Hypoxia‐inducible factor‐1α/interleukin‐1β signaling enhances hepatoma epithelial–mesenchymal transition through macrophages in a hypoxic‐inflammatory microenvironment

Zhang, Jingying; Zhang, Qi; Lou, Yiting; Fu, Qihan; Chen, Qi; Tao, Wei; Yang, Jiaqi; Tang, Jinlong; Wang, Jianxin; Chen, Yiwen; Zhang, Xiaoyu; Zhang, Jian; Bai, Xueli; Liang, Tingbo

doi:10.1002/hep.29681

Cited by 250 publications

(180 citation statements)

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“…In LT, a marked depletion of processes related to energy production was observed as well as moderate enrichment of functions related to hypoxia tolerance, which together point toward the well‐characterized strong reliance of cancer cells on glycolysis for energy production . It is also conceivable that the increased human leukocyte antigen class I antigen presentation in HCC may well represent the presence of infiltrating macrophages responding to the hypoxia inducible factor‐α in the hypoxic microenvironment . LR and LT represent snapshots of different stages of HCC, and the differences observed in the molecular profile of such samples likely reflect temporal divergences in cancer cell physiology.…”

Section: Discussionmentioning

confidence: 99%

“…(27) It is also conceivable that the increased human leukocyte antigen class I antigen presentation in HCC may well represent the presence of infiltrating macrophages responding to the hypoxia inducible factor-a in the hypoxic microenvironment. (28) LR and LT represent snapshots of different stages of HCC, and the differences observed in the molecular profile of such samples likely reflect temporal divergences in cancer cell physiology. For instance, initial stages of tumorigenesis are associated with highly proliferative cellular phenotypes (tumor growth).…”

Section: Discussionmentioning

confidence: 99%

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A Survey of Molecular Heterogeneity in Hepatocellular Carcinoma

Jovel

Lin

OʼKeefe

et al. 2018

Hepatology Communications

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Understanding the heterogeneity of dysregulated pathways associated with the development of hepatocellular carcinoma (HCC) may provide prognostic and therapeutic avenues for disease management. As HCC involves a complex process of genetic and epigenetic modifications, we evaluated expression of both polyadenylated transcripts and microRNAs from HCC and liver samples derived from two cohorts of patients undergoing either partial hepatic resection or liver transplantation. Copy number variants were inferred from whole genome low‐pass sequencing data, and a set of 56 cancer‐related genes were screened using an oncology panel assay. HCC was associated with marked transcriptional deregulation of hundreds of protein‐coding genes. In the partially resected livers, diminished transcriptional activity was observed in genes associated with drug catabolism and increased expression in genes related to inflammatory responses and cell proliferation. Moreover, several long noncoding RNAs and microRNAs not previously linked with HCC were found to be deregulated. In liver transplant recipients, down‐regulation of genes involved in energy production and up‐regulation of genes associated with glycolysis were detected. Numerous copy number variants events were observed, with hotspots on chromosomes 1 and 17. Amplifications were more common than deletions and spanned regions containing genes potentially involved in tumorigenesis. Colony stimulating factor 1 receptor (CSF1R), fibroblast growth factor receptor 3 (FGFR3), fms‐like tyrosine kinase 3 (FLT3), nucleolar phosphoprotein B23 (NPM1), platelet‐derived growth factor receptor alpha polypeptide (PDGFRA), phosphatase and tensin homolog (PTEN), G‐protein‐coupled receptors‐like receptor Smoothened (SMO), and tumor protein P53 (TP53) were mutated in all tumors; another 26 cancer‐related genes were mutated with variable penetrance. Conclusion: Our results underscore the marked molecular heterogeneity between HCC tumors and reinforce the notion that precision medicine approaches are needed for management of individual HCC. These data will serve as a resource to generate hypotheses for further research to improve our understanding of HCC biology. (Hepatology Communications 2018; 00:000‐000)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Survey of Molecular Heterogeneity in Hepatocellular Carcinoma

Jovel

Lin

OʼKeefe

et al. 2018

Hepatology Communications

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“…Immunoblotting was performed as described previously . In brief, total proteins were extracted from whole‐lung homogenates using RIPA lysis buffer (ThermoFisher Scientific, Waltham, MA).…”

