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Junctional Adhesion Molecule-Like Protein Promotes Tumor Progression and Metastasis via p38 Signaling Pathway in Gastric Cancer.

ABSTRACT: Junctional adhesion molecule-like protein (JAML), a newly discovered junctional adhesion molecule (JAM), mediates the adhesion and migration processes of various immune cells and endothelial/epithelial cells, ultimately regulating inflammation reaction. However, its role in tumors remains to be determined. The expression of JAML was examined in gastric cancer (GC) and peritumoral tissues from 63 patients. The relationship between JAML expression and clinical characteristics was also observed. In vitro, GC cell migration and proliferation were assessed by wound healing assay, transwell migration assay and EdU incorporation assay. Immunohistochemical staining results showed that JAML expression level was higher in GC tissues than in peritumoral tissues. High expression of JAML in cancer tissues was associated with worse cell differentiation, local lymph node involvement, deep infiltration, and advanced stage. In vitro, we found that JAML silencing inhibited GC cell migration and proliferation, while JAML overexpression promoted GC cell migration and proliferation, partially via p38 signaling. Taken together, our study revealed a critical role for JAML to promote GC cell migration and proliferation. JAML might be a novel diagnostic biomarker and therapeutic target for GC.

SUBMITTER: Fang Y

PROVIDER: S-EPMC7991718 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundLung adenocarcinoma (LUAD) is a heavy social burden worldwide. Because the mechanisms involved in LUAD remain unclear, the prognosis of LUAD remains poor. Consequently, it is urgent to investigate the potential mechanisms of LUAD. Junctional adhesion molecule-like protein (JAML), is recognized as a tumorigenesis molecule in gastric cancer. However, the role of JAML in LUAD is still unclear. Here we aimed to evaluate the role of JAML in LUAD.MethodsqRT-PCR, Western blotting and immunohistochemistry were conducted to investigate the expression of JAML in LUAD tissues. JAML was knocked down and overexpressed in LUAD cells using transient transfection by siRNA and plasmids or stable transfection by lentivirus. Proliferation potential of LUAD cells were detected by Cell Counting Kit-8, EdU incorporation and Colony formation assay. Migration and invasion abilities of LUAD cells were determined by wound healing, transwell migration and invasion assays. Cell cycle and cell apoptosis were detected by flow cytometry. The effects of JAML in vivo were studied in xenograft tumor models. Western blotting was used to explore the molecular mechanisms of JAML function. In addition, rescue experiments were performed to verify the possible mechanisms.ResultsJAML expression was elevated in LUAD tissues compared with peritumor tissues, and this upregulation was positively related to pT and pTNM. Furthermore, both in vitro and in vivo, JAML silencing markedly repressed malignant behaviors of LUAD cells and vice versa. Knockdown of JAML also mediated cell cycle arrest at G0/G1 phase and promoted apoptosis in LUAD cells. Mechanistically, silencing JAML repressed the process of epithelial-mesenchymal transition by inactivating the Wnt/β-catenin pathway in LUAD cells. Effects of JAML can be rescued by Wnt/β-catenin pathway activator in A549 cells.ConclusionsOur data reveal the oncogenic role of JAML in LUAD, indicating that JAML may be a predictive biomarker and novel therapeutic target for LUAD.

Project description:BackgroundGastric 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.MethodsQuantitative 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.ResultsICAM2 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.ConclusionsIn 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.

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Junctional Adhesion Molecule-Like Protein Promotes Tumor Progression and Metastasis via p38 Signaling Pathway in Gastric Cancer.

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