Abstract
BackgroundWe focused on the KCNQ1OT1/miR-15a/PD-L1 axis and explored its significance in regulating immune evasion and malignant behaviors of prostate cancer (PC) cells.MethodsThe expression levels of KCNQ1OT1, miR-15a, PD-L1, and CD8 in cells or tissues were examined by RT-qPCR, western blot or immunohistochemistry (IHC) assays. The direct regulations between KCNQ1OT1, miR-15a and PD-L1 were validated by luciferase reporter assay. PC cells were co-cultured with CD8+ T cells to study the immune evasion. Proliferation, apoptosis, migration and invasion abilities were detected by MTT, flow cytometry, wound healing and Transwell assays, respectively. The cytotoxicity of CD8+ T cells was determined by LDH cytotoxicity Kit. Epithelial–mesenchymal transition (EMT) and Ras/ERK signaling markers were evaluated by western blot.ResultsKCNQ1OT1, PD-L1 and CD8 were increased, while miR-15a was decreased in PC tissues. MiR-15a directly bound to the 3′-UTR of PD-L1 and inhibited the expression of PD-L1. Overexpressing miR-15a in PC cells was sufficient to promote cytotoxicity and proliferation, while inhibit apoptosis of CD8+ T cells, and also suppressed viability, migration, invasion and EMT while promoted apoptosis of PC cells. The above anti-tumor effects of miR-15a were reversed by overexpressing PD-L1. KCNQ1OT1 sponged miR-15a and released its inhibition on PD-L1. Functionally, KCNQ1OT1 in PC cells was essential for suppressing the cytotoxicity of CD8+ T cells and maintaining multiple malignant phenotypes of PC cells. The Ras/ERK signaling was suppressed after overexpressing miR-15a or knocking down KCNQ1OT1.ConclusionsLncRNA KCNQ1OT1 sponges miR-15a to promote immune evasion and malignant progression of PC via up-regulating PD-L1.
Highlights
We focused on the KCNQ1OT1/miR-15a/programmed death ligand 1 (PD-L1) axis and explored its significance in regulating immune evasion and malignant behaviors of prostate cancer (PC) cells
KCNQ1OT1, PD‐L1 and CD8 were up‐regulated, while miR‐15a down‐regulated in PC tissues To examine the potential crosstalk among KCNQ1OT1, miR-15a, PD-L1, and CD8+ cytotoxic T cells in PC, we compared the expression levels of these molecules between 30 pairs of PC tissues and matching para-tumor normal tissues
Further analysis revealed a negative correlation between KCNQ1OT1 and miR-15a (Fig. 1d) and between miR-15a and PD-L1 (Fig. 1e), while a positive correlation between KCNQ1OT1 and PD-L1 (Fig. 1f ), and between CD8 and PD-L1 (Fig. 1 h) in PC tissues
Summary
We focused on the KCNQ1OT1/miR-15a/PD-L1 axis and explored its significance in regulating immune evasion and malignant behaviors of prostate cancer (PC) cells. Chen et al Cancer Cell Int (2020) 20:394 and epithelial–mesenchymal transition (EMT), critically drive the malignant growth, the metastatic spread, and the resistance to therapy of PC. These biological behaviors link tumor cells with other cell types within the tumor microenvironment to nurture tumor development [5]. The high level of PD-L1 promotes tumor proliferation, invasion, angiogenesis, cancer stemness and EMT [6,7,8]. As a result, targeting PD-L1/PD-1 axis has become an intriguing immunotherapeutic strategy and has proved its clinical value in a variety of human cancers, such as melanoma [10, 11], non-small-cell lung cancer [12], hepatocellular carcinoma [13], gastric cancer [14], and etc
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