Deregulated Wnt/β-catenin signaling is one of the main genetic alterations in human hepatocellular carcinoma (HCC). Comprehensive genomic analyses have revealed that gain-of-function mutation of CTNNB1, which encodes β-catenin, and loss-of-function mutation of AXIN1 occur in approximately 35% of human HCC samples. Human HCCs with activation of the Wnt/β-catenin pathway demonstrate unique gene expression patterns and pathological features. Activated Wnt/β-catenin synergizes with multiple signaling cascades to drive HCC formation, and it functions through its downstream effectors. Therefore, strategies targeting Wnt/β-catenin have been pursued as possible therapeutics against HCC. Here, we review the genetic alterations and oncogenic roles of aberrant Wnt/β-catenin signaling during hepatocarcinogenesis. In addition, we discuss the implication of this pathway in HCC diagnosis, classification, and personalized treatment.

Hepatocellular carcinoma (HCC) is a leading cause of cancer related deaths worldwide. The PI3K cascade is one of the major signaling pathways underlying HCC development and progression. Activating mutations of PI3K catalytic subunit alpha (PIK3CA) and/or loss of Pten often occur in human HCCs. Serum and glucocorticoid kinase 3 (SGK3) belongs to the SGK family of AGK kinases and functions in parallel to AKT downstream of PI3K. Previous studies have shown that SGK3 may be the major kinase responsible for the oncogenic potential of PIK3CA helical domain mutants, such as PIK3CA(E545K), but not kinase domain mutants, such as PIK3CA(H1047R). We investigated the functional contribution of SGK3 in mediating activated PIK3CA mutant or loss of Pten induced HCC development using Sgk3 knockout mice. We found that ablation of Sgk3 does not affect PIK3CA(H1047R) or PIK3CA(E545K) induced lipogenesis in the liver. Using PIK3CA(H1047R)/c-Met, PIK3CA(E545K)/c-Met, and sgPten/c-Met murine HCC models, we also demonstrated that deletion of Sgk3 moderately delays PIK3CA(E545K)/c-Met driven HCC, while not affecting PIK3CA(H1047R)/c-Met or sgPten/c-Met HCC formation in mice. Similarly, in human HCC cell lines, silencing of SGK3 reduced PIK3CA(E545K) -but not PIK3CA(H1047R)- induced accelerated tumor cell proliferation. Altogether, our data suggest that SGK3 plays a role in transducing helical domain mutant PIK3CA signaling during liver tumor development.

Introduction: Hu-lu-su-pian (HLSP) is an oral tablet derived from the active compounds of Cucumis melo L., a traditional Chinese medicine. This contemporary formulation is frequently employed in clinical settings for the management of liver ailments. However, the molecular mechanism by which HLSP affects metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. This study aimed to explore the therapeutic potential of HLSP on MASLD and the underlying mechanism.Methods: The researchers used ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS) to identify the primary chemical components of HLSP. A mouse model of MASLD induced by AKT was established through hydrodynamic transfection with activated forms of AKT. Serum biochemical indices and liver pathological assessments were employed to evaluate the pharmacodynamic effects of HLSP on MASLD. Transcriptomic analysis of the liver was conducted to detect differentially expressed genes (DEGs). Further examination of significant DEGs and proteins was performed using quantitative real-time polymerase chain reaction (RT-qPCR), Western blotting, and immunohistochemistry (IHC) techniques, respectively. The efficacy and molecular mechanisms of HLSP in MASLD were further explored in HepG2 and Huh-7 cells in the presence of gene overexpression.Results: From the UPLC-Q-TOF-MS/MS results, we detected fifteen components from HLSP. From the results of serum biochemical indices and hepatic pathology analyses, it is clear that HLSP is effective in treating MASLD. The findings from hepatic transcription studies revealed CIDEA as an essential DEG that facilitates lipid droplet (LD) fusion and enhances de novo fatty acid synthesis from scratch in cases of hepatic steatosis, which HLSP has the potential to counteract. In addition, HLSP significantly reduced lipid accumulation and expression of critical genes for de novo fatty acid synthesis in HepG2 and Huh-7 cells overexpressing CIDEA.Discussion: The present study preliminarily suggests that HLSP can ameliorate hepatic steatosis by inhibiting CIDEA-mediated de novo fatty acid synthesis and LD formation, which may offer a potential strategy for treating MASLD.

