Intercellular adhesion molecule 2 as a novel prospective tumor suppressor induced by ERG promotes ubiquitination-mediated radixin degradation to inhibit gastric cancer tumorigenicity and metastasis

Abstract

Background Gastric cancer (GC) is a fatal cancer with unclear pathogenesis. In this study, we explored the function and potential mechanisms of intercellular adhesion molecule 2 (ICAM2) in the development and advancement of GC. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were performed to quantify ICAM2 expression in harvested GC tissues and cultured cell lines. Immunohistochemical analyses were conducted on a GC tissue microarray to quantify ICAM2 expression and explore its implication on the prognosis of GC patients. In vitro experiments were carried out to reveal the biological functions of ICAM2 in GC cell lines. Further, in vivo experiments were conducted using xenograft models to assess the impact of ICAM2 on GC development and metastasis. Western blot, immunofluorescence, immunoprecipitation, luciferase assay, chromatin immunoprecipitation, and ubiquitination analysis were employed to investigate the underlying mechanisms. Results ICAM2 expression was downregulated in GC, positively correlating with advanced T stage, distant metastasis, advanced clinical stage, vessel invasion, and shorter patient survival time. ICAM2 overexpression suppressed the proliferation, migration, invasion, metastasis of GC cells as well as their ability to form tumors, whereas ICAM2 knockdown yielded opposite results. Erythroblast transformation-specific-related gene (ERG) as a transcription factor promoted the transcription of ICAM2 by binding to the crucial response element localized within its promoter region. Further analysis revealed that ICAM2 reduced radixin (RDX) protein stability and expression. In these cells, ICAM2 bound to the RDX protein to promote the ubiquitination and degradation of RDX via NEDD4 Like E3 Ubiquitin Protein Ligase (NEDD4L), and this post-translational modification resulted in the inhibition of GC. Conclusions In summary, this study demonstrates that ICAM2, which is induced by ERG, suppresses GC progression by enhancing the ubiquitination and degradation of RDX in a NEDD4L-dependent manner. Therefore, these results suggest that ICAM2 is a potential prognostic marker and a therapeutic target for GC.

T cell interaction partners of DHHC20

“…Following this, the urea concentration was reduced to 2 M by adding 563 μL 100 mM ABC buffer, and the samples were subjected to additional digestion with trypsin at a 1:100 enzyme-to-substrate ratio (0,55 μg Trypsin for 55 μg protein) overnight at 37°C. After digestion, salts and detergents were removed before LC-MS analysis by SDB-RPS StageTips (Empore™ 2241) as described previously 25 . Eluted peptides were dried by vacuum centrifugation and stored at -20°C.…”

NEDD4 and NEDD4L: Ubiquitin Ligases Closely Related to Digestive Diseases

“…Although the exact molecular mechanism has not been fully clarified yet, it may facilitate the development of new anticancer strategies [124]. Xiaocheng Tang et al revealed that intercellular adhesion molecule 2 (ICAM 2) was significantly downregulated in GC cells and tissues and could be used to evaluate prognoses, and that ICAM 2 promoted the ubiquitination degradation of radixin (RDX) in a NEDD4L-dependent manner to inhibit GC cell proliferation and migration [88]. Overall, the above evidence suggests that NEDD4 and NEDD4L are involved in the development of GC via a variety of signaling pathways, but some of the molecular mechanisms are still uncertain and require further study (Figure 3) (Table 1).…”

Cellular elasticity in cancer: a review of altered biomechanical features

“…The rate of intercellular adhesions differs between cancer cells and normal cells. 48,58 The collective dynamics and activity of cells in thick tissue, which can be connected to embryonic development, are to blame, 49 including in wound healing 59 and cancer. 60 The epithelial and mesenchymal transition was seen in vivo as a solid–liquid transition phase where cell mobility increases and adhesion diminishes, and this has been shown to play a significant role in tissue healing, inflammation, and tumor growth.…”