mass-cytometry-analysis-systemic-local-immune-responses

Mass Cytometry Analysis of Systemic and Local Immune Responses in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most common and deadliest forms of liver cancer worldwide. Despite advances in treatment, the prognosis for ...

Zhejiang University School of Medicine

Pirarubicin (THP) is a new generation cell cycle nonspecific anthracycline anticancer drug. Pirarubicin and pirarubicin-based combination therapies have been demonstrated to be effective against HCC in TACE. However, the drug resistance limits its therapeutic efficacy. Receptor-interacting protein kinase 1 (RIPK1) displays a critical role in cell death. Here we found that RIPK1 and p21 may participate in the resistance to pirarubicin. In this study, we first found that inhibition of RIPK1 significantly decreased pAKT and increased p21, accompanied by G0/G1 phase cell cycle arrest and cell anti-proliferation in pirarubicin-treated hepatocellular carcinoma cells. Moreover, phosphorylation of AKT reversed the anti-proliferative effect of RIPK1 inhibitor in HCC, which proved that RIPK1-AKT-P21-dependent pathway played a key role in pirarubicin resistance. Using a mouse xenograft model, we further found that RIPK1 inhibitor combined with pirarubicin exerted synergistic anti-tumor effect . Upon exposure to pirarubicin treatment, xenografts under RIPK1 inhibition maintained higher levels of p21 than control xenografts. In conclusion, the results in our study demonstrated that RIPK1 inhibition enhances the anti-tumor effect of pirarubicin by overcoming drug resistance. RIPK1 inhibitor might be used as an adjuvant to potentiate the inhibitory effect of pirarubicin against primary hepatocellular carcinoma.

RIPK1 Inhibition Enhances Pirarubicin Cytotoxic Efficacy through AKT-P21-dependent Pathway in Hepatocellular Carcinoma.

The gut-liver axis plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC). However, the correlations between the gut microbiome and the liver tumor transcriptome in patients with HCC and the impact of the gut microbiota on clinical outcome are less well-understood.

Integrated analysis of microbiome and host transcriptome reveals correlations between gut microbiota and clinical outcomes in HBV-related hepatocellular carcinoma.

Instantaneous blood coagulation after bioengineered liver transplantation is a major issue, and the key process in its prevention is the construction of the endothelial vascular bed on biomimetic scaffolds. However, the specific molecules involved in the regulation of the vascular bed formation remain unclear. Syndecan-4 is a type I transmembrane glycoprotein commonly expressed in the human body; its receptor has been reported as critical for optimal cell adhesion and initiation of intracellular signaling, indicating its promising application in vascular bed formation. In the current study, bioinformatics analysis and in vitro experiments were performed to evaluate whether syndecan-4 promoted endothelial cell migration and functional activation. Exogenous syndecan-4-overexpressing endothelial cells were perfused into the decellularized liver scaffold, which was assessed by Masson's trichrome staining. Western blotting and qRT-PCR were used to evaluate the effects of syndecan-4 on the thrombospondin 1 (THBS1) stability. We found that syndecan-4 promoted the adhesion of vascular endothelial cells and facilitated cell migration and angiogenesis. Furthermore, syndecan-4 overexpression resulted in a well-aligned endothelium on the decellularized liver scaffolds. Mechanistically, syndecan-4 destabilized THBS1 at the protein level. Therefore, our data revealed that syndecan-4 promoted the biological activity of endothelial cells on the bionic liver vascular bed through THBS1. These findings provide scientific evidences for solving transient blood coagulation after bionic liver transplantation.

Syndecan-4 promotes vascular beds formation in tissue engineered liver via thrombospondin 1.

The tumor microenvironment (TME) plays a critical role in the pathogenesis of hepatocellular carcinoma (HCC). However, underlying compositions and functions that drive the establishment and maintenance of the TME classifications are less-well understood.

