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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
Tyrosine phosphatase SHP2 accelerated ovarian cancer via modulating integrin/ E-Cadherin/ ZEB1 induced EMT
Xiaofei Li1, Haibo Zhang1, Jianan Dong1
1Department of Obstetrics and Gynecology, The Fourth Hospital of Hebei Medical University, No.12, Health Road, Shijiazhuang City, 050011, Hebei Province, China.
Abstract:
This article focusing on examining the function and further, molecular function of SHP2 in ovarian cancer (OC). For the molecular mechanism, bioinformatics was applied to study the specifically expressed genes in ovarian cancer ; the western blotting was applied to identify the EGF, p-SHP2, ZEB1, and E-Cadherin expressions in ovarian cancer tissue and pair adjacent tissue; then SKOV3 cells were treated with EGF and infected with E-Cadherin overexpression lentivirus, and then cells were treated with benzyl butyl phthalate and IRS-1 respectively. Detection of expression of p-SHP2, ZEB1, E-Cadherin, α3-integrin, p-Src, p-SMAD2, Snail, Slug and SKOV3 cells of migration and invasion abilities were detected using Western blot method and cell scratch assay and Transwell assay; Progression of ovarian cancer was detected using subcutaneous tumor transplantation assay in nude mice and HE staining method and immunocyto. The bioinformatics analysis results suggested that SHP2 is highly specifically expressed and E-Cadherin, which is low specifically expressed in ovarian cancer tissues, while EGF, p-SHP2 or ZEB1 are highly expressed and E-Cadherin is low expressed in ovarian cancer tissues; Overexpression of E-Cadherin could reduce the expressions of p-SHP2, ZEB1, α3-integrin, p-Src, p-SMAD2, Snail and Slug might has roles in alleviating the ovarian cancer development and decreasing the levels of p-SHP2 and ZEB1 in tumor samples. And E-Cadherin overexpression reduced the migration and invasion ability of SKOV3 cells. SHP2 tyrosine phosphatase enhances the ovarian cancer cells' motility and invasiveness by upregulation of the integrin/E-Cadherin switch through ZEB1 signal.
Insights
SHP2 tyrosine phosphatase promotes ovarian cancer progression by upregulating the integrin/E-Cadherin switch via ZEB1 signaling. E-Cadherin overexpression inhibits ovarian cancer cell migration and invasion, suggesting therapeutic potential.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- SHP2 (PTPN11) is implicated in various cancers.
- Its specific role and molecular mechanisms in ovarian cancer (OC) require further elucidation.
Purpose of the Study:
- To investigate the function and molecular mechanisms of SHP2 in ovarian cancer.
- To explore the relationship between SHP2, E-Cadherin, and cancer progression.
Main Methods:
- Bioinformatics analysis of gene expression in OC.
- Western blotting to detect protein expression (EGF, p-SHP2, ZEB1, E-Cadherin, etc.).
- In vitro assays (cell migration, invasion) and in vivo tumor xenograft models in mice.
Main Results:
- SHP2 and ZEB1 were highly expressed, while E-Cadherin was lowly expressed in OC tissues.
- E-Cadherin overexpression reduced p-SHP2, ZEB1, and downstream signaling proteins, and inhibited SKOV3 cell migration and invasion.
- SHP2 enhances OC cell motility and invasiveness by upregulating the integrin/E-Cadherin switch through ZEB1.
Conclusions:
- SHP2 plays a crucial role in promoting ovarian cancer progression.
- Targeting SHP2 or restoring E-Cadherin may represent a therapeutic strategy for ovarian cancer.
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