Section: Evaluation Of Airway Hyperresponsivenessmentioning

confidence: 99%

Gallic acid attenuates allergic airway inflammation via suppressed interleukin‐33 and group 2 innate lymphoid cells in ovalbumin‐induced asthma in mice

Wang

Zhao

et al. 2018

Int Forum Allergy Rhinol

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“…Therefore, in addition to tumor cells, tumor‐infiltrating leukocytes (TILs), and tumor‐associated macrophages (TAMs), for instance, are susceptible to oxygen shortage and tumor metabolites, eventually resulting in immunosuppression and tumor escape . TAMs are widely present in the tumor microenvironment and are able to promote angiogenesis, cell invasion, and TILs accumulation . However, in hypoxic context, the functions of TAMs and their relevant mechanisms of immunosuppression are far less understood.…”

mentioning

confidence: 99%

Blocking Triggering Receptor Expressed on Myeloid Cells‐1‐Positive Tumor‐Associated Macrophages Induced by Hypoxia Reverses Immunosuppression and Anti‐Programmed Cell Death Ligand 1 Resistance in Liver Cancer

et al. 2019

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Tumor‐associated macrophages (TAMs) are recognized as antitumor suppressors, but how TAMs behave in the hypoxic environment of hepatocellular carcinoma (HCC) remains unclear. Here, we demonstrated that hypoxia inducible factor 1α induced increased expression of triggering receptor expressed on myeloid cells‐1 (TREM‐1) in TAMs, resulting in immunosuppression. Specifically, TREM‐1‐positive (TREM‐1+) TAMs abundant at advanced stages of HCC progression indirectly impaired the cytotoxic functions of CD8+ T cells and induced CD8+ T‐cells apoptosis. Biological and functional assays showed that TREM‐1+ TAMs had higher expression of programmed cell death ligand 1 (PD‐L1) under hypoxic environment. However, TREM‐1+ TAMs could abrogate spontaneous and PD‐L1‐blockade‐mediated antitumor effects in vivo, suggesting that TREM‐1+ TAM‐induced immunosuppression was dependent on a pathway separate from PD‐L1/programmed cell death 1 axis. Moreover, TREM‐1+ TAM‐associated regulatory T cells (Tregs) were crucial for HCC resistance to anti‐PD‐L1 therapy. Mechanistically, TREM‐1+ TAMs elevated chemokine (C‐C motif) ligand 20 expression through the extracellular signal‐regulated kinase/NF‐κβ pathway in response to hypoxia and tumor metabolites leading to CCR6+Foxp3+ Treg accumulation. Blocking the TREM‐1 pathway could significantly inhibit tumor progression, reduce CCR6+Foxp3+ Treg recruitment, and improve the therapeutic efficacy of PD‐L1 blockade. Thus, these data demonstrated that CCR6+Foxp3+ Treg recruitment was crucial for TREM‐1+ TAM‐mediated anti‐PD‐L1 resistance and immunosuppression in hypoxic tumor environment. Conclusion: This study highlighted that the hypoxic environment initiated the onset of tumor immunosuppression through TREM‐1+ TAMs attracting CCR6+Foxp3+ Tregs, and TREM‐1+ TAMs endowed HCC with anti‐PD‐L1 therapy resistance.

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Hypoxia‐inducible factor‐1α/interleukin‐1β signaling enhances hepatoma epithelial–mesenchymal transition through macrophages in a hypoxic‐inflammatory microenvironment

Cited by 250 publications

References 44 publications

A Survey of Molecular Heterogeneity in Hepatocellular Carcinoma

A Survey of Molecular Heterogeneity in Hepatocellular Carcinoma

Gallic acid attenuates allergic airway inflammation via suppressed interleukin‐33 and group 2 innate lymphoid cells in ovalbumin‐induced asthma in mice

Blocking Triggering Receptor Expressed on Myeloid Cells‐1‐Positive Tumor‐Associated Macrophages Induced by Hypoxia Reverses Immunosuppression and Anti‐Programmed Cell Death Ligand 1 Resistance in Liver Cancer

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