RNF219/<i>α</i>‐Catenin/LGALS3 Axis Promotes Hepatocellular Carcinoma Bone Metastasis and Associated Skeletal Complications

Zhang, Shuxia; Xu, Yinfeng; Xie, Chan; Lang, Ren; Wu, Geyan; Yang, Meisongzhu; Wu, Xingui; Tang, Miaoling; Hu, Yameng; Li, Ziwen; Yu, Ruyuan; Liao, Xinyi; Mo, Shuang; Wu, Jueheng; Li, Mengfeng; Song, Erwei; Qi, Yanfei; Song, Libing; Li, Jun

doi:10.1002/advs.202001961

Cited by 28 publications

(16 citation statements)

References 44 publications

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“…The galectin-3 promoter construct was generated as previously described [ 63 ]. Briefly, − 2000 to − 1 galectin-3 was generated from mouse genomic DNA.…”

Section: Methodsmentioning

confidence: 99%

Twist1 regulates macrophage plasticity to promote renal fibrosis through galectin-3

Sun

Wei

et al. 2022

Cell. Mol. Life Sci.

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Renal interstitial fibrosis is the pathological basis of end-stage renal disease, in which the heterogeneity of macrophages in renal microenvironment plays an important role. However, the molecular mechanisms of macrophage plasticity during renal fibrosis progression remain unclear. In this study, we found for the first time that increased expression of Twist1 in macrophages was significantly associated with the severity of renal fibrosis in IgA nephropathy patients and mice with unilateral ureteral obstruction (UUO). Ablation of Twist1 in macrophages markedly alleviated renal tubular injury and renal fibrosis in UUO mice, accompanied by a lower extent of macrophage infiltration and M2 polarization in the kidney. The knockdown of Twist1 inhibited the chemotaxis and migration of macrophages, at least partially, through the CCL2/CCR2 axis. Twist1 downregulation inhibited M2 macrophage polarization and reduced the secretion of the profibrotic factors Arg-1, MR (CD206), IL-10, and TGF-β. Galectin-3 was decreased in the macrophages of the conditional Twist1-deficient mice, and Twist1 was shown to directly activate galectin-3 transcription. Up-regulation of galectin-3 recovered Twist1-mediated M2 macrophage polarization. In conclusion, Twist1/galectin-3 signaling regulates macrophage plasticity (M2 phenotype) and promotes renal fibrosis. This study could suggest new strategies for delaying kidney fibrosis in patients with chronic kidney disease.

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“…The galectin-3 promoter construct was generated as previously described [ 63 ]. Briefly, − 2000 to − 1 galectin-3 was generated from mouse genomic DNA.…”

Section: Methodsmentioning

confidence: 99%

Twist1 regulates macrophage plasticity to promote renal fibrosis through galectin-3

Sun

Wei

et al. 2022

Cell. Mol. Life Sci.

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“…After seeding and forming micrometastases in the bone, tumor cells may die, or turn into dormancy or grow to a metastatic lesion in bone. To survive and establish metastases in the bone, tumor cells may also secrete such factors as lectin galactoside-binding soluble 3 (LGALS3) in hepatocellular carcinoma (HCC) to form a “vicious cycle” which facilitates seeding and expansion of metastatic tumor cells in the bone [ 26 ]. So far, there remain a great deal of unknown mechanisms underlying the bone metastasis of breast cancer, examples including the bone metastasis characteristics of different types breast cancer with high potential of bone metastasis, the regulation of homing receptors like CXCR4 and CXCR7, and impact of the immune microenvironment in bone metastases.…”

Section: Introductionmentioning

confidence: 99%

Silencing CTNND1 Mediates Triple-Negative Breast Cancer Bone Metastasis via Upregulating CXCR4/CXCL12 Axis and Neutrophils Infiltration in Bone

