Proteoglycan-4 is correlated with longer survival in HCC patients and enhances sorafenib and regorafenib effectiveness via CD44 in vitro

Dituri, Francesco; Scialpi, Rosanna; Schmidt, Tannin A.; Frusciante, Martina; Mancarella, Serena; Lupo, L.; Villa, Erica; Giannelli, Gianluigi

doi:10.1038/s41419-020-03180-8

Cited by 16 publications

(18 citation statements)

References 64 publications

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“…For instance, versican was observed in various types of malignancies, including breast cancer, prostate cancer, and HCC, where it is associated with high rates of cancer relapse and poor outcomes [38][39][40][41]. In contrast, DCN and protein proteoglycan 4 demonstrate protective functions in HCC cases [42,43]. Our results demonstrate that DCN is one of the CSPGs that are modified by CHPF, and the shortened CS on DCN may alter its extracellular distribution around HCC cells.…”

Section: Discussionmentioning

confidence: 99%

CHPF Regulates the Aggressive Phenotypes of Hepatocellular Carcinoma Cells via the Modulation of the Decorin and TGF-β Pathways

Liu

et al. 2021

Cancers

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Aberrant composition of glycans in the tumor microenvironment (TME) and abnormal expression of extracellular matrix proteins are hallmarks of hepatocellular carcinoma (HCC); however, the mechanisms responsible for establishing the TME remain unclear. We demonstrate that the chondroitin polymerizing factor (CHPF), an enzyme that mediates the elongation of chondroitin sulfate (CS), is a critical elicitor of the malignant characteristics of HCC as it modifies the potent tumor suppressor, decorin (DCN). CHPF expression is frequently downregulated in HCC tumors, which is associated with the poor overall survival of HCC patients. We observed that restoring CHPF expression suppressed HCC cell growth, migration, and invasion in vitro and in vivo. Mechanistic investigations revealed that TGF-β signaling is associated with CHPF-induced phenotype changes. We found that DCN, as a TGF-β regulator, is modified by CHPF, and that it affects the distribution of DCN on the surface of HCC cells. Importantly, our results confirm that CHPF and DCN expression levels are positively correlated in primary HCC tissues. Taken together, our results suggest that CHPF dysregulation contributes to the malignancy of HCC cells, and our study provides novel insights into the significance of CS, which affects DCN expression in the TME.

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Section: Discussionmentioning

confidence: 99%

CHPF Regulates the Aggressive Phenotypes of Hepatocellular Carcinoma Cells via the Modulation of the Decorin and TGF-β Pathways

Liu

et al. 2021

Cancers

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“… 16 The validation cohort for the relationship between ACBD4 expression level and HCC prognosis was derived from the TCGA cohort and was calculated by the Kaplan-Meier plotter ( http://kmplot.com/analysis/index.php?p=service ) online analysis tool. 18 To further verify the expression difference of ACBD4 gene between HCC tumor and paracancerous tissues, we also used four GEO datasets as validation queues, including GSE25097, 19–21 GSE36376, 22–24 GSE54236, 25–27 and GSE64041. 28 At the same time, we also used the GEPIA online analysis tool ( http://gepia.cancer-pku.cn/index.html ) TCGA HCC cohort tumor samples and GTEx normal liver samples dataset to compare the expression difference of ACBD4 gene.…”

Section: Methodsmentioning

confidence: 99%

Acyl-CoA Binding Domain Containing 4 Polymorphism rs4986172 and Expression Can Serve as Overall Survival Biomarkers for Hepatitis B Virus-Related Hepatocellular Carcinoma Patients After Hepatectomy

