Abstract
Evidence has indicated that M2 macrophages promote the progression of cancers, but few focus on the ability of M2 macrophage‐derived exosomes in pancreatic cancer (PC). This study aims to explore how M2 macrophages affect malignant phenotypes of PC through regulating long non‐coding RNA SET‐binding factor 2 antisense RNA 1 (lncRNA SBF2‐AS1)/microRNA‐122‐5p (miR‐122‐5p)/X‐linked inhibitor of apoptosis protein (XIAP) axis. THP‐1 cells were transformed into M1 macrophages by lipopolysaccharide and interferon‐γ treatment, and into M2 macrophages after interleukin‐4 treatment. The PANC‐1 PC cell line with the largest lncRNA SBF2‐AS1 expression was selected, and M2 macrophage‐derived exosomes were isolated and identified. A number of assays were applied for the examination of lncRNA SBF2‐AS1 expression, PC cell biological functions and subcellular localization of lncRNA SBF2‐AS1. XIAP expression was detected, along with the interaction among lncRNA SBF2‐AS1, miR‐122‐5p and XIAP. M2 macrophage exosomal lncRNA SBF2‐AS1 expression's effects on the tumorigenic ability of PANC‐1 cells in nude mice were also investigated. M2 macrophage‐derived exosomes promoted progression of PC cells. Overexpressed lncRNA SBF2‐AS1 promoted progression of PC cells. LncRNA SBF2‐AS1 was found to act as a competing endogenous RNA to repress miR‐122‐5p and up‐regulate XIAP. Constrained lncRNA SBF2‐AS1 in M2 macrophage‐derived exosomes contributed to restraining tumorigenic ability of PC cells. Collectively, our study reveals that constrained lncRNA SBF2‐AS1 in M2 macrophage‐derived exosomes increases miR‐122‐5p expression to restrain XIAP expression, which further inhibits PC progression.
Highlights
Pancreatic cancer (PC) is a major cause accounting for the cancer mortality in developed countries, and it is mainly comprised of adenocarcinoma (85%) and pancreatic endocrine tumours.[1]
A study has showed that X-linked inhibitor of apoptosis protein (XIAP) is a direct target of miR-130,16 and it is a cytosolic suppressor of caspases 3, 7 and 9.17 Young Kim et al[18] have revealed that XIAP silencing is able to increase PC cell apoptosis stimulated by tumour necrosis factor-related apoptosis-inducing ligand
Our study revealed that silencing of Long non-coding RNAs (lncRNAs) SBF2-AS1 in M2 macrophage exosomes increased miR-122-5p expression to repress XIAP expression, which further depressed PC progression
Summary
Pancreatic cancer (PC) is a major cause accounting for the cancer mortality in developed countries, and it is mainly comprised of adenocarcinoma (85%) and pancreatic endocrine tumours (under 5%).[1]. Macrophages are considered as differentiated cells of the mononuclear phagocytic lineage which feature special phenotypic characteristics and particular marker expression, and have been reported to have positive effects on the tumorigenesis and tumour prognosis.[5] In recent years, alternatively activated (M2) macrophages have been reported to play a critical part in gastric cancer development.[6] Macrophage-derived exosomes are capable of modulating drug resistance in pancreatic adenocarcinoma.[7] Long non-coding RNAs (lncRNAs) are a kind of ncRNAs that possess over 200 nucleotides and can function in gene expression and some tumours’ development.[8] As a newly discovered lncRNA, SET-binding factor 2 antisense RNA 1 (SBF2-AS1) has been found to be involved in non–small-cell lung cancer and results in unfavourable prognosis in patients.[9] By functioning as a competitive endogenous RNA, lncRNA SBF2-AS1 is found to elevate twinfilin-1 (TWF1) to sponge miR142-3p and participate in gemcitabine resistance in PC.[10] Long et al[11] have demonstrated that SBF2 up-regulation can substantially depress cell proliferation and promote apoptosis in PC possibly through restriction of transforming growth factor β/SMAD signalling pathway. This study is meant to discuss how M2 macrophages affect malignant phenotypes of PC through lncRNA SBF2-AS1/miR-122-5p/XIAP axis
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