Tumor Immune Microenvironment Characterization in Hepatocellular Carcinoma Identifies Four Prognostic and Immunotherapeutically Relevant Subclasses.

Although cell-based or animal-based research evidence support the association of Holliday junction recognition protein (HJURP) with cancers, no pan-cancer investigation has been reported. The datasets of Gene Expression Omnibus database along with The Cancer Genome Atlas project were used to evaluate the expression of HJURP in various types of tumors. HJURP is overexpressed in a considerable number of cancers, and some changes in DNA methylation and genetic alterations are discovered in some types of tumors, such as kidney-related and adrenal gland-related tumors. Based on PrognoScan and gene expression profiling interactive analysis (GEPIA), the elevated expression of HJURP worsened the survival time of individuals with cancer. The biological general repository for interaction datasets (BioGRID) and The database for annotation, visualization and integrated discovery (DAVID) were used to establish the functional molecular network. It revealed that the cell cycle and p53 signaling pathway are the key molecular mechanisms that HJURP promotes carcinogenesis. The nomograms between HJURP and clinical pathological factors based on the Cox proportional hazards model showed a good prognostic performance in kidney carcinoma, hepatocellular carcinoma, and lung adenocarcinoma. Our first pan-cancer study provides a relatively profound insights into the oncogenic roles of HJURP across different tumors.

A pan-cancer analysis of the oncogenic role of Holliday junction recognition protein in human tumors.

Some chemotherapeutic agents have been found to enhance antitumor immunity by inducing immunogenic cell death (ICD). The combination of disulfiram (DSF) and copper (Cu) has demonstrated anti-tumor effects in a range of malignancies including hepatocellular carcinoma (HCC). However, the potential of DSF/Cu as an ICD inducer and whether it can enhance the efficacy of the immune checkpoint blockade in HCC remains unknown. Here, we showed that DSF/Cu-treated HCC cells exhibited characteristics of ICD in vitro, such as calreticulin (CRT) exposure, ATP secretion, and high mobility group box 1 (HMGB1) release. DSF/Cu-treated HCC cells elicited significant immune memory in a vaccination assay. DSF/Cu treatment promoted dendritic cell activation and maturation. The combination of DSF/Cu and CD47 blockade further facilitated DC maturation and subsequently enhanced CD8 T cell cytotoxicity. Mechanically, DSF/Cu promoted the nuclear accumulation and aggregation of nuclear protein localization protein 4 (NPL4) to inhibit the ubiquitin-proteasome system; thus, inducing endoplasmic reticulum (ER) stress. The inhibition of NPL4 induced ICD-associated damage-associated molecular patterns. Collectively, our findings demonstrated that DSF/Cu-induced ICD-mediated immune activation in HCC enhanced the efficacy of CD47 blockade.

Article	Year
RIPK1 Inhibition Enhances Pirarubicin Cytotoxic Efficacy through AKT-P21-dependent Pathway in Hepatocellular Carcinoma. International journal of medical sciences\| PubMed ID: 30588188	2018
Integrated analysis of microbiome and host transcriptome reveals correlations between gut microbiota and clinical outcomes in HBV-related hepatocellular carcinoma. Genome medicine\| PubMed ID: 33225985	2020
Syndecan-4 promotes vascular beds formation in tissue engineered liver via thrombospondin 1. Bioengineered\| PubMed ID: 33251971	2020
Tumor Immune Microenvironment Characterization in Hepatocellular Carcinoma Identifies Four Prognostic and Immunotherapeutically Relevant Subclasses. Frontiers in oncology\| PubMed ID: 33680932	2020
A pan-cancer analysis of the oncogenic role of Holliday junction recognition protein in human tumors. Open medicine (Warsaw, Poland)\| PubMed ID: 35274047	2022
Disulfiram/Copper Induces Immunogenic Cell Death and Enhances CD47 Blockade in Hepatocellular Carcinoma. Cancers\| PubMed ID: 36230638	2022

Hechen Huang

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