Search Results (9)

Liver cancer is caused by complex interactions among genetic factors, viral infection, alcohol abuse, and metabolic diseases. We conducted a genome-wide association study and polygenic risk score (PRS) model in Taiwan, employing a nonspecific etiology approach, to identify genetic risk factors for hepatocellular carcinoma (HCC). Our analysis of 2836 HCC cases and 134,549 controls revealed 13 novel associated loci such as the FAM66C gene, noncoding genes, liver-fibrosis-related genes, metabolism-related genes, and HCC-related pathway genes. We incorporated the results from the UK Biobank and Japanese database into our study for meta-analysis to validate our findings. We also identified specific subtypes of the major histocompatibility complex that influence both viral infection and HCC progression. Using this data, we developed a PRS to predict HCC risk in the general population, patients with HCC, and HCC-affected families. The PRS demonstrated higher risk scores in families with multiple HCCs and other cancer cases. This study presents a novel approach to HCC risk analysis, identifies seven new genes associated with HCC development, and introduces a reproducible PRS model for risk assessment. Full article

Background: Human endogenous retroviruses (HERVs) play an important role in the development of cancer and many diseases. Here, we comprehensively explored the impact of HERVs on hepatocellular carcinomas (HCCs). Methods: We employed Telescope to identify HERVs and quantify their expression in the total RNA sequencing data obtained from 254 HCC samples, comprising 254 tumor tissues and 34 matched normal tissues. Results: In total, 3357 locus-specific activations of HERVs were differentially expressed, and 180 were correlated with patient survival. Using these 180 HERVs for classification, we found four subgroups with survival correlation. Higher expression levels of the 180 HERVs were correlated with poorer survival, while age, AFP, some mutations, and copy and structural variants differed among subgroups. The differential expression of host genes in high expression of these 180 HERVs primarily involved the activation of pathways related to immunity and infection, lipid and atherosclerosis, MAPK and NF-kB signaling, and cytokine–cytokine receptor interactions. Conversely, there was a suppression of pathways associated with RNA processing, including nucleocytoplasmic transport, surveillance and ribosome biogenesis, and transcriptional misregulation in cancer pathways. Almost all genes involved in HERV activation restriction, KRAB zinc finger proteins, RNA nucleocytoplasmic transport, stemness, HLA and antigen processing and presentation, and immune checkpoints were overexpressed in cancerous tissues, and many over-expressed HERV-related nearby genes were correlated with high HERV activation and poor survival. Twenty-three immune and stromal cells showed higher expression in non-cancerous than cancerous tissues, and seven were correlated with HERV activation. Small-molecule modulation of alternative splicing (AS) altered the expression of survival-related HERVs and their activation-related genes, as well as nearby genes. Conclusion: Comprehensive and integrated approaches for evaluating HERV expression and their correlation with specific pathways have the potential to provide new companion diagnostics and therapeutic strategies for HCC. Full article

Epidemiologic data have suggested that etiologic variations of hepatocellular carcinoma (HCC) exist in different geographic areas, and might be associated with different outcomes. We compared the viral etiology, clinicopathological characteristics and surgical outcomes between 706 Taiwanese and 1704 Vietnamese patients with HCC undergoing liver resection. Vietnamese patients had a significantly higher ratio of hepatitis B virus (HBV) (p < 0.001) and a lower ratio of hepatitis C virus (HCV) (p < 0.001) and non-B non-C than Taiwanese patients. Among patients with HBV or non-B non-C, the mean age was younger in Vietnam than in Taiwan (p < 0.001, p = 0.001, respectively). The HCC patients in Vietnam had significantly higher serum alpha-fetoprotein (AFP) levels (p < 0.001), larger tumors (p < 0.001), and a higher ratio of macrovascular invasion (p < 0.001) and extrahepatic metastasis (p < 0.001), compared to those in Taiwan. Patients treated in Vietnam had a higher tumor recurrent rate (p < 0.001), but no difference in overall survival was found between both groups. In subgroup analysis, the recurrent rate of HCC was the highest in patients with dual HBV/HCV, followed by HCV or HBV, and non-B non-C (p < 0.001). In conclusion, although the viral etiology and clinicopathological characteristics of HCC differed, postoperative overall survival was comparable between patients in Taiwan and Vietnam. Full article

