<p>Overexpression of Cancer Upregulated Gene 2 (CUG2) Decreases Spry2 Through c-Cbl, Leading to Activation of EGFR and β-Catenin Signaling</p>

Abstract

The mechanism by which cancer upregulated gene 2 (CUG2) overexpression induces cancer stem cell-like phenotypes is not fully understood. Because the increased activity and expression of epidermal growth factor receptor (EGFR) kinase have been reported in A549 cancer cells overexpressing CUG2 (A549-CUG2) compared with control cells (A549-Vec), the Sprouty2 (Spry2) protein has gained attention as the downstream molecule of EGFR signaling. Therefore, we aim to identify the role of Spry2 in CUG2overexpressing lung cancer cells. Materials and Methods: Spry2 expression levels were examined in A549-CUG2 and A549-Vec cells by Western blotting and qRT-PCR. Cell migration, invasion, and sphere formation were examined after Spry2 suppression and overexpression. EGFR-Stat1 and Akt-ERK protein phosphorylation levels were detected via immunoblotting. NEK2 kinase and βcatenin reporter assay were performed for downstream of Spry2 signaling. Results: Although A549-CUG2 cells showed lower levels of the Spry2 protein than A549-Vec cells, no difference in levels of Spry2 transcript was observed between both cells via qRT-PCR. Furthermore, MG132 treatment enhanced the protein levels and ubiquitination of Spry2, suggesting that Spry2 protein expression can be regulated via the ubiquitinproteasome pathway. The enforced expression of c-Cbl, known as the binding partner of Spry2, decreased the Spry2 protein levels, whereas its knockdown oppositely increased them. Epithelial-mesenchymal transition (EMT) and sphere formation were increased in A549-Vec cells during Spry2 siRNA treatment, confirming the role of Spry2 in CUG2-induced oncogenesis. Furthermore, EMT and sphere formation were determined by the Spry2 protein levels through the regulation of EGFR-Stat1 and β-catenin-NEK2-Yap1 signaling pathways. Conclusion: CUG2 reduces Spry2 protein levels, the negative signaling molecule of cell proliferation, via c-Cbl, possibly activating the EGFR and β-catenin signaling pathways and, in turn, contributing to the induction of cancer stem cell-like phenotypes.

Investigating CENPW as a Novel Biomarker Correlated With the Development and Poor Prognosis of Breast Carcinoma

“…To illustrate the specific molecular function of the CENPW gene in breast cancer, we constructed CNEPW gene silenced cells and found that CENPW suppression could inhibit the proliferation and migration of MDA-MB-231 and BT-549 cells, hindering the cell cycle signaling pathway, thereby causing apoptosis of breast tumor cells. Previous studies have confirmed that CENPW accelerates cell transformation and stemness through nuclear NPM1 protein and TGF-β signaling (Kaowinn et al, 2019a;Yawut et al, 2020). Moreover, Kaowinn et al (Kaowinn et al, 2019b) found that CENPW elevated the expression of YAP1, resulting in the increase of the EMT in lung cancer cells.…”

Role of NIMA‐related kinase 2 in lung cancer: Mechanisms and therapeutic prospects

“…Thus, overexpression of NEK2 was also used as a biomarker for lung cancer [56]. Overexpression of NEK2 in different types of cancer is associated with a poor prognosis [57].…”

Hsa-miR-22-3p inhibits liver cancer cell EMT and cell migration/ invasion by indirectly regulating SPRY2

“…It is thought that the function of CBL is largely based on its ubiquitin ligase activities that catalyze many signaling molecules for degradation. SPRY2 has been found to be a substrate of CBL [34] and participates in inhibiting EMT, cell migration and invasion [41][42][43].…”