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 19 publications

(10 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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“…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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“…LGALS3 produced by HCC is located on the outer surface of osteoclast progenitor cells (OPs) and promotes CD98- and integrin 𝛼α/𝛽β complex–mediated fusion and podosome formation of osteoclasts. This is explained by increased the formation of TRAP + -multinuclear OCs and TRAP activity, but no alteration of ALP + -OBs along with the interface of bone-tumor ( 68 ). Furthermore, E3 ligase RNF219-mediated α-catenin degradation promotes the overexpression of LGALS3 through YAP1/β-catenin-dependent epigenetic modifications, resulting in HCC-BM and following SREs.…”

Section: Possible Hcc-bm Therapeutic Pathwaysmentioning

confidence: 99%

Emerging Perspectives of Bone Metastasis in Hepatocellular Carcinoma

et al. 2022

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Recent evidence suggests the global incidence and mortality of hepatocellular carcinoma (HCC) are increasing. Although the highest incidence of HCC remains entrenched in WHO regions with high levels of HBV-HCV infection, the etiology of this disease is rapidly changing to include other lifestyle risk factors. Extrahepatic metastasis is a frequent feature of advanced HCC and most commonly locates in the lungs and bone. Bone metastasis in HCC (HCC-BM) signals a more aggressive stage of disease and a poorer prognosis, simultaneously HCC-BM compromises the function and integrity of bone tissue. HCC induced osteolysis is a prominent feature of metastasis that complicates treatment needed for pathologic fractures, bone pain and other skeletal events like hypercalcemia and nerve compression. Early detection of bone metastases facilitates the treatment strategy for avoiding and relieving complications. Although recent therapeutic advances in HCC like targeting agents and immunotherapy have improved survival, the prognosis for patients with HCC-BM remains problematic. The identification of critical HCC-BM pathways in the bone microenvironment could provide important insights to guide future detection and therapy. This review presents an overview of the clinical development of bone metastases in HCC, identifying key clinical features and identifying potential molecular targets that can be deployed as diagnostic tools or therapeutic agents.

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

Cited by 19 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

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

Emerging Perspectives of Bone Metastasis in Hepatocellular Carcinoma

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