MICAL2 contributes to gastric cancer cell migration via Cdc42-dependent activation of E-cadherin/β-catenin signaling pathway

Abstract

Background Gastric cancer is a common and lethal human malignancy worldwide and cancer cell metastasis is the leading cause of cancer-related mortality. MICAL2, a flavoprotein monooxygenase, is an important regulator of epithelial-to-mesenchymal transition. The aim of this study was to explore the effects of MICAL2 on gastric cancer cell migration and determine the underlying molecular mechanisms. Methods Cell migration was examined by wound healing and transwell assays. Changes in E-cadherin/β-catenin signaling were determined by qPCR and analysis of cytoplasmic and nuclear protein fractions. E-cadherin/β-catenin binding was determined by co-immunoprecipitation assays. Cdc42 activity was examined by pulldown assay. Results MICAL2 was highly expressed in gastric cancer tissues. The knockdown of MICAL2 significantly attenuated migratory ability and β-catenin nuclear translocation in gastric cancer cells while LiCl treatment, an inhibitor of GSK3β, reversed these MICAL2 knockdown-induced effects. Meanwhile, E-cadherin expression was markedly enhanced in MICAL2-depleted cells. MICAL2 knockdown led to a significant attenuation of E-cadherin ubiquitination and degradation in a Cdc42-dependent manner, then enhanced E-cadherin/β-catenin binding, and reduced β-catenin nuclear translocation. Conclusions Together, our results indicated that MICAL2 promotes E-cadherin ubiquitination and degradation, leading to enhanced β-catenin signaling via the disruption of the E-cadherin/β-catenin complex and, consequently, the promotion of gastric cell migration.

CSTA: A Biomarker Regulating Esophageal Stricture Epithelial Barrier, Potential Medication Target

“…β-catenin, or CTNNB1, is an evolutionarily conserved, multifunctional intracellular protein. β-catenin was originally identified in cell adhesion junctions (AJs), where it functions to link the cytoplasmic domains of cadherins to the a-catenin and actin cytoskeletons in response to cell-cell adhesion(Nakayama et al , 2014; Puthia et al , 2014; Wang et al , 2022). CDH1 and β- catenin form a complex in cells.…”

“…CDH1 and β- catenin form a complex in cells. This complex is a critical component of the cell-cell adhesion complex(Wang et al , 2022; Liu et al , 2022; Jovov et al , 2011). Thus, in this work, K14 was measured as a biomarker of HaCaT cells, while CDH1, β-catenin, and ZO-1 were measured as functional biomarkers of cell-cell adhesion.…”

MICAL2 implies immunosuppressive features and acts as an independent and adverse prognostic biomarker in pancreatic cancer

“…In recent years, MICAL2 has been identified as a novel pro-tumorigenic factor 39 . Previous studies have indicated that, in addition to being highly expressed in cancers, MICAL2 is associated with poor prognosis 23 , 24 , 40 , 41 . In our study, we found that MICAL2 was highly expressed in pancreatic cancer samples.…”

“…In recent years, MICAL2 has been found to be highly expressed in many tumors and promote tumor progression by inducing tumor cell proliferation and migration 19 – 22 . In gastric cancer, MICAL2 has been shown to promote gastric cell migration by disrupting the impaired binding of E-cadherin to β-catenin, resulting in the accumulation of β-catenin in the nucleus, which enhances β-catenin signaling 23 . High expression of MICAL2 is associated with poor prognosis for glioblastoma patients, as well as the promotion of glioblastoma in mice 24 .…”

DNA methylation alterations of ADCY5, MICAL2, and PLEKHG2 during the developmental stage of cryptogenic hepatocellular carcinoma

“…MICAL family members are associated with cytoskeletal remodeling and cell migration (Table ), 43 which can result in invasion and metastasis 44 . MICAL2 is reportedly overexpressed in various tumors, including gastric cancer 45 and lung cancer 46 . Moreover, silencing of MICAL2 promotes mesenchymal to epithelial transition, and inhibits the viability, as well as the motility and invasive properties, of human cancer cells 47 .…”