Junctional adhesion molecule‐A is down‐regulated in anaplastic thyroid carcinomas and reduces cancer cell aggressiveness by modulating p53 and GSK3 α/β pathways

Abstract

Junctional adhesion molecule A (JAM‐A) is a transmembrane protein that contributes to different biological process, including the epithelial to mesenchymal transition (EMT). Through an EMT profiler array, we explored the molecular players associated with human thyroid cancer progression and identified JAM‐A as one of the genes mostly deregulated. The quantitative real‐time polymerase chain reaction and immunohistochemistry analyses showed that downregulation of JAM‐A occurred in anaplastic thyroid carcinoma (ATC) compared with normal thyroid (NT) and papillary thyroid carcinoma (PTC) tissues and correlated with extrathyroid infiltration, tumor size, and ATC histotype. In ATC cell lines, JAM‐A restoration suppressed malignant hallmarks of transformation including cell proliferation, motility, and transendothelial migration. Accordingly, knockdown of JAM‐A enhanced thyroid cancer cell proliferation and motility in PTC cells. Through the proteome profiler human phospho‐kinase array, we demonstrated that higher expression of JAM‐A was associated with a significant increased level of phosphorylation of p53 and GSK3 α/β proteins. In conclusion, our findings highlight a novel role of JAM‐A in thyroid cancer progression and suggest that JAM‐A restoration could have potential clinical relevance in thyroid cancer treatment.

Thyroid hormone receptor beta inhibits the PI3K-Akt-mTOR signaling axis in anaplastic thyroid cancer via genomic mechanisms

“…In order to test the impact of long-term T 3 exposure and heightened TRβ expression we measured a well-studied downstream effector, glycogen synthase kinase 3 beta (GSK3β) and its substrate glycogen synthase 1 (GYS1). GSK3β is a multi-substrate kinase and, importantly, is implicated in the progression of numerous cancers including ATC (25,26). We observed a modest increase in phosphorylated, and thus inactivated, GYS1 in the presence of T 3 and a marked increase of pGYS1 in the presence of both TRβ and T 3 (Fig.…”

Targeting Opposing Immunological Roles of the Junctional Adhesion Molecule-A in Autoimmunity and Cancer

“…In vitro studies using human triple negative breast cancer or thyroid carcinoma cell lines showed increased tumor cell proliferation and migration under JAM-A gene silencing (67,68). Transfection of a JAM-A plasmid to these cell lines impaired transendothelial migration and colony formation.…”

“…Evidence from the literature suggest that circulating, soluble JAM-A could be used as a biomarker for the detection of some types of cancer, such as multiple myeloma (65) and head and neck squamous cell carcinoma (66). Although few studies show that JAM-A can be downregulated in tumor sites of metastatic breast (67) and anaplastic thyroid carcinoma tissues (68), high levels of JAM-A protein expression in tumor tissues have been correlated with poor prognosis in breast cancer (69) and nasopharyngeal carcinoma (70) patients.…”

The TUSC2 Tumour Suppressor Inhibits the Malignant Phenotype of Human Thyroid Cancer Cells via SMAC/DIABLO Protein

“…Migration and invasion abilities were assessed by wound healing and by Matrigel matrix assays, respectively, as previously described [38].…”

“…Cell cycle progression and cell death were determined by fluorescence-activated cell sorting (FACS) analysis using propidium iodide staining and an FC500 Cytometer (Beckman Coulter, Milan, Italy) as previously described [38].…”