Hepatitis B protein x (HBx) has been reported to promote tumorigenesis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), but the mechanism awaits further investigation. In this study, we found that cFAM210A (a circular RNA derived from the third exon of transcript NM_001098801 of the FAM210A gene; CircBase ID: hsa_circ_0003979) can be silenced by HBx. cFAM210A expression was downregulated and negatively correlated with tumorigenesis in patients with HBV-related HCC. Furthermore, cFAM210A reduced the proliferation, stemness, and tumorigenicity of HCC cells. Mechanistically, HBx increased the N6-methyladenosine (m6A) level of cFAM210A by promoting the expression of RBM15 (an m6A methyltransferase), thus inducing the degradation of cFAM210A via the YTHDF2-HRSP12-RNase P/MRP pathway. cFAM210A bound to YBX1 and inhibited its phosphorylation, suppressing its transactivation function toward MET. These findings suggest the important role of circular RNAs in HBx-induced hepatocarcinogenesis and identify cFAM210A a potential target in the prevention and treatment of HBV-related HCC.

Sorafenib is a multi-kinase blocker and one of the few suggested drug treatments for aggressive hepatocellular carcinoma (HCC) patients. However, drug resistance to sorafenib may often occur over time and cause further tumor aggression. Recently, cancer stem cells were found in HCC and were speculated to be involved in tumor progression. SOX9 is highly expressed in HCC cancer stem cells and promotes cell proliferation and self-renewal. Meanwhile, HCC patients with higher SOX9 expression show poorer prognosis. Whether SOX9 is involved in sorafenib resistance in HCC is still unclear. Here, we found that sorafenib treatment increased the proportion of SOX9 positive cells in HCC cell lines. Overexpression of exogenous SOX9 in HCC increased sorafenib resistance both in vitro and in vivo, whereas down-regulation led to inhibition of sorafenib resistance. Knock-down of SOX9 by RNA interference caused down-regulation of downstream genes, including ATP binding cassette subfamily G member 2 (ABCG2). The drug resistance to sorafenib caused by SOX9 overexpression could be ameliorated by ABCG2 inhibition in HCC cell lines. In the cohort of patients taken sorafenib, we found that patients with lower SOX9 expression had more prolonged overall survival (OS) and progression-free survival (PFS). Univariate and multivariate Cox analysis shows that SOX9 expression exerts as an independent risk factor for the OS and PFS of HCC patients with sorafenib treatment. These findings demonstrate that SOX9 enhances sorafenib resistance and may regulate this process by modulating ABCG2 expression.

Importance: Tenofovir disoproxil and entecavir are both commonly used first-line antiviral treatments, but their comparative recurrence and overall survival (OS) benefits remain unclear.Objective: To explore differences of tenofovir disoproxil vs entecavir in recurrence-free survival (RFS) and OS after liver resection with curative intent in patients with hepatocellular cancer (HCC) related to hepatitis B virus (HBV).Design, Setting, and Participants: This retrospective cohort study was conducted at Eastern Hepatobiliary Surgery Hospital, a tertiary referral hospital in Shanghai, China, between January 4, 2015, and April 1, 2023. Participants included patients with HBV-related HCC who underwent liver resection with curative intent from January 2015 to December 2018. Patients who received tenofovir disoproxil were matched with patients who received entecavir in a 1:1 ratio using propensity score matching. Data were analyzed from April 3 to May 31, 2023.Exposures: Receiving tenofovir disoproxil or entecavir as antiviral treatment for HBV.Main Outcomes and Measures: Primary end points were RFS and OS rates.Results: Among 4451 patients (mean [SD] age, 58.1 [10.0] years; 3764 male [84.6%]; median [range] follow-up, of 51 [3 to 91] months), 989 patients in each of the groups were selected in propensity score matching. Baseline characteristics were comparable. In propensity score–matched groups, OS rates were 92.2% at 1 year, 70.9% at 3 years, and 54.2% at 5 years in the entecavir group, compared with 90.9% at 1 year, 75.2% at 3 years, and 64.0% at 5 years in the tenofovir disoproxil group. RFS rates were 83.9% at 1 year, 50.0% at 3 years, and 43.3% at 5 years in the entecavir group, compared with 85.3% at 1 year, 55.6% at 3 years, and 51.4% at 5 years in the tenofovir disoproxil group. Patients in the tenofovir disoproxil group had better OS (hazard ratio, 0.82; 95% CI, 0.72 to 0.94; P = .004) and RFS rates (hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = .001) compared with the entecavir group. Restricted mean survival time differences of entecavir vs tenofovir disoproxil groups were −0.05 (95% CI, −0.18 to 0.08) months at 1 year (P = .45), 0.20 (95% CI, −0.62 to 1.03) months at 3 years (P = .63), and 1.82 (95% CI, 0.14 to 3.51) months at 5 years (P = .03).Conclusions and Relevance: These findings suggest that in patients undergoing curative liver resection for HBV-related HCC, tenofovir disoproxil was associated with better long-term OS and RFS rates compared with entecavir, providing insights for antiviral treatment.

Background: Compared with 2D evaluation, 3D evaluation possesses the virtues of displaying spatial anatomy of intrahepatic blood vessels and its relations to tumors, and enabling calculation of liver volumes, thus facilitating preoperative surgery planning. Methods: The objective of this study is to study whether preoperative 3D (three-dimensional) evaluation produced better long-term overall survival (OS) outcomes compared to the traditional 2D (two-dimensional) evaluation in patients who underwent major hepatectomy for hepatocellular carcinoma (HCC). This retrospective study matched patients who underwent preoperative 2D evaluation with those who underwent preoperative 3D evaluation in a 1:1 ratio using propensity score matching. The primary endpoints were long-term survival outcomes in the two groups after major hepatectomy for HCC. Results: Of the 248 patients in each of the 2 matched groups, the baseline characteristics were comparable. The median follow-up for all patients was 36 months (range, 0–40 months). The 3-year OS of patients in the PSM cohort was 38.5%. Compared with the 2D Group, patients in the 3D Group had a better OS rate (HR 0.722, 95% CI: 0.556–0.938, P=0.015) and disease-free survival (DFS) rate (HR 0.741, 95% CI: 0.590–0.929, P=0.009). The 3-year OS and DFS rate for the 3D Group versus the 2D group were 58.9% and 44.0% versus 47.4% and 33.1%, respectively. Conclusions: 3D preoperative evaluation resulted in significantly better intermediate-term (3-year) overall survival rate than the traditional 2D evaluation.

One- versus two-stage partial hepatectomy for large resectable solitary hepatocellular carcinomas determined preoperatively to have a narrow resection margin: a propensity score matching analysis Yao Li, Peng-Peng Li, Da-Peng Sun, Jun-Sheng Ni, Hui Liu, Ze-Ya Pan, Yuan Yang, Ling-Hao Zhao, Wan Yee Lau, Gang Huang, Wei-Ping Zhou