ATG101-related signature predicts prognosis and therapeutic option in hepatocellular carcinoma.

Autophagy plays a critical role in tumor pathogenesis. However, autophagy-related signature in Hepatocellular carcinoma (HCC) has not been revealed yet. We quantified the levels of various cancer hallmarks and identified ATG101 as the major risk factor for overall survival in HCC. A robust ATG101-related gene signature (ATS) for prognosis was constructed using a combination of bioinformatic and statistical approaches. Additionally, genetic and immunological properties were measured between ATS-high and ATS-low groups. The ATS signature was associated with shortened overall survival in HCC patients independently of clinicopathological characteristics. ATS status defines an inflamed yet exhausted tumor microenvironment, in which the activities of the exhausted CD8+ or CD4+ T cells were strongly associated with ATS. The ATS signature predicts the drug resistance to the immunotherapy, thus a combination of targeted therapy and immunotherapy might be suitable for ATS-high patients. This work shed light on the function of ATG101-related genes in HCC and revealed that the ATS signature may be a useful prognostic biomarker for differentiating molecular and immunological features and predicting probable response to the therapy.

BZW2/5MP1 acts as a promising target in hepatocellular carcinoma.

Basic leucine zipper and W2 domain 2 (BZW2), also known as 5MP1, is a protein related to translation regulation. Evidence from previous studies indicates that BZW2 is involved in tumorigenesis in several cancers. However, little is known about the role of BZW2 in hepatocellular carcinoma (HCC). In this study, we first analyzed the gene expression profile of BZW2 in multiple HCC datasets. Next, we explored the biological effects of BZW2 in HCC cell lines. BZW2 was overexpressed in different HCC cohorts. Multivariate analysis confirmed that increased BZW2 expression is an independent prognostic indicator of shorter overall survival. BZW2 coexpressed genes were mainly enriched in the biological processes of ribonucleoprotein complex biogenesis, rRNA metabolism, translational initiation, and negative regulation of metabolic processes. BZW2 depletion reduced proliferation, clonality, and invasion and increased apoptosis in MHCC97-H cells. Furthermore, BZW2 overexpression or knockdown enhanced or impaired c-Myc expression, respectively. Overall, these findings identified BZW2 as a biomarker of HCC and provided novel insight that the effect of BZW2 on the translatome is a potential mechanism that promotes HCC progression via the c-Myc pathway.

A Deep Look into the Program of Rapid Tumor Growth of Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Great efforts have been made towards increasing our understanding of the pathogenesis involved in hepatocellular carcinoma (HCC), but the rapid growth inherent to such tumor development remains to be explored. METHODS: We identified distinct gene coexpression modes upon liver tumor growth using weighted gene coexpression network analysis. Modeling of tumor growth as signaling activity was employed to understand the main cascades responsible for the growth. Hub genes in the modules were determined, examined in vitro, and further assembled into the growth signature. RESULTS: We revealed modules related to the different growth states in HCC, especially the fastest growth module, which is preserved among different HCC cohorts. Moreover, signaling flux in the cell cycle pathway was found to act as a driving force for rapid growth. Twenty hub genes in the module were identified and assembled into the growth signature, and two genes (NCAPH, and RAD54L) were tested for their growth potential in vitro. Genetic alteration of the growth signature affected the global gene expression. The activity of the signature was associated with tumor metabolism and immunity in HCC. Finally, the prognosis effect of the growth signature was reproduced in nine cancers. CONCLUSIONS: These results collectively demonstrate the molecule organization of rapid tumor growth in HCC, which is a highly synergistic process, with implications for the future management of patients.

Identification and characterization of dynamically regulated hepatitis-related genes in a concanavalin A-induced liver injury model.

BACKGROUND: Concanavalin A (ConA)-induced liver damage of mice is a well-established murine model mimicking the human autoimmune hepatitis (AIH). However, the pathogenic genes of the liver injury remain to be revealed. METHODS: Using time-series liver transcriptome, top dynamic genes were inferred from a set of segmented regression models, and cross-checked by weighted correlation network analysis (WGCNA). AIH murine models created by ConA were used to verify the in vivo effect of these genes. RESULTS: We identified 115 top dynamic genes, of which most were overlapped with the hub genes determined by WGCNA. The expression of several top dynamic genes including Cd63, Saa3, Slc10a1, Nrxn1, Ugt2a3, were verified in vivo. Further, Cluster determinant 63 (Cd63) knockdown in mice treated with ConA showed significantly less liver pathology and inflammation as well as higher survival rates than the corresponding controls. CONCLUSION: We have identified the top dynamic genes related to the process of acute liver injury, and highlighted a targeted strategy for Cd63 might have utility for the protection of hepatocellular damage.

Discovering master regulators in hepatocellular carcinoma: one novel MR, SEC14L2 inhibits cancer cells.

Identification of master regulator (MR) genes offers a relatively rapid and efficient way to characterize disease-specific molecular programs. Since strong consensus regarding commonly altered MRs in hepatocellular carcinoma (HCC) is lacking, we generated a compendium of HCC datasets from 21 studies and identified a comprehensive signature consisting of 483 genes commonly deregulated in HCC. We then used reverse engineering of transcriptional networks to identify the MRs that underpin the development and progression of HCC. After cross-validation in different HCC datasets, systematic assessment using patient-derived data confirmed prognostic predictive capacities for most HCC MRs and their corresponding regulons. Our HCC signature covered well-established liver cancer hallmarks, and network analyses revealed coordinated interaction between several MRs. One novel MR, SEC14L2, exerted an anti-proliferative effect in HCC cells and strongly suppressed tumor growth in a mouse model. This study advances our knowledge of transcriptional MRs potentially involved in HCC development and progression that may be targeted by specific interventions.