Evidence has shown that single nucleotide polymorphism located in pre-miRNA or mature microRNA may modify various biological processes and affect the processing of carcinogenesis. Published results about the association between miR-146a rs2910164 G/C polymorphism and human gastric cancer susceptibility are inconclusive. The aim of this study was to acquire a more precise effect of the association between the miR-146a rs2910164 polymorphism and gastric risk by meta-analysis. Eligible genetic association studies were searched from PubMed, Web of Knowledge and Chinese Biomedicine Database on human subject. Quantitative data synthesis was conducted for the associations of miR-146a rs2910164 G/C polymorphism with susceptibility to gastric cancer. Nine eligible studies that included a total of 3,885 gastric cancer patients and 5,396 controls were identified in the present meta-analysis. The overall OR indicated a potential association between rs2910164 polymorphism and GC but the effect was not statistically significant (GG vs. CG/CC: OR = 1.076, 95% CI 0.925-1.251, P = 0.342). When stratifying for population, the result showed that miR-146a rs2910164 GG genotype was associated with increased gastric cancer risk among Chinese in recessive model (GG vs. CG/CC: OR = 1.171, 95% CI 1.050-1.306, P = 0.005). Besides, no significant difference was found in gender, smoking, location, metastasis of lymph node and Laurèn’s classification. The present meta-analysis suggests an increased risk between miR-146a rs2910164 GG genotype and gastric cancer susceptibility in Chinese based on published literatures.

Background.Neuropilin 1 (NRP1) is involved in tumorigenesis, development, invasion, and metastasis by promoting angiogenesis of tumors. The study is aimed at evaluating the correlation between the expression of NRP1 protein and clinicopathological features of gastric cancer by meta-analysis.Methods.The published studies were searched in databases including CNKI, Wanfang, Chongqing VIP, Web of Science, and PubMed online. Clinical case studies were included to compare the correlation between NRP1 protein expression and clinicopathological characteristics of gastric cancer. The quality of the included literatures was evaluated by NOS scale. Meta-analysis was performed by Stata software to calculate the odds ratio (OR) and 95% confidence interval (CI).Results.A total of 12 studies were included in this analysis, involving 1,225 patients with gastric cancer. The analysis indicated that the expression of NRP1 protein in gastric cancer tissues was lower in the group of early stage versus advanced stage (OR=0.128,95%CI=0.059−0.277,P≤0.001), tumor size less than 5 cm versus more than 5 cm (OR=0.443,95%CI=0.310−0.632,P≤0.001), TNM stage I-II group versus stage III-IV patients (OR=0.736,95%CI=0.589−0.919,P=0.007), well to medium differentiation group versus poor differentiation group (OR=0.735,95%CI=0.632−0.854,P≤0.001), and nonlymph node metastasis group versus lymph node metastasis group (OR=0.667,95%CI=0.522−0.854,P≤0.001). The expression of NRP1 protein in gastric cancer was not related to gender, age, and Laurèn’s classification.Conclusion.The expression of NRP1 protein in gastric cancer is closely correlated to clinical stage, tumor size, TNM stage, differentiation, and lymph node metastasis.

Hepatitis B virus (HBV) infections promote liver cancer initiation by inducing inflammation and cellular stress. Despite a primarily indirect effect on oncogenesis, HBV is associated with a recurrent genomic phenotype in hepatocellular carcinoma (HCC), suggesting that it impacts the biology of established HCC. Characterization of the interaction of HBV with host proteins and the mechanistic contributions of HBV to HCC initiation and maintenance could provide insights into HCC biology and uncover therapeutic vulnerabilities. In this study, we used affinity purification mass spectrometry to comprehensively map a network of 145 physical interactions between HBV and human proteins in HCC. A subset of the host factors targeted by HBV proteins were preferentially mutated in non–HBV-associated HCC, suggesting that their interaction with HBV influences HCC biology. HBV interacted with proteins involved in mRNA splicing, mitogenic signaling, and DNA repair, with the latter set interacting with the HBV oncoprotein X (HBx). HBx remodeled the PP2A phosphatase complex by excluding striatin regulatory subunits from the PP2A holoenzyme, and the HBx effects on PP2A caused Hippo kinase activation. In parallel, HBx activated mTOR complex 2, which can prevent YAP degradation. mTOR complex 2–mediated upregulation of YAP was observed in human HCC specimens and mouse HCC models and could be targeted with mTOR kinase inhibitors. Thus, HBV interaction with host proteins rewires HCC signaling rather than directly activating mitogenic pathways, providing an alternative paradigm for the cellular effects of a tumor-promoting virus. Significance: Integrative proteomic and genomic analysis of HBV/host interactions illuminated modifiers of hepatocellular carcinoma behavior and key signaling mechanisms in advanced disease, which suggested that HBV may have therapeutically actionable effects.