In Taiwan, a combination of hepatitis B and C infection, economic boom-related food and alcohol overconsumption, and Chinese medicine prescriptions has led to a high rate of hepatocellular carcinoma (HCC). However, the causative factors and underlying tumor biology for this unique HCC environment have not been identified. Wnt and Hippo signaling pathways play an important regulatory role in HCC development, and their functions are generally considered as positive and negative regulators of cell proliferation, respectively. In this study, we characterized the molecular features of HCC using a newly developed classification system based on the expression of the Wnt–Hippo signaling pathway-related genes. RNA sequencing (RNA-Seq) was performed on liver tumor tissues from 100 patients with liver cancer. RNA-Seq data for 272 previously characterized Wnt–Hippo signaling pathway-related genes were used for hierarchical clustering. We analyzed the data in terms of prognostic value, transcriptome features, immune infiltration, and clinical characteristics, and compared the resulting subclasses with previously published classifications. Four subclasses of HCC (HCCW1–4) were identified. Subclass HCCW1 displayed the highest PCDHB4 expression. Subclass HCCW2 displayed lower Edmondson–Steiner grades (I and II) and CTNNB1 mutation frequencies. Subclass HCCW3 was associated with a good prognosis, the highest PCDHGB7 expression, high CD8+ naïve T cells abundance, and relatively low TP53 mutation rates. Subclass HCCW4 was associated with a poor prognosis, the highest PCDHB2 and PCDHB6 expression, a relatively high abundance of Th1 cells, NKT and class-switched memory B cells, relatively low enrichment of cDC, iDC, and CD4+ memory T cells, and high Edmondson–Steiner grades (III and IV). We also identified Wnt–Hippo signaling pathway-related genes that may influence immune cell infiltration. We developed a panel of 272 Wnt–Hippo signaling pathway-related genes to classify HCC into four groups based on Taiwanese HCC and The Cancer Genome Atlas Liver Hepatocellular Carcinoma datasets. This novel molecular classification system may aid the treatment of HCC. Full article

Aim: Currently, atezolizumab combined with bevacizumab is the standard first-line treatment for unresectable hepatocellular carcinoma (HCC), but lenvatinib or sorafenib are still recommended for these patients for some reasons. The aim of the study was to determine the outcomes of Taiwanese patients with advanced-stage HCC who received lenvatinib or sorafenib. Methods: Data on patients with BCLC stage C HCC who were receiving lenvatinib or sorafenib as the first-line therapy from May 2018 to August 2020 was collected. The individuals with lenvatinib and sorafenib were propensity score-matched at a ratio of 1:2. Results: A total of 22 patients with lenvatinib and 44 patients with sorafenib were enrolled. The ORR (36.4% vs. 11.4%, p = 0.023) and DCR (81.9% vs. 56.9%, p = 0.039) were both higher in the lenvatinib group compared with the sorafenib group. The median overall survival (OS) of the lenvatinib group and the sorafenib group was 9.36 months and 8.36 months, respectively. The best median OS was detected in patients receiving lenvatinib and having an objective tumor response (11.29 months), with a significant difference (p = 0.031) compared with the other groups. Conclusion: Lenvatinib, compared to sorafenib, had better ORR and DCR, but similar OS, in Taiwanese patients with advanced-stage HCC. The patients with an objective tumor response had a better OS. Full article

Hepatocellular carcinoma (HCC) is the second common cause of cancer-related death in Taiwan. Tumor recurrence is frequently observed in HCC patients receiving surgical resection, resulting in unsatisfactory overall survival (OS). Therefore, it is pivotal to identify effective prognostic makers, so that intensive surveillance or adjuvant treatments can be applied to predictively unfavorable patients. Previous studies indicated that Annexin A2 (ANXA2) was an effective prognostic marker in several cancers, including HCC. However, the prognostic value of ANXA2 in Taiwanese HCC patients remains unclear, where a great proportion of patients had chronic hepatitis B with liver cirrhosis. Here, ANXA2 was highly expressed in HCC tissues compared with para-neoplastic noncancerous tissues. Furthermore, high ANXA2 expression in HCC tissues independently predicted shorter OS. In subgroup analysis, however, ANXA2 expression could not effectively predict OS in the following subgroups: female, age > 65 years old, Child–Pugh classification B, hepatitis B virus surface antigen negative or anti-hepatitis C antibody positive, alcoholism, tumor number >1, presence of micro- or macrovascular invasion, absence of capsule, non-cirrhosis and high alpha-fetoprotein. In conclusion, ANXA2 expression in HCC tissues could predict postoperative OS. However, the predictive value was limited in patients with specific clinical conditions. Full article

Transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) plays a crucial role in regulating the expression of genes participating in cellular defense mechanisms against oxidative or xenobiotic insults. However, there is increasing evidence showing that hyperactivation of NRF2 is associated with chemoresistance in several cancers, including hepatocellular carcinoma (HCC), thus making NRF2 an attractive target for cancer therapy. Another important issue in cancer medication is the adverse effects of these substances on normal cells. Here, we attempted to identify a dual-selective NRF2 regulator that exerts opposite effects on NRF2-hyperactivated HCC cells and normal keratinocytes. An antioxidant response element driven luciferase reporter assay was established in Huh7 and HaCaT cells as high-throughput screening platforms. Screening of 3,000 crude extracts from the Taiwanese Indigenous Plant Extract Library resulted in the identification of Beilschmiedia tsangii (BT) root extract as a dual-selective NRF2 regulator. Multiple compounds were found to contribute to the dual-selective effects of BT extract on NRF2 signaling in two cell lines. BT extract reduced NRF2 protein level and target gene expression levels in Huh7 cells but increased them in HaCaT cells. Furthermore, notable combinatory cytotoxic effects of BT extract and sorafenib on Huh7 cells were observed. On the contrary, sorafenib-induced inflammatory reactions in HaCaT cells were reduced by BT extract. In conclusion, our results suggest that the combination of a selective NRF2 activator and inhibitor could be a practical strategy for fine-tuning NRF2 activity for better cancer treatment and that plant extracts or partially purified fractions could be a promising source for the discovery of dual-selective NRF2 regulators. Full article

Hepatocellular carcinoma (HCC) often develops from chronic hepatitis B (CHB) through replication of hepatitis B virus (HBV) infection. Calcium (Ca²⁺) signaling plays an essential role in HBV replication. Store-operated calcium (SOC) channels are a major pathway of Ca²⁺ entry into non-excitable cells such as immune cells and cancer cells. The basic components of SOC signaling include the STIM1 and ORAI1 genes. However, the roles of STIM1 and ORAI1 in HBV-mediated HCC are still unclear. Thus, long-term follow-up of HBV cohort was carried out in this study. This study recruited 3631 patients with chronic hepatitis (345 patients with HCC, 3286 patients without HCC) in a Taiwanese population. Genetic variants of the STIM1 and ORAI1 genes were detected using an Axiom CHB1 genome-wide array. Clinical associations of 40 polymorphisms were analyzed. Three of the STIM1 single-nucleotide polymorphisms (SNPs) (rs6578418, rs7116520, and rs11030472) and one SNP of ORAI1 (rs6486795) showed a trend of being associated with HCC disease (p < 0.05). However, after correction for multiple testing, none of the SNPs reached a significant level (q > 0.05); in contrast, neither STIM1 nor ORAI1 showed a significant association with HCC progression in CHB patients. Functional studies by both total internal reflection fluorescence images and transwell migration assay indicated the critical roles of SOC-mediated signaling in HCC migration. In conclusion, we reported a weak correlation between STIM1/ORAI1 polymorphisms and the risk of HCC progression in CHB patients. Full article

Background and Objectives: Non-selective β-blockers (NSBB) could prevent decompensation and hepatocellular carcinoma (HCC) in cirrhotic patients with clinically significant portal hypertension (CSPH), but remained uncertain for compensated cirrhotic patients without major complications. We aimed to compare the clinical outcomes between propranolol users and non-users of a CC group without major complications. Material and Methods: We conducted this population-based cohort study by using the Taiwanese Longitudinal Health Insurance Database 2000. Propranolol users (classified as cumulative defined daily dose (cDDD)) and non-PPL users were matched with a 1:1 propensity score in both cohorts. Results: This study comprised 6896 propranolol users and 6896 non-propranolol users. There was no significant impact on the development of spontaneous bacterial peritonitis between the two groups (aHR: 1.24, 95% confidence interval (CI): 0.88~1.75; p = 0.2111). Male gender, aged condition, and non-liver related diseases (peripheral vascular disease, cerebrovascular disease, dementia, pulmonary disease, and renal disease) were the independent risk factors of mortality. PPL users had significantly lower incidence of HCC development than non-users (aHR: 0.81, p = 0.0580; aHR: 0.80, p = 0.1588; and aHR: 0.49, p < 0.0001 in the groups of 1–28, 29–90, and >90 cDDD, respectively). Conclusion: The current study suggested that high cumulative doses of propranolol could decrease the risk of hepatocellular carcinoma among compensated cirrhotic patients without major complications. Further large-scale prospective studies are still required to confirm the findings in this study. Results: It remained uncertain whether non-selective β-blockers (NSBB) could prevent decompensation and hepatocellular carcinoma (HCC) in compensatory cirrhotic patients without major complications. This study aimed to compare the clinical outcomes between propranolol users and non-users of the CC group without major complications. Full article