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.
Highlights
The retinoblastoma protein (Rb) is one of the most important tumor suppressors, as illustrated by the fact that either Rb itself or some of its pathway components is the target of oncogenic driver mutations in most, if not all, human cancers [1,2,3,4,5,6,7,8]
We propose that combined immunohistochemistry staining of non-small cell lung carcinomas (NSCLC) samples for Rb phosphorylation on serine 249 (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
We focused our subsequent studies on H1666 and H520 cells, in which we studied the expression of epithelial-to-mesenchymal transition (EMT) markers by immunoblot and Quantitative reverse transcription PCR (qRT-PCR) analyses
Summary
The retinoblastoma protein (Rb) is one of the most important tumor suppressors, as illustrated by the fact that either Rb itself or some of its pathway components is the target of oncogenic driver mutations in most, if not all, human cancers [1,2,3,4,5,6,7,8]. Given that Rb’s function is regulated by phosphorylation, and that Rb inactivation by hyper-phosphorylation is a frequent occurrence in human cancers [2,7,17,18,19] and in light of Rb’s role in cell adhesion, we postulated that there is a specific Rb phosphorylation signature that abrogates Rbs capacity to promote cell adhesion, and that such a phosphorylation signature could be a clinically informative biomarker for establishing metastatic potential based on a biopsy of a primary tumor. We propose that pathologists should perform combined immunohistochemistry staining of lung tumor samples for Rb S249 phosphorylation and for p39 protein expression to aid in the clinical assessment of SCC tumor staging, histological NSCLC subtyping and metastatic potential in those patients who are not amenable to tumor resection and for whom treatment must be informed predominantly by evaluations of small tumor biopsies
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