Interaction of transforming growth factor‐β‐Smads/microRNA‐362‐3p/CD82 mediated by M2 macrophages promotes the process of epithelial‐mesenchymal transition in hepatocellular carcinoma cells

Huang, Feng; Yao, Yongliang; Wang, Jianjun; Wei, Jue; Wu, Qiong; Xiang, Shihao; Xu, Ling

doi:10.1111/cas.14101

Cited by 49 publications

(36 citation statements)

References 41 publications

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“…Surface proteins, such as CD206 (mannose receptor-1), CD204 and CD163 (macrophage scavenger receptors), are also overexpressed ( 28 ). These M2-like TAMs have critical roles in facilitating epithelial-mesenchymal transition (EMT), angiogenesis and immunosuppression ( 29 , 30 ). Moreover, M2-like TAMs are one of the factors hampering the efficacy of chemotherapy and radiotherapy through suppression of CD8 + T cell function, leading to tumor progression and poor outcomes ( 28 , 31 , 32 ).…”

Section: Characteristics Of Tamsmentioning

confidence: 99%

Redefining Tumor-Associated Macrophage Subpopulations and Functions in the Tumor Microenvironment

et al. 2020

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The immunosuppressive status of the tumor microenvironment (TME) remains poorly defined due to a lack of understanding regarding the function of tumor-associated macrophages (TAMs), which are abundant in the TME. TAMs are crucial drivers of tumor progression, metastasis, and resistance to therapy. Intra-and inter-tumoral spatial heterogeneities are potential keys to understanding the relationships between subpopulations of TAMs and their functions. Antitumor M1-like and pro-tumor M2-like TAMs coexist within tumors, and the opposing effects of these M1/M2 subpopulations on tumors directly impact current strategies to improve antitumor immune responses. Recent studies have found significant differences among monocytes or macrophages from distinct tumors, and other investigations have explored the existence of diverse TAM subsets at the molecular level. In this review, we discuss emerging evidence highlighting the redefinition of TAM subpopulations and functions in the TME and the possibility of separating macrophage subsets with distinct functions into antitumor M1-like and pro-tumor M2-like TAMs during the development of tumors. Such redefinition may relate to the differential cellular origin and monocyte and macrophage plasticity or heterogeneity of TAMs, which all potentially impact macrophage biomarkers and our understanding of how the phenotypes of TAMs are dictated by their ontogeny, activation status, and localization. Therefore, the detailed landscape of TAMs must be deciphered with the integration of new technologies, such as multiplexed immunohistochemistry (mIHC), mass cytometry by time-of-flight (CyTOF), single-cell RNA-seq (scRNA-seq), spatial transcriptomics, and systems biology approaches, for analyses of the TME.

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Section: Characteristics Of Tamsmentioning

confidence: 99%

Redefining Tumor-Associated Macrophage Subpopulations and Functions in the Tumor Microenvironment

et al. 2020

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“…9,10 Recent studies demonstrate that S100A9 could promote growth and metastasis of HCC cells. 11,12 Previous studies have revealed the cross talk between TAMs and cancer cells in HCC through soluble factors, including transforming growth factor-β (TGF-β), 13 hepatocyte growth factor 14 and IL-6. 15 These factors secreted from TAMs could promote the tumor progression by activating intrinsic signaling pathways of cancer cells, which are associated with epithelialmesenchymal transition, drug resistance and stemness.…”

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confidence: 99%

S100 calcium‐binding protein A9 from tumor‐associated macrophage enhances cancer stem cell‐like properties of hepatocellular carcinoma

