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LncRNA HLA-F-AS1 promotes colorectal cancer metastasis by inducing PFN1 in colorectal cancer-derived extracellular vesicles and mediating macrophage polarization

Cancer Gene Therapy volume 28, pages 1269–1284 (2021)Cite this article

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Abstract

Colorectal cancer (CRC) is a prevalent malignancy with high incidence and low 5-year survival. Long non-coding RNAs (lncRNAs), a kind of specific RNA transcript, are increasingly implicated in tumor growth, metastasis, invasion, and prognosis by regulating the tumor microenvironment in extracellular vesicles (EVs). This study aims at investigating the potential effect of lncRNA HLA-F-AS1 on CRC by affecting the profilin 1 (PFN1) expression pattern in the tumor EVs. The expression patterns of HLA-F-AS1 and miR-375 were determined by RT-qPCR in the CRC tissues and cells. CCK-8 and Transwell assays were conducted to detect the cell proliferation and migration, and invasion, respectively. Western blot analysis was performed to measure the expression pattern of the epithelial–mesenchymal transition (EMT) markers. Bioinformatics prediction website and dual-luciferase reporter assay were conducted to verify the interaction between HLA-F-AS1 and miR-375. The CRC-derived EVs were extracted with the expression pattern of PFN1 determined by ELISA, while its effect on the macrophage polarization was assessed by flow cytometry. The effect of PFN1-treated macrophages on CRC cell proliferation and migration was observed by subcutaneous tumorigenesis experiments in nude mice. The results indicated that the HLA-F-AS1 expression pattern was increased in the CRC tissues and cells, which promoted the migration, invasion, and EMT of CRC cells in vitro. Mechanistically, HLA-F-AS1 competitively bound to miR-375 and inversely regulated miR-375 expression pattern. Interestingly, PFN1 was identified as a direct target of miR-375, and positively modulated by HLA-F-AS1 by binding to miR-375. Overexpression of HLA-F-AS1 repressed miR-375 and promoted the PFN1 expression pattern in CRC cells and CRC-derived EVs, further promoting M2 polarization of macrophages. Furthermore, macrophages treated with PFN1 in CRC-derived EVs stimulated CRC cell proliferation and migration in vitro and in vivo. Collectively, these outcomes highlight that HLA-F-AS1 promotes the expression pattern of PFN1 in CRC-EVs by inhibiting miR-375, thereby polarizing macrophages toward M2 phenotype, and aggravating the tumorigenesis of CRC, eliciting that HLA-F-AS1 may serve as a viable and promising therapeutic strategy for CRC.

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Fig. 1: LncRNA HLA-F-AS1 is overexpressed in CRC tissues and cells, and potentiates proliferation, migration, and invasion of CRC cells in vitro.
Fig. 2: LncRNA HLA-F-AS1 targets miR-375 and inhibits its expression, and miR-375 reverts the effect of HLA-F-AS1 on CRC cell malignant phenotype in vitro.
Fig. 3: LncRNA HLA-F-AS1 targets miR-375 to promote CRC metastasis in vivo.
Fig. 4: LncRNA HLA-F-AS1 increases the PFN1 expression pattern by inhibiting miR-375 in vitro.
Fig. 5: PFN1 from tumor-derived EVs promotes macrophages polarized to M2 phenotype in vitro.
Fig. 6: PFN1 from tumor-derived EVs mediates the M2 polarization of macrophage to promote the CRC migration and metastasis in vitro and in vivo.
Fig. 7: LncRNA HLA-F-AS1 promotes EVs PFN1 to modulate M2 polarization of macrophage by inhibiting miR-375.
Fig. 8: The graphical summary of the function and mechanism of the lncRNA HLA-F-AS1.

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Acknowledgements

We would like to show sincere appreciation to the reviewers for critical comments on this article.

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Author notes

  1. These authors contributed equally: Jing Zhang, Shiqun Li

Authors and Affiliations

  1. Department of Colorectal and Anal Surgery, The First Hospital of Jilin University, Changchun, 130000, P.R. China

    Jing Zhang, Shiquan Li, Chao Li & Jiantao Zhang

  2. Department of Anesthesiology, The First Hospital of Jilin University, Changchun, 130000, P.R. China

    Xiaona Zhang

  3. Department of Neonatology, The First Hospital of Jilin University, Changchun, 130000, P.R. China

    Wenli Zhou

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JZ and SL designed the study. XZ, CL, and JZ collated the data, carried out data analyses, and produced the initial draft of the manuscript. JZ and WZ contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

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Correspondence to Jiantao Zhang or Wenli Zhou.

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Zhang, J., Li, S., Zhang, X. et al. LncRNA HLA-F-AS1 promotes colorectal cancer metastasis by inducing PFN1 in colorectal cancer-derived extracellular vesicles and mediating macrophage polarization. Cancer Gene Ther 28, 1269–1284 (2021). https://doi.org/10.1038/s41417-020-00276-3

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