Up-regulated GRB7 protein in gastric cancer cells correlates with clinical properties and increases proliferation and stem cell properties

Pei, Yuanyuan; Ran, Jian; Wen, L.; Liu, Xiaoyi; Li, Xiang; Liu, Weiqiang; Wei, Fengxiang

doi:10.3389/fonc.2022.1054976

Cited by 5 publications

(1 citation statement)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GRB7 has been linked with several tissues in the context of cancer progression, including liver (hepatocellular carcinoma [72]) and pancreas [73], and a contribution to Insr signalling functions in these tissues cannot be excluded. The strong Grb7 expression we observed in the developing gut epithelium is interesting in view of evidence that GRB7 has an oncogenic role in cancers of the intestinal tract, including those of the oesophagus [74], stomach [75] and colon [76].…”

Section: Discussionmentioning

confidence: 98%

Grb7,Grb10andGrb14,encoding the growth factor receptor-bound 7 family of signalling adaptor proteins have overlapping functions in the regulation of fetal growth and post-natal glucose metabolism

Moorwood,

Smith,

Garfield

et al. 2024

Preprint

View full text Add to dashboard Cite

BackgroundThe growth factor receptor bound 7 (Grb7) family of signalling adaptor proteins comprises Grb7, Grb10 and Grb14. Each can interact with the insulin receptor and other receptor tyrosine kinases, where Grb10 and Grb14 inhibit insulin receptor activity. In cell culture studies they mediate functions including cell survival, proliferation, and migration. Mouse knockout (KO) studies have revealed physiological roles forGrb10andGrb14in glucose-regulated energy homeostasis. BothGrb10KO andGrb14KO mice exhibit increased insulin signalling in peripheral tissues, with increased glucose and insulin sensitivity and a modestly increased ability to clear a glucose load. In addition,Grb10strongly inhibits fetal growth such that at birthGrb10KO mice are 30% larger by weight than wild type littermates.ResultsHere, we generate aGrb7KO mouse model. We show that during fetal development the expression patterns of Grb7 and Grb14 each overlap with that of Grb10. Despite this,Grb7andGrb14did not have a major role in influencing fetal growth, either alone or in combination withGrb10. At birth, in most respects bothGrb7KO andGrb14KO single mutants were indistinguishable from wild type, whileGrb7:Grb10double knockout (DKO) were near identical toGrb10KO single mutant andGrb10:Grb14DKO mutants slightly smaller. In the developing kidneyGrb7had a subtle positive influence on growth. An initial characterisation ofGrb7KO adult mice revealed sexually dimorphic effects on energy homeostasis, with females having significantly smaller white adipose tissue (WAT) depots and an enhanced ability to clear glucose from the circulation, compared to wild type littermates. Males had elevated fasted glucose levels with a trend towards smaller WAT depots, without improved glucose clearance.ConclusionsGrb7andGrb14do not have significant roles as inhibitors of fetal growth, unlikeGrb10, and insteadGrb7may promote growth of the developing kidney. In adulthood,Grb7contributes subtly to glucose mediated energy homeostasis, raising the possibility of redundancy between all three adaptors in physiological regulation of insulin signalling and glucose handling.

show abstract

Section: Discussionmentioning

confidence: 98%

Grb7,Grb10andGrb14,encoding the growth factor receptor-bound 7 family of signalling adaptor proteins have overlapping functions in the regulation of fetal growth and post-natal glucose metabolism

Moorwood,

Smith,

Garfield

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

Grb7, Grb10 and Grb14, encoding the growth factor receptor-bound 7 family of signalling adaptor proteins have overlapping functions in the regulation of fetal growth and post-natal glucose metabolism