Wei

Zhu

et al. 2020

Intl Journal of Cancer

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Tumor‐associated macrophages (TAMs) are crucial components of the tumor microenvironment. They play vital roles in hepatocellular carcinoma (HCC) progression. However, the interactions between TAMs and HCC cells have not been fully characterized. In this study, TAMs were induced using human monocytic cell line THP‐1 cells in vitro to investigate their functions in HCC progression. S100 calcium‐binding protein A9 (S100A9), an inflammatory microenvironment‐related secreted protein, was identified to be significantly upregulated in TAMs. S100A9 expression in tumor tissues was associated with poor survival of HCC patients. It could enhance the stem cell‐like properties of HepG2 and MHCC‐97H cells by activating nuclear factor‐kappa B signaling pathway through advanced glycosylation end product‐specific receptor in a Ca2+‐dependent manner. Furthermore, we found that, after treatment with S100A9, HepG2 and MHCC‐97H cells recruited more macrophages via chemokine (CC motif) ligand 2, which suggests a positive feedback between TAMs and HCC cells. Taken together, our findings reveal that TAMs could upregulate secreted protein S100A9 and enhance the stem cell‐like properties of HCC cells and provide a potential therapeutic target for combating HCC.

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“…Furthermore, there are other precedents of miRNA positive regulation of the EMT process via feedback, double feedback or forward-feed loops between miRNAs and the targets, such as SNAI1 and E-cadherin (reviewed in 26 , 27 ). Zhang et al (2019) 49 have recently shown that the SMAD2/3 complex binds to the promoter of the miR-362 gene to positively regulate miR-362 expression (Fig. 6 A, blue lines).…”

Section: Discussionmentioning

confidence: 91%

MicroRNA-362 negatively and positively regulates SMAD4 expression in TGF-β/SMAD signaling to suppress cell migration and invasion

Cheng¹,

Huang²,

Tsai³

et al. 2021

Int. J. Med. Sci.

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Cell migration and invasion are modulated by epithelial-to-mesenchymal transition (EMT) and the reverse MET process. Despite the detection of microRNA-362 (miR-362, both the miR-362-5p and -3p species) in cancers, none of the identified miR-362 targets is a mesenchymal or epithelial factor to link miR-362 with EMT/MET and metastasis. Focusing on the TGF-β/SMAD signaling pathway in this work, luciferase assays and western blot data showed that miR-362 targeted and negatively regulated expression of SMAD4 and E-cadherin, but not SNAI1, which is regulated by SMAD4. However, miR-362 knockdown also down-regulated SMAD4 and SNAI1, but up-regulated E-cadherin expression. Wound-healing and transwell assays further showed that miR-362 knockdown suppressed cell migration and invasion, effects which were reversed by over-expressing SMAD4 or SNAI1, or by knocking down E-cadherin in the miR-362 knockdown cells. In orthotopic mice, miR-362 knockdown inhibited metastasis, and displayed the same SMAD4 and E-cadherin expression profiles in the tumors as in the in vitro studies. A scheme is proposed to integrate miR-362 negative regulation via SMAD4, and to explain miR-362 positive regulation of SMAD4 via miR-362 targeting of known SMAD4 suppressors, BRK and DACH1, which would have resulted in SMAD4 depletion and annulment of subsequent involvement in TGF-β signaling actions. Hence, miR-362 both negatively and positively regulates SMAD4 expression in TGF-β/SMAD signaling pathway to suppress cell motility and invasiveness and metastasis, and may explain the reported clinical association of anti-miR-362 with suppressed metastasis in various cancers. MiR-362 knockdown in miR-362-positive cancer cells may be used as a therapeutic strategy to suppress metastasis.

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Interaction of transforming growth factor‐β‐Smads/microRNA‐362‐3p/CD82 mediated by M2 macrophages promotes the process of epithelial‐mesenchymal transition in hepatocellular carcinoma cells

Cited by 49 publications

References 41 publications

Redefining Tumor-Associated Macrophage Subpopulations and Functions in the Tumor Microenvironment

Redefining Tumor-Associated Macrophage Subpopulations and Functions in the Tumor Microenvironment

S100 calcium‐binding protein A9 from tumor‐associated macrophage enhances cancer stem cell‐like properties of hepatocellular carcinoma

MicroRNA-362 negatively and positively regulates SMAD4 expression in TGF-β/SMAD signaling to suppress cell migration and invasion

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