Guifu Dai

C22 steroidal intermediates, including 22‑hydroxy‑23,24‑bisnorchol‑4‑ene‑3‑one (4‑HBC) and its Δ1̴

Tumor angiogenesis plays a crucial role in the progression of hepatocellular carcinoma (HCC), serving as a key process for metastasis and invasion. Leucine-rich repeat-containing 1 (LRRC1) has been reported to be abnormally upregulated in HCC. Nevertheless, the specific mechanism through which LRRC1 affects HCC is poorly understood. In our study, analysis of public datasets reveals a positive correlation between LRRC1 and VEGFA, which drives us to hypothesize the linkage between LRRC1 and tumor angiogenesis. Herein, we aimed to explore the role of LRRC1 in HCC angiogenesis and the involved mechanisms. In vitro, LRRC1 overexpression significantly increased the mRNA, protein, and secretory levels of VEGFA and promoted tumor-induced migration, invasion, and tube formation of HUVECs. Conversely, these effects were suppressed by the knockdown of LRRC1. In vivo, LRRC1 promoted the formation of new blood vessels in the chick embryo chorioallantois membrane, together with tumor growth and angiogenesis in xenograft mice. Further mechanism studies showed that LRRC1 enhances PDK1 stability by promoting its deubiquitination via USP7, thereby increasing AKT1 phosphorylation levels and activating the AKT/GSK3β/β-catenin/VEGFA signaling pathway, ultimately accelerating tumor angiogenesis in HCC. These findings demonstrated a novel role of LRRC1 in tumor angiogenesis, opening up new avenues for future research and treatment development.

Hepatocellular carcinoma (HCC) is a deadly cancer with limited treatment options for patients at advanced stages. It is urgent to develop reliable prognostic risk models and identify more biomarkers to improve the clinical outcomes of patients with HCC. Disulfidptosis is a newly discovered form of regulated cell death (RCD), and research on the comprehensive roles of disulfidptosis-related genes (DRGs) in HCC prognosis and development remains limited. In this paper, we systematically analyzed the expression levels and prognostic profiles of 26 DRGs in HCC samples from The Cancer Genome Atlas (TCGA) cohort and developed a prognostic risk model using seven hub DRGs. The independent prognostic value of the risk model was further validated in the external cohort. The overall survival of patients with HCC in the low-risk group was significantly longer than that of those in the high-risk group. Subsequently, the protein level of CD2-associated protein (CD2AP) was found to be highly expressed in HCC clinical tissues and associated with the severity of HCC. In vitro experiments demonstrated that the down-regulation of CD2AP attenuated the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) abilities of HCC cells. Taken together, our study revealed that the DRG CD2AP may serve as a potential biomarker for HCC and offer support for prognosis prediction of patients with HCC.

Liver fibrosis poses a significant global health risk due to its association with hepatocellular carcinoma (HCC) and the lack of effective treatments. Thus, the need to discover additional novel therapeutic targets to attenuate liver diseases is urgent. Leucine-rich repeat containing 1 (LRRC1) reportedly promotes HCC development. Previously, we found that LRRC1 was significantly upregulated in rat fibrotic liver according to the transcriptome sequencing data. Herein, in the current work, we aimed to explore the role of LRRC1 in liver fibrosis and the underlying mechanisms involved. LRRC1 expression was positively correlated with liver fibrosis severity and significantly elevated in both human and murine fibrotic liver tissues. LRRC1 knockdown or overexpression inhibited or enhanced the proliferation, migration, and expression of fibrogenic genes in the human hepatic stellate cell line LX-2. More importantly, LRRC1 inhibition in vivo significantly alleviated CCl₄-induced liver fibrosis by reducing collagen accumulation and hepatic stellate cells’ (HSCs) activation in mice. Mechanistically, LRRC1 promoted HSC activation and liver fibrogenesis by preventing the ubiquitin-mediated degradation of phosphorylated mothers against decapentaplegic homolog (Smad) 2/3 (p-Smad2/3), thereby activating the TGF-β1/Smad pathway. Collectively, these results clarify a novel role for LRRC1 as a regulator of liver fibrosis and indicate that LRRC1 is a promising target for antifibrotic therapies.

Background: Although immune microenvironment-related chemokines, extracellular matrix (ECM), and intrahepatic immune cells are reported to be highly involved in hepatitis B virus (HBV)-related diseases, their roles in diagnosis, prognosis, and drug sensitivity evaluation remain unclear. Here, we aimed to study their clinical use to provide a basis for precision medicine in hepatocellular carcinoma (HCC) via the amalgamation of artificial intelligence.Methods: High-throughput liver transcriptomes from Gene Expression Omnibus (GEO), NODE (https://www.bio.sino.org/node), the Cancer Genome Atlas (TCGA), and our in-house hepatocellular carcinoma patients were collected in this study. Core immunosignals that participated in the entire diseases course of hepatitis B were explored using the “Gene set variation analysis” R package. Using ROC curve analysis, the impact of core immunosignals and amino acid utilization related gene on hepatocellular carcinoma patient’s clinical outcome were calculated. The utility of core immunosignals as a classifier for hepatocellular carcinoma tumor tissue was evaluated using explainable machine-learning methods. A novel deep residual neural network model based on immunosignals was constructed for the long-term overall survival (LS) analysis. In vivo drug sensitivity was calculated by the “oncoPredict” R package.Results: We identified nine genes comprising chemokines and ECM related to hepatitis B virus-induced inflammation and fibrosis as CLST signals. Moreover, CLST was co-enriched with activated CD4+ T cells bearing harmful factors (aCD4) during all stages of hepatitis B virus pathogenesis, which was also verified by our hepatocellular carcinoma data. Unexpectedly, we found that hepatitis B virus-hepatocellular carcinoma patients in the CLST^highaCD4^high subgroup had the shortest overall survival (OS) and were characterized by a risk gene signature associated with amino acids utilization. Importantly, characteristic genes specific to CLST/aCD4 showed promising clinical relevance in identifying patients with early-stage hepatocellular carcinoma via explainable machine learning. In addition, the 5-year long-term overall survival of hepatocellular carcinoma patients can be effectively classified by CLST/aCD4 based GeneSet-ResNet model. Subgroups defined by CLST and aCD4 were significantly involved in the sensitivity of hepatitis B virus-hepatocellular carcinoma patients to chemotherapy treatments.Conclusion: CLST and aCD4 are hepatitis B virus pathogenesis-relevant immunosignals that are highly involved in hepatitis B virus-induced inflammation, fibrosis, and hepatocellular carcinoma. Gene set variation analysis derived immunogenomic signatures enabled efficient diagnostic and prognostic model construction. The clinical application of CLST and aCD4 as indicators would be beneficial for the precision management of hepatocellular carcinoma.