Comprehensive analysis of MICALL2 reveals its potential roles in EGFR stabilization and ovarian cancer cell invasion

Abstract

Abstract Molecules interacting with CasL (MICALs) are critical mediators of cell motility that act by cytoskeleton rearrangement. However, the molecular mechanisms underlying the regulation of cancer cell invasion remain elusive. The aim of this study was to investigate the potential role of one member of MICALs, i.e., MICAL-like 2 (MICALL2), in the invasion and function of ovarian cancer cells. Bioinformatics analysis showed that MICALL2 expression was significantly higher in tissues of advanced-stage ovarian cancer and associated with poor overall survival of patients. MICALL2 was strongly correlated with the infiltration of multiple types of immune cells and T-cell exhaustion markers. Moreover, enrichment analyses showed that MICALL2 was involved in the tumor-related matrix degradation pathway. Mechanistically, matrix metallopeptidase 9 (MMP9) was identified as the target gene of MICALL2 for the regulation of invadopodium formation and ovarian cancer cell invasion. In addition, epidermal growth factor receptor/protein kinase B/mechanistic target of rapamycin (EGFR/AKT/mTOR) signaling was identified as the downstream pathway of MICALL2 in the regulation of MMP9 expression. Furthermore, MICALL2 silencing promoted EGFR degradation; however, this effect was abrogated by treatment with autophagy inhibitors acadesine and chloroquine diphosphate. Silencing of MICALL2 resulted in a suppressive activity of Rac family small GTPase 1 (Rac1), while suppressing Rac1 activation attenuated the pro-EGFR, pro-MMP9, and pro-invasive effects induced by the overexpression of MICALL2. Collectively, our results indicated that MICALL2 participated in the process of immune infiltration and invasion by ovarian cancer cells. Moreover, MICALL2 prevented EGFR degradation in a Rac1-dependent manner, consequently leading to EGFR/AKT/mTOR/MMP9 signaling activation and invadopodia-mediated matrix degradation.