7 promotes proliferation and tumorigenesis of Bladder Cancer via Phospho-AKT pathway. Int J Biol Sci. 2020;16(16):3221–30.CrossRefPubMedPubMedCentral Zheng Y, Pei Y, Yang L, Zeng Z, Wang J, Xie G, Wang L, Yuan J. Upregulated GRB7 promotes proliferation and tumorigenesis of Bladder Cancer via Phospho-AKT pathway. Int J Biol Sci. 2020;16(16):3221–30.CrossRefPubMedPubMedCentral
11.
go back to reference Ambaye N, Gunzburg M, Lim R, Price J, Wilce M, Wilce J. Benzopyrazine derivatives: a novel class of growth factor receptor bound protein 7 antagonists. Bioorg Med Chem. 2011;19(1):693–701.CrossRefPubMed Ambaye N, Gunzburg M, Lim R, Price J, Wilce M, Wilce J. Benzopyrazine derivatives: a novel class of growth factor receptor bound protein 7 antagonists. Bioorg Med Chem. 2011;19(1):693–701.CrossRefPubMed
12.
go back to reference Pero S, Daly R, Krag D. Grb7-based molecular therapeutics in cancer. Expert Rev Mol Med. 2003;5(14):1–11.CrossRefPubMed Pero S, Daly R, Krag D. Grb7-based molecular therapeutics in cancer. Expert Rev Mol Med. 2003;5(14):1–11.CrossRefPubMed
13.
go back to reference Yu C, Luo D, Yu J, Zhang M, Zheng X, Xu G, Wang J, Wang H, Xu Y, Jiang K et al. Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon Cancer. Oncogene 2021. Yu C, Luo D, Yu J, Zhang M, Zheng X, Xu G, Wang J, Wang H, Xu Y, Jiang K et al. Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon Cancer. Oncogene 2021.
14.
go back to reference Katoh M, Katoh M. MGC9753 gene, located within PPP1R1B-STARD3-ERBB2-GRB7 amplicon on human chromosome 17q12, encodes the seven-transmembrane receptor with extracellular six-cystein domain. Int J Oncol. 2003;22(6):1369–74.PubMed Katoh M, Katoh M. MGC9753 gene, located within PPP1R1B-STARD3-ERBB2-GRB7 amplicon on human chromosome 17q12, encodes the seven-transmembrane receptor with extracellular six-cystein domain. Int J Oncol. 2003;22(6):1369–74.PubMed
15.
go back to reference Liu H, Qin Y, Zhou N, Ma D, Wang Y. ZNF280A promotes lung adenocarcinoma development by regulating the expression of EIF3C. Cell Death Dis. 2021;12(1):39.CrossRefPubMedPubMedCentral Liu H, Qin Y, Zhou N, Ma D, Wang Y. ZNF280A promotes lung adenocarcinoma development by regulating the expression of EIF3C. Cell Death Dis. 2021;12(1):39.CrossRefPubMedPubMedCentral
16.
go back to reference Gaweł AM, Ratajczak M, Gajda E, Grzanka M, Paziewska A, Cieślicka M, Kulecka M, Oczko-Wojciechowska M, Godlewska M. Analysis of the role of FRMD5 in the Biology of Papillary thyroid carcinoma. Int J Mol Sci 2021, 22(13). Gaweł AM, Ratajczak M, Gajda E, Grzanka M, Paziewska A, Cieślicka M, Kulecka M, Oczko-Wojciechowska M, Godlewska M. Analysis of the role of FRMD5 in the Biology of Papillary thyroid carcinoma. Int J Mol Sci 2021, 22(13).
17.
go back to reference Mejías-Luque R, Lozano-Pope I, Wanisch A, Heikenwälder M, Gerhard M, Obonyo M. Increased LIGHT expression and activation of non-canonical NF-κB are observed in gastric lesions of MyD88-deficient mice upon Helicobacter felis Infection. Sci Rep. 2019;9(1):7030.CrossRefPubMedPubMedCentral Mejías-Luque R, Lozano-Pope I, Wanisch A, Heikenwälder M, Gerhard M, Obonyo M. Increased LIGHT expression and activation of non-canonical NF-κB are observed in gastric lesions of MyD88-deficient mice upon Helicobacter felis Infection. Sci Rep. 2019;9(1):7030.CrossRefPubMedPubMedCentral
18.
go back to reference Chu P, Tai Y, Shen T. Grb7, a critical mediator of EGFR/ErbB signaling, in Cancer Development and as a potential therapeutic target. Cells 2019, 8(5). Chu P, Tai Y, Shen T. Grb7, a critical mediator of EGFR/ErbB signaling, in Cancer Development and as a potential therapeutic target. Cells 2019, 8(5).
