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Abstract Liver cancer is a global health challenge, causing a significant social-economic burden. Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, which is highly heterogeneous in terms of molecular and cellular signatures. Early-stage or small tumors are typically treated with surgery or ablation. Currently, chemotherapies and immunotherapies are the best treatments for unresectable tumors or advanced HCC. However, drug response and acquired resistance are not predictable with the existing systematic guidelines regarding mutation patterns and molecular biomarkers, resulting in sub-optimal treatment outcomes for many patients with atypical molecular profiles. With advanced technological platforms, valuable information such as tumor genetic alterations, epigenetic data, and tumor microenvironments can be obtained from liquid biopsy. The inter- and intra-tumoral heterogeneity of HCC are illustrated, and these collective data provide solid evidence in the decision-making process of treatment regimens. This article reviews the current understanding of HCC detection methods and aims to update the development of HCC surveillance using liquid biopsy. Recent critical findings on the molecular basis, epigenetic profiles, circulating tumor cells, circulating DNAs, and omics studies are elaborated for HCC diagnosis. Besides, biomarkers related to the choice of therapeutic options are discussed. Some notable recent clinical trials working on targeted therapies are also highlighted. Insights are provided to translate the knowledge into potential biomarkers for detection and diagnosis, prognosis, treatment response, and drug resistance indicators in clinical practice.

Abstract Background and aims Sorafenib is a major nonsurgical option for patients with advanced hepatocellular carcinoma (HCC); however, its clinical efficacy is largely undermined by the acquisition of resistance. The aim of this study was to identify the key lncRNA involved in the regulation of the sorafenib response in HCC. Materials and methods A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) single-guide RNA (sgRNA) synergistic activation mediator (SAM)-pooled lncRNA library was applied to screen for the key lncRNA regulated by sorafenib treatment. The role of the identified lncRNA in mediating the sorafenib response in HCC was examined in vitro and in vivo. The underlying mechanism was delineated by proteomic analysis. The clinical significance of the expression of the identified lncRNA was evaluated by multiplex immunostaining on a human HCC microtissue array. Results CRISPR/Cas9 lncRNA library screening revealed that Linc01056 was among the most downregulated lncRNAs in sorafenib-resistant HCC cells. Knockdown of Linc01056 reduced the sensitivity of HCC cells to sorafenib, suppressing apoptosis in vitro and promoting tumour growth in mice in vivo. Proteomic analysis revealed that Linc01056 knockdown in sorafenib-treated HCC cells induced genes related to fatty acid oxidation (FAO) while repressing glycolysis-associated genes, leading to a metabolic switch favouring higher intracellular energy production. FAO inhibition in HCC cells with Linc01056 knockdown significantly restored sensitivity to sorafenib. Mechanistically, we determined that PPARα is the critical molecule governing the metabolic switch upon Linc01056 knockdown in HCC cells and indeed, PPARα inhibition restored the sorafenib response in HCC cells in vitro and HCC tumours in vivo. Clinically, Linc01056 expression predicted optimal overall and progression-free survival outcomes in HCC patients and predicted a better sorafenib response. Linc01056 expression indicated a low FAO level in HCC. Conclusion Our study identified Linc01056 as a critical epigenetic regulator and potential therapeutic target in the regulation of the sorafenib response in HCC.

Abstract Background Par-3 Family Cell Polarity Regulator (PARD3) is a cellular protein essential for asymmetric cell division and polarized growth. This study aimed to study the role of PARD3 in hepatic tumorigenesis. Methods The essential role of PARD3 in mediating hepatic tumorigenesis was assessed in diet-induced spontaneous liver tumour and syngeneic tumour models. The mechanism of PARD3 was delineated by bulk and single-cell RNA sequencing. The clinical significance of PARD3 was identified by tissue array analysis. Results PARD3 was overexpressed in tumour tissues and PARD3 overexpression was positively correlated with high tumour stage as well as the poor prognosis in patients. In models of spontaneous liver cancer induced by choline-deficient, amino acid-defined (CDAA) and methionine-choline-deficient (MCD) diets, upregulation of PARD3 was induced specifically at the tumorigenesis stage rather than other early stages of liver disease progression. Site-directed knockout of PARD3 using an adeno-associated virus 8 (AAV8)-delivered CRISPR/Cas9 single-guide RNA (sgRNA) plasmid blocked hepatic tumorigenesis, while PARD3 overexpression accelerated liver tumour progression. In particular, single-cell sequencing analysis suggested that PARD3 was enriched in primitive tumour cells and its overexpression enhanced tumour-initiating cell (TICs). Overexpression of PARD3 maintained the self-renewal ability of the CD133+ TIC population within hepatocellular carcinoma (HCC) cells and promoted the in vitro and in vivo tumorigenicity of CD133+ TICs. Transcriptome analysis revealed that Sonic Hedgehog (SHH) signalling was activated in PARD3-overexpressing CD133+ TICs. Mechanistically, PARD3 interacted with aPKC to further activate SHH signalling and downstream stemness-related genes. Suppression of SHH signalling and aPKC expression attenuated the in vitro and in vivo tumorigenicity of PARD3-overexpressing CD133+ TICs. Tissue array analysis revealed that PARD3 expression was positively associated with the phosphorylation of aPKC, SOX2 and Gli1 and that the combination of these markers could be used to stratify HCC patients into two clusters with different clinicopathological characteristics and overall survival prognoses. The natural compound berberine was selected as a potent suppressor of PARD3 expression and could be used as a preventive agent for liver cancer that completely blocks diet-induced hepatic tumorigenesis in a PARD3-dependent manner. Conclusion This study revealed PARD3 as a potential preventive target of liver tumorigenesis via TIC regulation.

