MicroRNA‑519 inhibits hypoxia‑induced tumorigenesis of pancreatic cancer by regulating immune checkpoint PD‑L1

Abstract

Pancreatic cancer is highly prevalent and exhibits a high incidence and mortality rate. Hypoxia contributes to tumorigenesis and the progression of pancreatic cancer. To the best of our knowledge, the role of microRNA (miR)-519 has not been investigated in hypoxia-induced pancreatic cancer progression. The purpose of the present study was to elucidate the mechanism underlying miR-519-mediated regulation of pancreatic cancer progression. Reverse transcription-quantitative PCR and western blotting were performed to investigate miR-519 and programmed death ligand 1 (PD-L1) mRNA and protein levels, respectively. Additionally, a Transwell assay was performed to examine the invasiveness of PANC-1 and SW1990 cells. Cells were subsequently stained with Annexin V to determine the apoptotic rate of cells. Furthermore, bioinformatics analysis and a dual-luciferase reporter assay were performed to confirm the direct association between miR-519 and PD-L1, and a xenograft experiment was conducted to test the role of miR-519 in vivo. The results revealed that the expression levels of miR-519 in pancreatic cancer cells were reduced following hypoxia treatment. Furthermore, transfection with miR-519 mimics inhibited PANC-1 and SW1990 cell invasiveness, and induced apoptosis under hypoxic conditions. PD-L1 was also identified as a downstream target of miR-519, and rescued the miR-519 mimic-attenuated tumorigenesis of pancreatic cancer cells under hypoxic conditions. Additionally, treatment with miR-519 mimics significantly suppressed the tumor growth of PANC-1 cells. The results of the present study indicated a novel mechanism of miR-519-mediated tumorigenesis in pancreatic cancer cells under hypoxic conditions. The conclusions may be crucial for the improvement of future pancreatic cancer treatment.

Targeting hypoxic tumor microenvironment in pancreatic cancer

“…Figure 3 depicts the effects of microenvironmental remodeling on PC progression under hypoxic conditions. [104] miR-142 Down miR-142-HIF-1α-vimentin, VEGF-C, E-cadherin Inhibits proliferation, EMT, and invasion [184] miR-150 Down miRNA-150-CXCR4 Inhibits migration and invasion [185] miR-519 Down miR-519-PD-L1 Inhibits cell invasiveness, and induces apoptosis [186] miR-548an Down HIF-1α-HDAC1-miR-548an-vimentin Inhibits the proliferation and invasion [187] Pathological angiogenesis under hypoxia…”

Diagnostic Utility of PD-L1 and TP-53 mRNA As Well As microRNAs Expression in Liquid Biopsy of NSCLC Patients – Pilot Study

“…Application of miR-519 inhibited invasiveness and tumor growth as well as induced apoptosis of pancreatic cancer in a mouse model [40].…”

MicroRNAs and Their Influence on the ZEB Family: Mechanistic Aspects and Therapeutic Applications in Cancer Therapy

“…Enhancing the expression of miR-519 appears to sensitize pancreatic cancer cells to apoptosis and inhibits their proliferation and migration. This miR prevents the activation of programmed death ligand 1 (PD-L1), under hypoxic conditions to suppress tumorigenesis [ 74 ]. In all, various studies have shown that miRs are efficient upstream mediators that target various molecular pathways.…”

“…In all, various studies have shown that miRs are efficient upstream mediators that target various molecular pathways. Enhancing the expression of tumor suppressor miRs may prove to be an advantageous strategy and extensive research is currently being performed to exploit this strategy [ 74 , 75 , 76 , 77 , 78 ]. Conversely, oncogenic miRs are able to elevate the malignancy and proliferation of cancer cells and are associated with poor prognosis.…”