Abstract
BackgroundMiRNAs are vital in functioning as either oncogenes or tumor suppressors in the cell cycle. Target transcripts for immune checkpoint molecules such as PD-1/PD-L1 and (programmed cell death-1/its ligand and cytotoxic T-lymphocyte antigen 4) have proven to be beneficial against several solid tumors, including lung adenocarcinoma.MethodsSimultaneous quantification of the expression level of miR-33a and PD-1, PD-L1 and CTLA4 mRNAs with NanoString technology was performed in 88 lung adenocarcinoma specimens. A cohort of 323 lung adenocarcinoma patients from the cancer genome atlas (TCGA) database was further analyzed, in order to test our hypothesis. Potential interference of PD-1, PD-L1 and CTLA4 gene expression by miR-33a was predicted using the microRNA target prediction program RNA22.ResultsHigh miR-33a expression was significantly associated with younger (p = 0.005), female (p = 0.04), patients with low grade (p < 0.0001), early stage (p = 0.03) tumors, and better survival. The hypothesis of the involvement of miR-33a in PD-1/PD-L1/CTLA4 mechanisms was corroborated by the finding of putative miR-33a binding sites in all three genes using the RNA22 method. We found an inverse correlation between miR-33a and PD-1 levels (p = 0.01), as well as for PD-L1 (p = 0.01) and CTLA4 (p = 0.03) expression, and a significant better prognosis for patients with high miR-33a/low PD-1. TCGA database analysis confirmed that miR-33a high levels were associated with low PD-1 expression and with longer survival on a larger population.ConclusionsOur study emphasizes the notion of a potential value of miR-33a as a favorable prognostic marker through PD-1 regulation.
Highlights
MiRNAs are vital in functioning as either oncogenes or tumor suppressors in the cell cycle
MicroRNAs are small non-coding RNA molecules that function as indispensable regulators of an increasing number of cellular processes [1,2,3]. miRNAs are vital in regulating cell proliferation and apoptosis, in addition to functioning as either oncogenes or tumor suppressors in the cell cycle [4]
The nCounter custom code set used in this study included three genes (PD-1, PD-L1 and CTLA4) with five housekeeping genes for reference [clathrin heavy chain 1 (CLTC), beta-glucuronidase (GUSB), tubulin beta (TUBB), hypoxanthine phosphoribosyltransferase (HPRT1), phosphoglycerate kinase 1 (PGK1)]
Summary
MiRNAs are vital in functioning as either oncogenes or tumor suppressors in the cell cycle. MiRNAs are vital in regulating cell proliferation and apoptosis, in addition to functioning as either oncogenes or tumor suppressors in the cell cycle [4]. There are limited data on the prognostic significance of PD-1/PD-L1, with some showing poor [9], better prognosis [10] or no prognostic role [11]. Another approach to regulating the immune response in the tumor microenvironment is by modulating the level of miRNAs. A recent review [12] emphasized the role of miRNAs as modulators of immune checkpoint molecules and as potential cancer therapeutic targets
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