For hundreds of years, the drug discovery and development industry has aimed at identifying single components with a clear mechanism of action as desirable candidates for potential drugs. However, this conventional strategy of drug discovery and development has faced challenges including a low success rate and high development costs. Herein, we critically review state-of-the-art drug discovery and development based on multi-component Chinese medicine formulas. We review the policies and application status of new drugs based on multi-component Chinese medicines in the US, China, and the European Union. Moreover, we illustrate several excellent cases of ongoing applications. Biomedical technologies that may facilitate drug discovery and development based on multi-component Chinese medicine formulas are discussed, including network pharmacology, integrative omics, CRISPR gene editing, and chemometrics. Finally, we discuss potential problems and solutions in pre-clinical and clinical research in drug discovery and development based on multi-component Chinese medicine formulas. We hope that this review will promote discussion of the roles of multi-component Chinese medicine formulas in the discovery and development of new drugs for the treatment of human diseases.

The growth location and plant variety may influence the active components and biological activities of plants used in phytomedicine. In this study, nine sets of different Epimedii Folium, from different representative cultivation locations and Epimedium species, were collected for comparison, using HPLC-DAD combined with multivariate analysis. The objective was to investigate the influence of geographical origin and Epimedium species on the quality of Epimedii Folium, and provide applicable guidance for cultivation and quality control of Epimedii Folium. Several Epimedium spp. sets were used to establish the HPLC-DAD fingerprints and 91 peaks (compounds) were selected for the multivariate analysis. Major compounds were analyzed by HPLC-DAD combined with principal component analysis (PCA). HPLC quantitative analysis of known bioactive compounds was performed. Application of PCA to HPLC data showed that Epimedium samples sharing the same geographical origin or species clustered together, indicating that both species and geographical origin have impacts on the quality of Epimedii Folium. The major bioactive flavonoid compounds, epimedin C, icariin and baohuoside I, were identified and quantified. The concentration of bioactive compounds was significantly influenced both by species and geographical origin. E. sagittatum from Sichuan showed the highest content of bioactive compounds. The results showed that both Epimedium species and geographical origin have strong impact into quality of Epimedii Folium. HPLC data combined with multivariate analysis is a suitable approach to inform the selection of cultivation areas and choose Epimedium spp. most suitable for different geographical areas, resulting in improved quality of Epimedii Folium.

Small ubiquitin-like modifier (SUMO) is a highly conserved post-translational modification protein, mainly found in eukaryotes. They are widely expressed in different tissues, including the liver. As an essential post-translational modification, SUMOylation is involved in many necessary regulations in cells. It plays a vital role in DNA repair, transcription regulation, protein stability and cell cycle progression. Increasing shreds of evidence show that SUMOylation is closely related to Hepatocellular carcinoma (HCC). The high expression of SUMOs in the inflammatory hepatic tissue may lead to the carcinogenesis of HCC. At the same time, SUMOs will upregulate the proliferation and survival of HCC, migration, invasion and metastasis of HCC, tumour microenvironment as well as drug resistance. This study reviewed the role of SUMOylation in liver cancer. In addition, it also discussed natural compounds that modulate SUMO and target SUMO drugs in clinical trials. Considering the critical role of SUMO protein in the occurrence of HCC, the drug regulation of SUMOylation may become a potential target for treatment, prognostic monitoring and adjuvant chemotherapy of HCC.