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

Abstract

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.

Identification of prognostic signature of non–small cell lung cancer based on TCGA methylation data

“…GCLC is another tumor suppressor gene that induces synthetic lethality of cancer cells; GCLC deletion is associated with lung cancer development 44 . Moreover, CDK5R2/p39 increased the invasiveness of lung cancer by impairing cell adhesion and promoting epithelial-to-mesenchymal transition 45 . FOXA1 promoted lung cancer development as a suppressor of the tumor immune microenvironment, which facilitates immune evasion of cancer cells 46 .…”

Candidate Genes Identified by Constructing a Weighted Gene Co-Expression Network and Key Prognostic Factors of Pancreatic Adenocarcinoma

“…CDK5R2 was involved in positive regulation of cyclin-dependent protein serine/threonine kinase activity, the main ligands were TGF-βs, including TGF-β1~TGF-β5, these members had similar structures and functions that inhibited cell proliferation. It had been demonstrated that decreased expression of CDK5R2 was correlated with poor prognosis of hepatocellular carcinoma (Lu et al, 2011), andPérez-Morales et al(2018) indicated CDK5R2 could be a potential lung cancer grading and staging biomarker, it may have similar effects on PAAD patients. NAP1L2 was a kind of nucleosome assembly protein, regulated cell differentiation and tissue maturation.…”

Zoledronic Acid Abrogates Restraint Stress-Induced Macrophage Infiltration, PDGF-AA Expression, and Ovarian Cancer Growth

“…Immunohistochemistry (IHC) was performed on formalin-fixed, paraffin-embedded tumor samples sliced at 4 μm. Samples were stained for CD68 (1:200; MCA1957, BioRad, Hercules, CA, USA), and PDGF-AA (1:250; sc-9974, Santa Cruz Biotechnology, Dallas, TX, USA) following protocol by Pérez-Morales et al, 2018 [ 48 ]. Briefly, slides were heated at 65 °C for 30 min and then deparaffinized using graded xylenes.…”