Moorwood,

Smith,

Garfield

et al. 2024

BMC Biol

View full text Add to dashboard Cite

Background The growth factor receptor bound protein 7 (Grb7) family of signalling adaptor proteins comprises Grb7, Grb10 and Grb14. Each can interact with the insulin receptor and other receptor tyrosine kinases, where Grb10 and Grb14 inhibit insulin receptor activity. In cell culture studies they mediate functions including cell survival, proliferation, and migration. Mouse knockout (KO) studies have revealed physiological roles for Grb10 and Grb14 in glucose-regulated energy homeostasis. Both Grb10 KO and Grb14 KO mice exhibit increased insulin signalling in peripheral tissues, with increased glucose and insulin sensitivity and a modestly increased ability to clear a glucose load. In addition, Grb10 strongly inhibits fetal growth such that at birth Grb10 KO mice are 30% larger by weight than wild type littermates. Results Here, we generate a Grb7 KO mouse model. We show that during fetal development the expression patterns of Grb7 and Grb14 each overlap with that of Grb10. Despite this, Grb7 and Grb14 did not have a major role in influencing fetal growth, either alone or in combination with Grb10. At birth, in most respects both Grb7 KO and Grb14 KO single mutants were indistinguishable from wild type, while Grb7:Grb10 double knockout (DKO) were near identical to Grb10 KO single mutants and Grb10:Grb14 DKO mutants were slightly smaller than Grb10 KO single mutants. In the developing kidney Grb7 had a subtle positive influence on growth. An initial characterisation of Grb7 KO adult mice revealed sexually dimorphic effects on energy homeostasis, with females having a significantly smaller renal white adipose tissue depot and an enhanced ability to clear glucose from the circulation, compared to wild type littermates. Males had elevated fasted glucose levels with a trend towards smaller white adipose depots, without improved glucose clearance. Conclusions Grb7 and Grb14 do not have significant roles as inhibitors of fetal growth, unlike Grb10, and instead Grb7 may promote growth of the developing kidney. In adulthood, Grb7 contributes subtly to glucose mediated energy homeostasis, raising the possibility of redundancy between all three adaptors in physiological regulation of insulin signalling and glucose handling.

show abstract

TCF12-regulated GRB7 facilitates the HER2+ breast cancer progression by activating Notch1 signaling pathway

Wang,

Wu,

et al. 2024

J Transl Med

View full text Add to dashboard Cite

Background Human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC), which accounts for approximately one-fifth of all BCs, are highly invasive with a high rate of recurrence and a poor prognosis. Several studies have shown that growth factor receptor-bound protein 7 (GRB7) might be a potential therapeutic target for tumor diagnosis and prognosis. Nevertheless, the role of GRB7 in HER2+ BC and its underlying mechanisms have not been fully elucidated. The aim of this study was to investigate the biological function and regulatory mechanism of GRB7 in HER2+ BC. Methods Bioinformatics analysis was performed using the TCGA, GEO and CancerSEA databases to evaluate the clinical significance of GRB7. RT quantitative PCR, western blot and immunofluorescence were conducted to assess the expression of GRB7 in BC cell lines and tissues. MTT, EdU, colony formation, wound healing, transwell, and xenograft assays were adopted to explore the biological function of GRB7 in HER2+ BC. RNA sequencing was performed to analyze the signaling pathways associated with GRB7 in SK-BR-3 cells after the cells were transfected with GRB7 siRNA. Chromatin immunoprecipitation analysis (ChIP) and luciferase reporter assay were employed to elucidate the potential molecular regulatory mechanisms of GRB7 in HER2+ BC. Results GRB7 was markedly upregulated and associated with poor prognosis in BC, especially in HER2+ BC. Overexpression of GRB7 increased the proliferation, migration, invasion, and colony formation of HER2+ BC cells, while depletion of GRB7 had the opposite effects in HER2+ BC cells and inhibited xenograft growth. ChIP-PCR and luciferase reporter assay revealed that TCF12 directly bound to the promoter of the GRB7 gene to promote its transcription. GRB7 facilitated HER2+ BC epithelial-mesenchymal transition (EMT) progression by interacting with Notch1 to activate Wnt/β-catenin pathways and other signaling (i.e., AKT, ERK). Moreover, forced GRB7 overexpression activated Wnt/β-catenin to promote EMT progression, and partially rescued the inhibition of HER2+ BC proliferation, migration and invasion induced by TCF12 silencing. Conclusions Our work elucidates the oncogenic role of GRB7 in HER2+ BC, which could serve as a prognostic indicator and promising therapeutic target. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-024-05536-6.

show abstract

Up-regulated GRB7 protein in gastric cancer cells correlates with clinical properties and increases proliferation and stem cell properties

Cited by 5 publications

References 38 publications

Grb7,Grb10andGrb14,encoding the growth factor receptor-bound 7 family of signalling adaptor proteins have overlapping functions in the regulation of fetal growth and post-natal glucose metabolism

Grb7,Grb10andGrb14,encoding the growth factor receptor-bound 7 family of signalling adaptor proteins have overlapping functions in the regulation of fetal growth and post-natal glucose metabolism

Grb7, Grb10 and Grb14, encoding the growth factor receptor-bound 7 family of signalling adaptor proteins have overlapping functions in the regulation of fetal growth and post-natal glucose metabolism

TCF12-regulated GRB7 facilitates the HER2+ breast cancer progression by activating Notch1 signaling pathway

Contact Info

Product

Resources

About