<p>Gain-Of-Function E76K-Mutant SHP2 Promotes Cell Proliferation, Metastasis, And Tumor Growth In Glioblastoma Through Activation Of The ERK/CREB Pathway</p>

Abstract

Purpose: The aim of this study was to investigate the effects of gain-of-function (GOF) E76K-mutant Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) on the biological behaviors of glioblastoma (GBM) cells, and explore the molecular mechanisms of GBM progression. Methods: Firstly, a negative control vector and vectors overexpressing SHP2 and E76Kmutant SHP2 were transduced into GBM cells (U87 and A172) using a lentivirus. The effect of GOF-mutant SHP2 on proliferation was measured using the MTT assay, flow cytometry, colony formation assay, and soft agar assay. Moreover, the migration and invasion of GBM cells were determined through the transwell assay. Related proteins of the extracellular signal-regulated kinase/cAMP response element binding protein (ERK/CREB) pathway were detected by Western blotting analysis. A xenograft model was established to confirm the tumor-promoting effect of GOF-mutant SHP2 in vivo. Finally, ERK was inhibited using a mitogen-activated protein kinase/ERK kinase inhibitor (U0126) to further explore the molecular mechanism of GOF-mutant SHP2 affecting GBM cells. Results: After transduction, the expression of SHP2 in the SHP2-mutant and SHP2-overexpression groups was higher than that observed in the control and normal groups. Our data indicated that GOF-mutant SHP2 enhanced the abilities of GBM cells for proliferation, migration, and invasion in vitro, and promoted tumor growth in vivo. Mechanistically, the ERK/CREB pathway was activated, and the levels of relevant proteins were increased in the SHP2-mutant group. Furthermore, following inhibition of ERK in the GOF-SHP2 mutant group, the activation of CREB was also depressed, and the malignant biological behaviors were weakened accordingly. Conclusion: The GOF-mutant SHP2 promoted GBM cell proliferation, metastasis, and tumor growth through the ERK/CREB pathway, providing a promising target for the treatment of GBM.

Inhibitory role of circRNA_100395 in the proliferation and metastasis of prostate cancer cells

“…Tumor cell proliferation, migration, and invasion are hallmarks of tumor development. 19 , 20 Given that circRNA_100395 expression was significantly correlated with tumor size, tumor stage, and lymph node metastasis, we hypothesized that it might be involved in the regulation of prostate cancer cell proliferation and metastasis. We therefore elucidated its function by examining the changes in cell proliferation and metastasis in prostate cancer cells overexpressing circRNA_100395.…”

Small‐Molecule Inhibitors of Shp2 Phosphatase as Potential Chemotherapeutic Agents for Glioblastoma: A Minireview

“…This activation leads to the recruitment of several molecular mediators in a so‐called protein kinase cascade, ultimately stimulating the MAPK pathway via the RAS‐RAF‐ERK stem (Figure 1). [23,24] ERK phosphorylation has been shown to silence the p53 oncogene which suppresses apoptosis and cell senescence. Often, some ligand binding to the allosteric site (like, SHP099) will stabilize the enzyme in its auto‐inhibited conformation thereby impeding its biological functions (Figure 4A, bottom right) [25] …”

“…The GOF E76 A‐mutant Shp2, for instance, is highly responsible for the proliferation, migration, invasion and increased malignancy of GBM cells via the ERK/CREB signalling pathway. Thus, PTPN11 is a mutational cancer driver in GBM [23] …”

“…Recent studies have found an important tumour biomarker, the protein programmed death ligand‐1 (PD‐L1) in the prognosis of GBM which as part of an immunoregulatory axis, correlates with Shp2 thereby eliciting a number of immunological responses which in turn promote invasion of GBM cells in the brain tissue and also, induce clonal anergy [23,26] . Augmented expression of PD‐L1 on glioblastoma cell surface by toll‐like receptor (TLR) and EGFR activation, for instance, activates PD‐1 receptor and triggers its interaction with PD‐1 ligand.…”

“…[22] This activation leads to the recruitment of several molecular mediators in a socalled protein kinase cascade, ultimately stimulating the MAPK pathway via the RAS-RAF-ERK stem (Figure 1). [23,24] ERK phosphorylation has been shown to silence the p53 oncogene which Protein phosphatase superfamily. [15] suppresses apoptosis and cell senescence.…”