Huang¹,

Liao²,

Zhu³

et al. 2022

PGPM

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Background The aim of our study was to evaluate the potential of expression and single nucleotide polymorphism of Acyl-CoA binding domain containing 4 (ACBD4) gene as prognosis biomarkers in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after hepatectomy. Methods HBV-related HCC patients from the First Affiliated Hospital of Guangxi Medical University and GSE14520 were included in the current study, as well as The Cancer Genome Atlas (TCGA) HCC verification cohort. Prognostic analysis and multiple functional enrichment analysis methods were used to evaluate the prognostic value and potential biological functions of the ACBD4 gene in HBV-related HCC. Results We found that ACBD4 gene is highly expressed in normal liver tissues and markedly down-regulated in HBV-related HCC tissues. ACBD4 gene was significantly related to overall survival (OS) of HCC in TCGA and GSE14520 cohorts, and patients with low ACBD4 expression were markedly related to poor OS. Rs4986172 was observed as an OS biomarker after hepatectomy in the Guangxi HBV-related HCC cohort. The OS of rs4986172 GG genotype was worse than that of HCC patients with A allele (AA and AG genotypes). Multifunctional enrichment analysis suggested that ACBD4 gene is closely related to the metabolic, peroxisome proliferator-activated receptor and cytochrome P450 pathway. Through connectivity map, we also identified eight compounds that may be used as targeted therapeutic agents for ACBD4 gene in HBV-related HCC; these compounds were scopoletin, alfaxalone, bephenium hydroxynaphthoate, apramycin, 4,5-dianilinophthalimide, DL-thiorphan, aminohippuric acid and quinidine. Immune microenvironment analysis revealed that there were significant differences in immune scores of HBV-related HCC tumor tissues with different ACBD4 expression levels. Conclusion Our study reveals that ACBD4 expression and rs4986172 can be serve as biomarkers of OS in HBV-related HCC patients after hepatectomy.

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“…Sorafenib and regorafenib are commonly used to treat patients with liver cancer; however, this is often with no satisfactory benefits ( 14 ). The activity of sorafenib and regorafenib is limited owing to primary and acquired resistance mechanisms.…”

Section: Introductionmentioning

confidence: 99%

DYRK1A suppression attenuates HIF‑1α accumulation and enhances the anti‑liver cancer effects of regorafenib and sorafenib under hypoxic conditions

Zhang

et al. 2022

Int J Oncol

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Hypoxia promotes drug resistance and induces the expression of hypoxia inducible factor (HIF)-1α in liver cancer cells. However, to date, no selective HIF-1α inhibitor has been clinically approved. The aim of this study is to investigate a drug-targetable molecule that can regulate HIF-1α under hypoxia. The present study demonstrated that hyperactivation of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A)/HIF-1α signaling was associated with an increased risk of liver cancer. In addition, DYRK1A knockdown using small interfering RNA transfection or treatment with harmine, a natural alkaloid, significantly reduced the protein expression levels of HIF-1α in liver cancer cells under hypoxic conditions in vitro. Conversely, DYRK1A overexpression-vector transfection in liver cancer cell lines notably induced HIF-1α expression under the same conditions. Furthermore, DYRK1A was shown to interact and activate STAT3 under hypoxia to regulate HIF-1α expression. These findings indicated that DYRK1A may be a potential upstream activator of HIF-1α and positively regulate HIF-1α via the STAT3 signaling pathway in liver cancer cells. Additionally, treatment with harmine attenuated the proliferative ability of liver cancer cells under hypoxic conditions using sulforhodamine B and colony formation assay. Furthermore, DYRK1A knockdown could significantly enhance the anti-liver cancer effects of regorafenib and sorafenib under hypoxia. Co-treatment with harmine and either regorafenib or sorafenib also promoted cell death via the STAT3/HIF-1α/AKT signaling pathway under hypoxia using PI staining and western blotting. Overall, the results from the present study suggested that DYRK1A/HIF-1α signaling may be considered a novel pathway involved in chemoresistance, thus providing a potentially effective therapeutic regimen for treating liver cancer.

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Proteoglycan-4 is correlated with longer survival in HCC patients and enhances sorafenib and regorafenib effectiveness via CD44 in vitro

Cited by 16 publications

References 64 publications

CHPF Regulates the Aggressive Phenotypes of Hepatocellular Carcinoma Cells via the Modulation of the Decorin and TGF-β Pathways

CHPF Regulates the Aggressive Phenotypes of Hepatocellular Carcinoma Cells via the Modulation of the Decorin and TGF-β Pathways

Acyl-CoA Binding Domain Containing 4 Polymorphism rs4986172 and Expression Can Serve as Overall Survival Biomarkers for Hepatitis B Virus-Related Hepatocellular Carcinoma Patients After Hepatectomy

DYRK1A suppression attenuates HIF‑1α accumulation and enhances the anti‑liver cancer effects of regorafenib and sorafenib under hypoxic conditions

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