HBV core promoter mutations and AKT upregulate S-phase kinase-associated protein 2 to promote postoperative hepatocellular carcinoma progression

Mutations in the hepatitis B virus (HBV) core promoter (CP) have been shown to be associated with hepatocellular carcinoma (HCC). The CP region overlaps HBV X gene, which activates AKT to regulate hepatocyte survival. However, the cooperation between these two cascades in HCC progression remains poorly understood. Here, we assayed virological factors and AKT expression in liver tissues from 56 HCC patients with better prognoses (BHCC, ≥5-year survival) and 58 with poor prognoses (PHCC, <5-year survival) after partial liver resection. Results showed double mutation A1762T/G1764A (TA) combined with other mutation(s) (TACO) in HBV genome and phosphorylated AKT (pAKT) were more common in PHCC than BHCC. TACO and pAKT levels correlated with proliferation and microvascularization but inversely correlated with apoptosis in HCC samples. These were more pronounced when TACO and pAKT co-expressed. Levels of p21 and p27 were decreased in TACO or pAKT overexpressing HCC due to SKP2 upregulation. Levels of E2F1 and both mRNA and protein of SKP2 were increased in TACO expressing HCC. Levels of 4EBP1/2 decreased and SKP2 mRNA level remained constant in pAKT-overexpressing HCC. Therefore, TACO and AKT are two independent predictors of postoperative survival in HCC. Their co-target, SKP2 may be a diagnostic or therapeutic marker

Prognostic and Clinicopathological Value of PINX1 in Various Human Tumors: A Meta-Analysis

PINX1 (Pin2/TRF1 interacting protein X1, an intrinsic telomerase inhibitor and putative tumor suppressor gene) may represent a novel prognostic tumor biomarker. However, the results of previous studies are inconsistent and the prognostic value of PINX1 remains controversial. Therefore, we conducted a meta-analysis to determine whether PINX1 expression is associated with overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), recurrence-free survival (RFS), and clinicopathological characteristics in patients with malignant tumors. A systematic search was performed in the PubMed, Web of Science, and Embase databases in April 2018. Quality assessment was performed according to the modified Newcastle-Ottawa Scale. Pooled odds ratios (ORs) and hazard ratios (HRs) with 95.0% confidence intervals (CIs) were calculated to determine the relationship between PINX1 expression and OS, DSS, DFS/RFS, and clinicopathological characteristics. Due to the heterogeneity across the included studies, subgroup and sensitivity analyses were performed. Fixed-effects models were used when the heterogeneity was not significant and random-effects models were used when the heterogeneity was significant. Fourteen studies of 16 cohorts including 2,624 patients were enrolled. Low PINX1 expression was associated with poor OS (HR: 1.51, 95.0% CI: 1.03–2.20; P = 0.035) and DFS/RFS (HR: 1.78, 95.0% CI: 1.28–2.47; P = 0.001) but not DSS (HR: 0.80, 95.0% CI: 0.38–1.67; P = 0.548). Low PINX1 expression was also associated with lymphatic invasion (OR: 2.23, 95.0% CI: 1.35–3.70; P = 0.002) and advanced tumor-node-metastasis stage (OR: 2.43, 95.0% CI: 1.29–4.57; P = 0.006). No significant associations were observed between low PINX1 expression and sex, depth of invasion, grade of differentiation, and distant metastasis. Low PINX1 expression was associated with poor OS and DFS/RFS and lymphatic invasion and advanced tumor-node-metastasis stage, suggesting that PINX1 expression may be a useful predictor of prognosis in patients with malignant tumors

circNFATC3 sponges miR-548I acts as a ceRNA to protect NFATC3 itself and suppressed hepatocellular carcinoma progression

Circular RNAs (circRNA) have been reported as regulators involved in hepatocellular carcinoma (HCC), but their mechanism of activity remains unknown. This study performed quantitative reverse-transcription polymerase chain reaction to determine if circNFATC3 was downregulated in 46 paired HCC tissues and cell lines. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, apoptotic, and transwell assay proved that circNFATC3 can inhibit hepatoma cell proliferation, apoptosis, and migration/invasion in vitro. Mouse xenograft assay demonstrated that circNFATC3 suppressed tumor size and weight and reduced lung metastasis in vivo, and vice versa. The RNA-seq results showed that NFATC3 itself was the most significantly differentially expressed gene when circNFATC3 was manipulated, and bioinformatics and luciferase reporter assays verified circNFATC3 regulated the expression of NFATC3 by interacting with the hsa-miR-548I. Additionally, it was also indicated that the level of NFATC3 was downregulated in HCC patients also and was significantly correlated with the staging and prognosis of HCC. Moreover, both circNFATC3 and NFATC3 were shown to inhibit the phosphorylation of JNK, c-Jun, AKT, and mTOR signaling pathways. Overall, the circNFATC3 can sponge miR-548I to protect NFATC3 itself, then it regulates hepatoma cell function via the JNK, c-Jun, AKT, and mTOR signaling pathways, and the circNFATC3 can be a tumor-repressor on HCC.status: publishe

A new strategy for overcoming drug resistance in liver cancer: Epigenetic regulation

Drug resistance in hepatocellular carcinoma has posed significant obstacles to effective treatment. Recent evidence indicates that, in addition to traditional gene mutations, epigenetic recoding plays a crucial role in HCC drug resistance. Unlike irreversible gene mutations, epigenetic changes are reversible, offering a promising avenue for preventing and overcoming drug resistance in liver cancer. This review focuses on various epigenetic modifications relevant to drug resistance in HCC and their underlying mechanisms. Additionally, we introduce current clinical epigenetic drugs and clinical trials of these drugs as regulators of drug resistance in other solid tumors. Although there is no clinical study to prevent the occurrence of drug resistance in liver cancer, the development of liquid biopsy and other technologies has provided a bridge to achieve this goal