Lin

Fang

Liang

et al. 2021

Cancers

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Bone metastasis from triple-negative breast cancer (TNBC) frequently results in poorer prognosis than other types of breast cancer due to the delay in diagnosis and intervention, lack of effective treatments and more skeletal-related complications. In the present study, we identified CTNND1 as a most reduced molecule in metastatic bone lesion from TNBC by way of high throughput sequencing of TNBC samples. In vivo experiments revealed that knockdown of CTNND1 enhanced tumor cells metastasis to bones and also increased neutrophils infiltration in bones. In vitro, we demonstrated that knockdown of CTNND1 accelerated epithelial–mesenchymal transformation (EMT) of tumor cells and their recruitment to bones. The involvement by CTNND1 in EMT and bone homing was achieved by upregulating CXCR4 via activating the PI3K/AKT/HIF-1αpathway. Moreover, TNBC cells with reduced expression of CTNND1 elicited cytotoxic T-cells responses through accelerating neutrophils infiltration by secreting more GM-CSF and IL-8. Clinically, patients with triple-negative breast cancer and lower level of CTNND1 had shorter overall survival (OS) and distant metastasis-free survival (DMFS). It was concluded that downregulation of CTNND1 played a critical role in facilitating bone metastasis of TNBC and that CTNND1 might be a potential biomarker for predicting the risk of bone metastases in TNBC.

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“…Bhat et al revealed that upregulation of LGALS3 expression was associated significantly with HCC recurrence (42). Zhang et al identified LGALS3 as a key gene in the development of bone metastases and associated skeletal complications in HCC (43). Furthermore, among our screened prognostic signature genes, KLF2 (the only protective factor for the prognosis) has been shown to inhibit the growth, migration, and metastasis of HCC cells, and its expression to be downregulated significantly in HCC (44,45).…”

Section: Discussionmentioning

confidence: 99%

M2-like tumor-associated macrophage-related biomarkers to construct a novel prognostic signature, reveal the immune landscape, and screen drugs in hepatocellular carcinoma

Zhao

Lin

et al. 2022

Front. Immunol.

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BackgroundM2-like tumor-associated macrophages (M2-like TAMs) have important roles in the progression and therapeutics of cancers. We aimed to detect novel M2-like TAM-related biomarkers in hepatocellular carcinoma (HCC) via integrative analysis of single-cell RNA-seq (scRNA-seq) and bulk RNA-seq data to construct a novel prognostic signature, reveal the “immune landscape”, and screen drugs in HCC.MethodsM2-like TAM-related genes were obtained by overlapping the marker genes of TAM identified from scRNA-seq data and M2 macrophage modular genes identified by weighted gene co-expression network analysis (WGCNA) using bulk RNA-seq data. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were carried out to screen prognostic genes from M2-like TAM-related genes, followed by a construction of a prognostic signature, delineation of risk groups, and external validation of the prognostic signature. Analyses of immune cells, immune function, immune evasion scores, and immune-checkpoint genes between high- and low-risk groups were done to further reveal the immune landscape of HCC patients. To screen potential HCC therapeutic agents, analyses of gene–drug correlation and sensitivity to anti-cancer drugs were conducted.ResultsA total of 127 M2-like TAM-related genes were identified by integrative analysis of scRNA-seq and bulk-seq data. PDLIM3, PAM, PDLIM7, FSCN1, DPYSL2, ARID5B, LGALS3, and KLF2 were screened as prognostic genes in HCC by univariate Cox regression and LASSO regression analyses. Then, a prognostic signature was constructed and validated based on those genes for predicting the survival of HCC patients. In terms of drug screening, expression of PAM and LGALS3 was correlated positively with sensitivity to simvastatin and ARRY-162, respectively. Based on risk grouping, we predicted 10 anticancer drugs with high sensitivity in the high-risk group, with epothilone B having the lowest half-maximal inhibitory concentration among all drugs tested.ConclusionsOur findings enhance understanding of the M2-like TAM-related molecular mechanisms involved in HCC, reveal the immune landscape of HCC, and provide potential targets for HCC treatment.

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RNF219/α‐Catenin/LGALS3 Axis Promotes Hepatocellular Carcinoma Bone Metastasis and Associated Skeletal Complications

Cited by 28 publications

References 44 publications

Twist1 regulates macrophage plasticity to promote renal fibrosis through galectin-3

Twist1 regulates macrophage plasticity to promote renal fibrosis through galectin-3

Silencing CTNND1 Mediates Triple-Negative Breast Cancer Bone Metastasis via Upregulating CXCR4/CXCL12 Axis and Neutrophils Infiltration in Bone

M2-like tumor-associated macrophage-related biomarkers to construct a novel prognostic signature, reveal the immune landscape, and screen drugs in hepatocellular carcinoma

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