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miR-128 Regulates Tumor Cell CD47 Expression and Promotes Anti-tumor Immunity in Pancreatic Cancer

Xi, Qing, Chen, Ying, Yang, Guang-Ze, Zhang, Jie-You, Zhang, Li-Juan, Guo, Xiang-Dong, Zhao, Jing-Yi, Xue, Zhen-Yi, Li, Yan, Zhang, Rongxin·2020·Frontiers in Immunology
DOI 10.3389/fimmu.2020.00890PMC PMC7267029
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Figure 1 miR-128 is related to overall survival of pancreatic adenocarcinoma (PDAC) and inversely correlated with cluster of differentiation 47 (CD47), which is positively related to zinc finger E-box-binding homeobox 1 (ZEB1) in PDAC. The clinical relevance was analyzed using the LinkedOmics database. (A,B) High expression of hsa–mir-128-1 (A, N = 172, p < 0.01) and hsa–mir-128-2 (B, N = 172, p < 0.01) indicates better progression-free survival in patients with PDAC. (C,D) Hsa–mir-128-1 (C, N = 178, R = −0.1851, p < 0.05) and hsa–mir-128-2 (D, N = 178, R = −0.1541, p < 0.05) are inversely related to CD47 in PDAC. (E,F) CD47 is positively related to ZEB1 in PDAC (E, N = 178, R = 0.2578, p < 0.001) and skin cutaneous melanoma (SKCM) (F, N = 103, R = 0.3396, p < 0.001).
Figure 1 miR-128 is related to overall survival of pancreatic adenocarcinoma (PDAC) and inversely correlated with cluster of differentiation 47 (CD47), which is positively related to zinc finger E-box-binding homeobox 1 (ZEB1) in PDAC. The clinical relevance was analyzed using the LinkedOmics database. (A,B) High expression of hsa–mir-128-1 (A, N = 172, p < 0.01) and hsa–mir-128-2 (B, N = 172, p < 0.01) indicates better progression-free survival in patients with PDAC. (C,D) Hsa–mir-128-1 (C, N = 178, R = −0.1851, p < 0.05) and hsa–mir-128-2 (D, N = 178, R = −0.1541, p < 0.05) are inversely related to CD47 in PDAC. (E,F) CD47 is positively related to ZEB1 in PDAC (E, N = 178, R = 0.2578, p < 0.001) and skin cutaneous melanoma (SKCM) (F, N = 103, R = 0.3396, p < 0.001).CC BY · PubMed Central
Figure 2 Overexpression of miR-128 inhibited tumor growth and metastasis in PDAC. To establish the orthotopic mouse model of PDAC, miR-NC/miR-128 stable overexpression Panc02 cells were directly injected into the pancreas of C57BL/6 mice (n = 5/group). (A) A schematic diagram of the mouse model of PDAC. (B) Typical tumor photograph. (C) Tumor volume. (D) Tumor weight. (E) Macroscopic image of liver metastasis. The red arrows point to the metastatic sites. (F) Hematoxylin and eosin (HE) staining of liver metastasis; the areas of metastasis were circled in red. (G) The statistics of liver metastasis. The results represent the mean ± SEM from three independent experiments. Comparisons between groups were determined by Student's t-test. *p < 0.05, **p < 0.01.
Figure 2 Overexpression of miR-128 inhibited tumor growth and metastasis in PDAC. To establish the orthotopic mouse model of PDAC, miR-NC/miR-128 stable overexpression Panc02 cells were directly injected into the pancreas of C57BL/6 mice (n = 5/group). (A) A schematic diagram of the mouse model of PDAC. (B) Typical tumor photograph. (C) Tumor volume. (D) Tumor weight. (E) Macroscopic image of liver metastasis. The red arrows point to the metastatic sites. (F) Hematoxylin and eosin (HE) staining of liver metastasis; the areas of metastasis were circled in red. (G) The statistics of liver metastasis. The results represent the mean ± SEM from three independent experiments. Comparisons between groups were determined by Student's t-test. *p < 0.05, **p < 0.01.CC BY · PubMed Central
Figure 3 Overexpression of miR-128 enhanced anti-tumor immunity. The tumors and spleens were isolated from in situ pancreas-tumor-bearing mice and stained for flow cytometry analysis. The dendritic cells (DCs) (A,B), macrophages (C,D), CD8+ T cells (E,F), and natural killer T (NKT) cells (G,H) were analyzed by flow cytometry analysis. The results represent the mean ± SEM from three independent experiments. Comparisons between groups were determined by Student's t-test. *p < 0.05, **p < 0.01.
Figure 3 Overexpression of miR-128 enhanced anti-tumor immunity. The tumors and spleens were isolated from in situ pancreas-tumor-bearing mice and stained for flow cytometry analysis. The dendritic cells (DCs) (A,B), macrophages (C,D), CD8+ T cells (E,F), and natural killer T (NKT) cells (G,H) were analyzed by flow cytometry analysis. The results represent the mean ± SEM from three independent experiments. Comparisons between groups were determined by Student's t-test. *p < 0.05, **p < 0.01.CC BY · PubMed Central
Figure 4 Overexpression of miR-128 in Panc02 cells enhanced the phagocytosis of macrophages and the activity of DCs. miR-NC or miR-128 overexpression Panc02 cells were incubated with mouse bone-marrow-derived macrophages (BMDMs) or peritoneal-cavity-derived macrophages for 4 h, stained with F4/80-APC antibody, and analyzed by flow cytometry. (A,C) Representative plots show the percentage of F4/80+GFP+ macrophages phagocytosing cancer cells among F4/80+ BMDMs and peritoneal-cavity-derived macrophages. (B,D) Statistical analysis of the phagocytosis of cancer cells by both BMDMs and peritoneal-cavity-derived macrophages. MiR-NC or miR-128 overexpression Panc02 cells were incubated with mouse bone-marrow-derived dendritic cells (BMDCs) for 48 h. The expression of costimulatory molecules CD80 (E) and CD86 (F) and antigen peptides MHC-I (G) and MHC-II (H) on DCs were analyzed by flow cytometry. These results represent the mean ± SEM from three independent experiments. Comparisons among three groups were determined by ANOVA. *p < 0.05, **p < 0.01, and ***p < 0.001.
Figure 4 Overexpression of miR-128 in Panc02 cells enhanced the phagocytosis of macrophages and the activity of DCs. miR-NC or miR-128 overexpression Panc02 cells were incubated with mouse bone-marrow-derived macrophages (BMDMs) or peritoneal-cavity-derived macrophages for 4 h, stained with F4/80-APC antibody, and analyzed by flow cytometry. (A,C) Representative plots show the percentage of F4/80+GFP+ macrophages phagocytosing cancer cells among F4/80+ BMDMs and peritoneal-cavity-derived macrophages. (B,D) Statistical analysis of the phagocytosis of cancer cells by both BMDMs and peritoneal-cavity-derived macrophages. MiR-NC or miR-128 overexpression Panc02 cells were incubated with mouse bone-marrow-derived dendritic cells (BMDCs) for 48 h. The expression of costimulatory molecules CD80 (E) and CD86 (F) and antigen peptides MHC-I (G) and MHC-II (H) on DCs were analyzed by flow cytometry. These results represent the mean ± SEM from three independent experiments. Comparisons among three groups were determined by ANOVA. *p < 0.05, **p < 0.01, and ***p < 0.001.CC BY · PubMed Central
Figure 5 MiR-128 inhibited the cell proliferation, migration, and invasion of PDAC cells. (A) Cell Counting Kit-8 (CCK-8) assay: the proliferation of miR-128 lentivirus-infected cells was lower than that of the control group at 24 and 48 h. (B) Clonogenicity assays: the miR-128 lentivirus-infected cells had a significantly lower survival rate than the control cells. (C,D) Wound healing assay: the migration of miR-128 lentivirus-infected cells was slower than that of the control cells. (E,F) Transwell assay: the percentage of cells that invaded through the Matrigel was lower in miR-128 lentivirus-infected cells than in the control cells. (G,H) The expression of genes associated with epithelial–mesenchymal transition (EMT) after mimic transfection and lentivirus infection. The results represent the mean ± SEM from three independent experiments. Comparisons between groups were determined by Student's t-test. ***p < 0.001.
Figure 5 MiR-128 inhibited the cell proliferation, migration, and invasion of PDAC cells. (A) Cell Counting Kit-8 (CCK-8) assay: the proliferation of miR-128 lentivirus-infected cells was lower than that of the control group at 24 and 48 h. (B) Clonogenicity assays: the miR-128 lentivirus-infected cells had a significantly lower survival rate than the control cells. (C,D) Wound healing assay: the migration of miR-128 lentivirus-infected cells was slower than that of the control cells. (E,F) Transwell assay: the percentage of cells that invaded through the Matrigel was lower in miR-128 lentivirus-infected cells than in the control cells. (G,H) The expression of genes associated with epithelial–mesenchymal transition (EMT) after mimic transfection and lentivirus infection. The results represent the mean ± SEM from three independent experiments. Comparisons between groups were determined by Student's t-test. ***p < 0.001.CC BY · PubMed Central
Figure 6 miR-128 promotes anti-tumor immunity through the ZEB1/CD47 axis. (A,B) The expression of CD47 and ZEB1 were downregulated in miR-128 mimic-transfected Panc02 cells. (C,D) The expression of CD47 and ZEB1 were downregulated in miR-128 lentivirus-infected Panc02 cells. (E,F) The expression of CD47 and ZEB1 were downregulated in miR-128 mimic-transfected H7 cells. (G,H) The expression of CD47 and ZEB1 were downregulated in miR-128 mimic-transfected PANC1 cells. (I,J) The expression of ZEB1, miR-128, and CD47 in ZEB1 knockdown Panc02 cells. (K) A schematic of the molecular mechanism by which miR-128 causes tumor regression. These results represent the mean ± SEM from three independent experiments. Comparisons between groups were determined by Student's t-test. *p < 0.05, **p < 0.01, and ***p < 0.001.
Figure 6 miR-128 promotes anti-tumor immunity through the ZEB1/CD47 axis. (A,B) The expression of CD47 and ZEB1 were downregulated in miR-128 mimic-transfected Panc02 cells. (C,D) The expression of CD47 and ZEB1 were downregulated in miR-128 lentivirus-infected Panc02 cells. (E,F) The expression of CD47 and ZEB1 were downregulated in miR-128 mimic-transfected H7 cells. (G,H) The expression of CD47 and ZEB1 were downregulated in miR-128 mimic-transfected PANC1 cells. (I,J) The expression of ZEB1, miR-128, and CD47 in ZEB1 knockdown Panc02 cells. (K) A schematic of the molecular mechanism by which miR-128 causes tumor regression. These results represent the mean ± SEM from three independent experiments. Comparisons between groups were determined by Student's t-test. *p < 0.05, **p < 0.01, and ***p < 0.001.CC BY · PubMed Central

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Metadata

Authors
Xi, Q., Chen, Y., Yang, G.-Z., Zhang, J.-Y., Zhang, L.-J., Guo, X.-D., Zhao, J.-Y., Xue, Z.-Y., Li, Y., & Zhang, R.
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2020-05-27
Volume
11
ISSN
1664-3224
DOI
10.3389/fimmu.2020.00890
PMC
PMC7267029
Cited by
47
References
3
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
National Natural Science Foundation of China

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