19.
go back to reference Gotovac J, Liu D, Yates M, Milne J, Macpherson A, Simpson K, Eslick G, Mitchell C, Duong C, Phillips W, et al. GRB7 is an oncogenic driver and potential therapeutic target in oesophageal adenocarcinoma. J Pathol. 2020;252(3):317–29.CrossRefPubMedPubMedCentral Gotovac J, Liu D, Yates M, Milne J, Macpherson A, Simpson K, Eslick G, Mitchell C, Duong C, Phillips W, et al. GRB7 is an oncogenic driver and potential therapeutic target in oesophageal adenocarcinoma. J Pathol. 2020;252(3):317–29.CrossRefPubMedPubMedCentral
20.
go back to reference Tang H, Yang P, Yang X, Peng S, Hu X, Bao G. Growth factor receptor bound protein-7 regulates proliferation, cell cycle, and mitochondrial apoptosis of thyroid cancer cells via MAPK/ERK signaling. Mol Cell Biochem. 2020;472:209–18.CrossRefPubMed Tang H, Yang P, Yang X, Peng S, Hu X, Bao G. Growth factor receptor bound protein-7 regulates proliferation, cell cycle, and mitochondrial apoptosis of thyroid cancer cells via MAPK/ERK signaling. Mol Cell Biochem. 2020;472:209–18.CrossRefPubMed
21.
go back to reference Wang C, Yin W, Chen P. MicroRNA-374a-5p promotes metastasis of colorectal cancer by targeting GRB7. Panminerva medica. 2020. Wang C, Yin W, Chen P. MicroRNA-374a-5p promotes metastasis of colorectal cancer by targeting GRB7. Panminerva medica. 2020.
22.
go back to reference Chen K, Liu M, Mak C, Yung M, Leung T, Xu D, Ngu S, Chan K, Yang H, Ngan H, et al. miR-193a-3pMethylation-associated silencing of promotes Ovarian cancer aggressiveness by targeting GRB7 and MAPK/ERK pathways. Theranostics. 2018;8(2):423–36.CrossRefPubMedPubMedCentral Chen K, Liu M, Mak C, Yung M, Leung T, Xu D, Ngu S, Chan K, Yang H, Ngan H, et al. miR-193a-3pMethylation-associated silencing of promotes Ovarian cancer aggressiveness by targeting GRB7 and MAPK/ERK pathways. Theranostics. 2018;8(2):423–36.CrossRefPubMedPubMedCentral
23.
go back to reference Paudyal P, Shrestha S, Madanayake T, Shuster C, Rohrschneider L, Rowland A, Lyons B. Grb7 and Filamin-a associate and are colocalized to cell membrane ruffles upon EGF stimulation. J Mol Recognition: JMR. 2013;26(11):532–41.CrossRef Paudyal P, Shrestha S, Madanayake T, Shuster C, Rohrschneider L, Rowland A, Lyons B. Grb7 and Filamin-a associate and are colocalized to cell membrane ruffles upon EGF stimulation. J Mol Recognition: JMR. 2013;26(11):532–41.CrossRef
24.
go back to reference Pero S, Oligino L, Daly R, Soden A, Liu C, Roller P, Li P, Krag D. Identification of novel non-phosphorylated ligands, which bind selectively to the SH2 domain of Grb7. J Biol Chem. 2002;277(14):11918–26.CrossRefPubMed Pero S, Oligino L, Daly R, Soden A, Liu C, Roller P, Li P, Krag D. Identification of novel non-phosphorylated ligands, which bind selectively to the SH2 domain of Grb7. J Biol Chem. 2002;277(14):11918–26.CrossRefPubMed
25.
go back to reference de Oliveira Peixoto J, Savoldi I, Ibelli A, Cantão M, Jaenisch F, Giachetto P, Settles M, Zanella R, Marchesi J, Pandolfi J, et al. Proximal femoral head transcriptome reveals novel candidate genes related to epiphysiolysis in broiler chickens. BMC Genomics. 2019;20(1):1031.CrossRefPubMedPubMedCentral de Oliveira Peixoto J, Savoldi I, Ibelli A, Cantão M, Jaenisch F, Giachetto P, Settles M, Zanella R, Marchesi J, Pandolfi J, et al. Proximal femoral head transcriptome reveals novel candidate genes related to epiphysiolysis in broiler chickens. BMC Genomics. 2019;20(1):1031.CrossRefPubMedPubMedCentral
26.
