Role of microRNA-33a in regulating the expression of PD-1 in lung adenocarcinoma

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.

Immunomodulatory MicroRNAs in cancer: targeting immune checkpoints and the tumor microenvironment

“…These miRNAs as miR-BHRF1-2, 2-5p, 10-3p, and 11-5p interfere with the host immune system at many levels, including T-cell differentiation, activation and recognition, B-cell differentiation, NK cell activity, and antigen processing. miR-33 is known to play a role in lipid metabolism [68]. There are many other virus-modulated miRNAs that change the expression of PD-1/PD-L1 such as miR-4717 which is encoded by hepatitis-B and could significantly downregulate PD-1 in lymphocytes isolated from chronic hepatitis-B patients with the polymorphic variant GG [67].…”

“…Moreover, EBV-encoded miRNAs enhance the immune exhaustion by boosting the generation of IL-10, TGF-b, and IFN-c [63]. The upregulation of miR-33a was found to be coupled with the downregulation of PD-1 immune checkpoint and better outcomes in lung cancer patients [68]. miR-33 is another miRNA that targets PD-1 and PD-L1, inhibiting their expression through the interaction with 3'UTR of both.…”

“…miR-33 is another miRNA that targets PD-1 and PD-L1, inhibiting their expression through the interaction with 3'UTR of both. miR-33 is known to play a role in lipid metabolism [68]. The upregulation of miR-33a was found to be coupled with the downregulation of PD-1 immune checkpoint and better outcomes in lung cancer patients [68].…”

“…miR-33 is known to play a role in lipid metabolism [68]. The upregulation of miR-33a was found to be coupled with the downregulation of PD-1 immune checkpoint and better outcomes in lung cancer patients [68]. Moreover, miR-33a has a tumor-suppressor function via reducing the expression of b-catenin [69].…”

LINC00461/miR-4478/E2F1 feedback loop promotes non-small cell lung cancer cell proliferation and migration

“…Although some NSCLC patients promisingly benefit from early diagnosis and surgical tumor dissection, most patients remain disappointed by poor outcome with 20% five year survival rate [3,4]. Thus, further exploration on the molecular mechanism underlying NSCLC is of paramount significance for therapy development of NSCLC [5][6][7].…”