Exosomal LINC00460/miR-503-5p/ANLN positive feedback loop aggravates pancreatic cancer progression through regulating T cell-mediated cytotoxicity and PD-1 checkpoint
- PMID: 36482354
- PMCID: PMC9733079
- DOI: 10.1186/s12935-022-02741-5
Exosomal LINC00460/miR-503-5p/ANLN positive feedback loop aggravates pancreatic cancer progression through regulating T cell-mediated cytotoxicity and PD-1 checkpoint
Abstract
Background: Long non-coding RNA (lncRNA) LINC00460 is an onco-lncRNA in a variety of cancers, including pancreatic cancer (PC). This study is aimed to investigate the regulatory mechanisms of LINC00460 in PC.
Methods: The tumor and adjacent normal tissues were collected from 73 PC patients. The expression of LINC00460, miR-503-5p, and ANLN was detected using qRT-PCR. We then analyzed the proliferation, migration, invasion, and apoptosis/cell cycle of PC cells by performing the MTT/EdU, transwell, and flow cytometry assays, respectively. The xenograft tumor model were utilized to confirm the effect of LINC00460 knockdown on PC through anti-PD-1 therapy in vivo, and the sensitivity of PANC-1 cells to the cytotoxicity of CD8+ T cells in vitro. Western blotting was used to determine the protein levels. A co-culture model was utilized to explore the effects of exosomes on macrophages.
Results: LINC00460 was up-regulated in PC tissues and cells. LINC00460 knockdown suppressed cell proliferation, migration, and invasion, facilitated cell apoptosis and G0/G1 phase arrest, and inhibited the tumor growth through anti-PD-1 therapy. Both miR-503-5p down-regulation and ANLN up-regulation reversed the effects of LINC00460 knockdown on inhibiting the proliferation, migration and invasion, and on promoting the apoptosis, G0/G1 phase arrest, and the sensitivity of PC cells to the cytotoxicity of CD8+ T cells. Exosomes were uptaken by the ambient PC cells. PANC-1 cells-derived exosomal LINC00460-induced M2 macrophage polarization accelerates the cell migration and invasion.
Conclusions: LINC00460 silencing attenuates the development of PC by regulating the miR-503-5p/ANLN axis and exosomal LINC00460-induced M2 macrophage polarization accelerates the migration and invasion of PANC-1 cells, thus LINC00460 may act as a possible therapeutic target for treating PC.
Keywords: ANLN; Exosomes; LINC00460; M2 polarization; Pancreatic cancer; miR-503-5p.
© 2022. The Author(s).
Conflict of interest statement
All authors declare that they have no conflict of interest.
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References
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- 81800489/National Natural Science Foundation of China
- SYLY201718/Three engineering training funds in Shenzhen
- JCYJ20170307100538697/Technical Research and Development Project of Shenzhen
- JCYJ20160429174927286/Technical Research and Development Project of Shenzhen
- JCYJ20170307100911479/Technical Research and Development Project of Shenzhen
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