go back to reference Zhou Y, Li Y, Zheng J, Liu K, Zhang H. Detecting of gastric cancer by Bcl-2 and Ki67. Int J Clin Exp Pathol. 2015;8(6):7287–90.PubMedPubMedCentral Zhou Y, Li Y, Zheng J, Liu K, Zhang H. Detecting of gastric cancer by Bcl-2 and Ki67. Int J Clin Exp Pathol. 2015;8(6):7287–90.PubMedPubMedCentral
27.
go back to reference Wang Y, Chan D, Liu V, Chiu P, Ngan H. Differential functions of growth factor receptor-bound protein 7 (GRB7) and its variant GRB7v in ovarian carcinogenesis. Clin cancer Research: Official J Am Association Cancer Res. 2010;16(9):2529–39.CrossRef Wang Y, Chan D, Liu V, Chiu P, Ngan H. Differential functions of growth factor receptor-bound protein 7 (GRB7) and its variant GRB7v in ovarian carcinogenesis. Clin cancer Research: Official J Am Association Cancer Res. 2010;16(9):2529–39.CrossRef
28.
go back to reference Lu F, Yang H, Lin SD, Zhao L, Jiang C, Chen ZB, Liu YY, Kan YJ, Hu J, Pang WS. Cyclic peptide extracts derived from Pseudostellaria heterophylla ameliorates COPD via Regulation of the TLR4/MyD88 pathway proteins. Front Pharmacol. 2020;11:850.CrossRefPubMedPubMedCentral Lu F, Yang H, Lin SD, Zhao L, Jiang C, Chen ZB, Liu YY, Kan YJ, Hu J, Pang WS. Cyclic peptide extracts derived from Pseudostellaria heterophylla ameliorates COPD via Regulation of the TLR4/MyD88 pathway proteins. Front Pharmacol. 2020;11:850.CrossRefPubMedPubMedCentral
29.
go back to reference Patra MC, Choi S. Recent progress in the Molecular Recognition and Therapeutic Importance of Interleukin-1 receptor-Associated kinase 4. Molecules 2016, 21(11). Patra MC, Choi S. Recent progress in the Molecular Recognition and Therapeutic Importance of Interleukin-1 receptor-Associated kinase 4. Molecules 2016, 21(11).
30.
go back to reference Chen J, Xia D, Xu M, Su R, Lin W, Guo D, Chen G, Liu S. Expression and significance of MyD88 in patients with gastric Cardia Cancer in a high-incidence area of China. Front Oncol. 2020;10:559.CrossRefPubMedPubMedCentral Chen J, Xia D, Xu M, Su R, Lin W, Guo D, Chen G, Liu S. Expression and significance of MyD88 in patients with gastric Cardia Cancer in a high-incidence area of China. Front Oncol. 2020;10:559.CrossRefPubMedPubMedCentral
31.
go back to reference Vogelaar I, Ligtenberg M, van der Post R, de Voer R, Kets C, Jansen T, Jacobs L, Schreibelt G, de Vries I, Netea M, et al. Recurrent candidiasis and early-onset gastric cancer in a patient with a genetically defined partial MYD88 defect. Fam Cancer. 2016;15(2):289–96.CrossRefPubMed Vogelaar I, Ligtenberg M, van der Post R, de Voer R, Kets C, Jansen T, Jacobs L, Schreibelt G, de Vries I, Netea M, et al. Recurrent candidiasis and early-onset gastric cancer in a patient with a genetically defined partial MYD88 defect. Fam Cancer. 2016;15(2):289–96.CrossRefPubMed
32.
go back to reference Chalmers SA, Eidelman AS, Ewer JC, Ricca JM, Serrano A, Tucker KC, Vail CM, Kurt RA. A role for HMGB1, HSP60 and Myd88 in growth of murine mammary carcinoma in vitro. Cell Immunol. 2013;282(2):136–45.CrossRefPubMedPubMedCentral Chalmers SA, Eidelman AS, Ewer JC, Ricca JM, Serrano A, Tucker KC, Vail CM, Kurt RA. A role for HMGB1, HSP60 and Myd88 in growth of murine mammary carcinoma in vitro. Cell Immunol. 2013;282(2):136–45.CrossRefPubMedPubMedCentral
Metadata
Title
GRB7 plays a promoting role in the progression of gastric cancer
Authors
Guomin Zhu
Hu Cai
Qiang Xiao
Shukun Zeng
Xiaohua Jiang
Donglan Liu
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2023
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-023-11694-5

Other articles of this Issue 1/2023

BMC Cancer 1/2023 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine