Abstract
Tumor-associated macrophages (TAMs) and their M2-type extremely promote tumor angiogenesis, invasion and metastasis, including hepatocellular carcinoma (HCC). Nogo-B is expressed in most tissues and participates in macrophage polarization. However, whether Nogo-B is involved in the polarization and the effects of TAMs has been unclear. The expression of Nogo-B in TAMs of HCC patients is significantly increased, which correlated with the poor prognosis of the patients with HCC. Coincidentally, HCC conditioned medium (HCM) facilitated Nogo-B expression and the M2 phenotype of macrophages. Nogo-B knockdown Nogo-B significantly suppressed the M2-type polarization of macrophages and inhibited HCC cells proliferation both in vivo and in vitro. Furthermore, interference of Nogo-B facilitates macrophage-mediated apoptosis of tumor cells. Nogo-B meaningfully enhanced IL4-stimulated the alternative activation of macrophages as well as expression of the transcriptional regulators Yes-associated protein (Yap)/transcriptional coactivator with PDZ-binding motif (Taz). An inhibitor of Yap, Verteporfin, could block Nogo-B-Yap/Taz-mediated macrophages M2 polarization. Nogo-B expression in macrophages facilitates tumor-associated macrophages M2 polarization and protumoral effects of TAMs in HCC. Targeting Nogo-B/Yap/Taz in macrophages could provide a new therapeutic strategy in HCC therapy.
Keywords:
HCC; M2-type polarization; Nogo-B; TAMs; Yap/Taz.
Copyright © 2020 Elsevier Inc. All rights reserved.
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Aged
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Animals
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Carcinoma, Hepatocellular / diagnosis
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Carcinoma, Hepatocellular / genetics*
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Carcinoma, Hepatocellular / mortality
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Carcinoma, Hepatocellular / surgery
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Cell Differentiation / drug effects
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Disease Progression
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Female
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Gene Expression Regulation, Neoplastic*
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Humans
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Interleukin-4 / genetics
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Interleukin-4 / metabolism
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Liver Neoplasms / diagnosis
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Liver Neoplasms / genetics*
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Liver Neoplasms / mortality
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Liver Neoplasms / surgery
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Middle Aged
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Prognosis
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Receptors, Cell Surface / antagonists & inhibitors
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Receptors, Cell Surface / genetics*
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Receptors, Cell Surface / metabolism
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Signal Transduction
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Survival Analysis
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Trans-Activators / genetics*
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Trans-Activators / metabolism
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Transcriptional Coactivator with PDZ-Binding Motif Proteins
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Tumor-Associated Macrophages / drug effects
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Tumor-Associated Macrophages / metabolism*
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Tumor-Associated Macrophages / pathology
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Verteporfin / pharmacology
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Xenograft Model Antitumor Assays
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YAP-Signaling Proteins
Substances
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Adaptor Proteins, Signal Transducing
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IL4 protein, human
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NUS1 protein, human
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RNA, Small Interfering
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Receptors, Cell Surface
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Trans-Activators
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Transcription Factors
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Transcriptional Coactivator with PDZ-Binding Motif Proteins
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WWTR1 protein, human
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YAP-Signaling Proteins
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YAP1 protein, human
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Verteporfin
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Interleukin-4