Hyper-phosphorylation of Rb S249 together with CDK5R2/p39 overexpression are associated with impaired cell adhesion and epithelial-to-mesenchymal transition: Implications as a potential lung cancer grading and staging biomarker

• Published in: PloS one Vol. 13; no. 11; p. e0207483
• Main Authors: Pérez-Morales, Jaileene, Mejías-Morales, Darielys, Rivera-Rivera, Stephanie, González-Flores, Jonathan, González-Loperena, Mónica, Cordero-Báez, Fernando Y., Pedreira-García, Wilfredo M., Chardón-Colón, Camille, Cabán-Rivera, Jennifer, Cress, W. Douglas, Gordian, Edna R., Muñoz-Antonia, Teresita, Cabrera-Ríos, Mauricio, Isidro, Angel, Coppola, Domenico, Rosa, Marilin, Boyle, Theresa A., Izumi, Victoria, Koomen, John M., Santiago-Cardona, Pedro G.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.11.2018; Public Library of Science (PLoS)
• Subjects: Biochemistry; Biology; Biology and Life Sciences; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Biopsy; Cadherins - biosynthesis; Cadherins - genetics; Cancer; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell adhesion; Cell adhesion & migration; Cell Adhesion - genetics; Cell cycle; Cell Line, Tumor; Correlation; Cytoskeletal Proteins - biosynthesis; Cytoskeletal Proteins - genetics; Departments; E-cadherin; Epithelial-Mesenchymal Transition; Evaluation; Gene Expression Regulation, Neoplastic; Health sciences; Histology; Humans; Immunohistochemistry; Keratin; Kinases; Lung cancer; Lung carcinoma; Lung diseases; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lymph nodes; Medicine and Health Sciences; Mesenchyme; Metastases; Metastasis; Neoplasm Grading; Neoplasm Metastasis; Non-small cell lung carcinoma; Oncology; Pathology; Phosphorylation; Physical Sciences; Predictions; Proteins; Regression analysis; Research and Analysis Methods; Retina; Retinoblastoma; Retinoblastoma protein; Retinoblastoma Protein - genetics; Retinoblastoma Protein - metabolism; Serine; Small cell lung carcinoma; Squamous cell carcinoma; Staining; Tumors; Florida; United States > US; Puerto Rico
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0207483

Prediction of lung cancer metastasis relies on post-resection assessment of tumor histology, which is a severe limitation since only a minority of lung cancer patients are diagnosed with resectable disease. Therefore, characterization of metastasis-predicting biomarkers in pre-resection small biopsy specimens is urgently needed. Here we report a biomarker consisting of the phosphorylation of the retinoblastoma protein (Rb) on serine 249 combined with elevated p39 expression. This biomarker correlates with epithelial-to-mesenchymal transition traits in non-small cell lung carcinoma (NSCLC) cells. Immunohistochemistry staining of NSCLC tumor microarrays showed that strong phospho-Rb S249 staining positively correlated with tumor grade specifically in the squamous cell carcinoma (SCC) subtype. Strong immunoreactivity for p39 positively correlated with tumor stage, lymph node invasion, and distant metastases, also in SCC. Linear regression analyses showed that the combined scoring for phospho-Rb S249, p39 and E-cadherin in SCC is even more accurate at predicting tumor staging, relative to each score individually. We propose that combined immunohistochemistry staining of NSCLC samples for Rb phosphorylation on S249, p39, and E-cadherin protein expression could aid in the assessment of tumor staging and metastatic potential when tested in small primary tumor biopsies. The intense staining for phospho-Rb S249 that we observed in high grade SCC could also aid in the precise sub-classification of poorly differentiated SCCs.