KLF4 Suppresses the Progression of Hepatocellular Carcinoma by Reducing Tumor ATP Synthesis through Targeting the Mir-206/RICTOR Axis.

To address the increased energy demand, tumor cells undergo metabolic reprogramming, including oxidative phosphorylation (OXPHOS) and aerobic glycolysis. This study investigates the role of Kruppel-like factor 4 (KLF4), a transcription factor, as a tumor suppressor in hepatocellular carcinoma (HCC) by regulating ATP synthesis. Immunohistochemistry was performed to assess KLF4 expression in HCC tissues. Functional assays, such as CCK-8, EdU, and colony formation, as well as in vivo assays, including subcutaneous tumor formation and liver orthotopic xenograft mouse models, were conducted to determine the impact of KLF4 on HCC proliferation. Luciferase reporter assay and chromatin immunoprecipitation assay were utilized to evaluate the interaction between KLF4, miR-206, and RICTOR. The findings reveal low KLF4 expression in HCC, which is associated with poor prognosis. Both in vitro and in vivo functional assays demonstrate that KLF4 inhibits HCC cell proliferation. Mechanistically, it was demonstrated that KLF4 reduces ATP synthesis in HCC by suppressing the expression of RICTOR, a core component of mTORC2. This suppression promotes glutaminolysis to replenish the TCA cycle and increase ATP levels, facilitated by the promotion of miR-206 transcription. In conclusion, this study enhances the understanding of KLF4's role in HCC ATP synthesis and suggests that targeting the KLF4/miR-206/RICTOR axis could be a promising therapeutic approach for anti-HCC therapeutics.

Atezolizumab and bevacizumab plus transarterial chemoembolization and hepatic arterial infusion chemotherapy for patients with high tumor burden unresectable hepatocellular carcinoma: A multi-center cohort study.

BACKGROUND: Though atezolizumab plus bevacizumab (A+B) offer promise for unresectable hepatocellular carcinoma (uHCC) treatment, the response rate remains suboptimal. Our previous studies highlighted the potential of transarterial chemoembolization (TACE) when combined with FOLFOX-based hepatic arterial infusion chemotherapy (HAIC) in HCC treatment. This study aims to evaluate the safety and efficacy of A+B plus TACE-HAIC for high tumor burden uHCC (HTB-uHCC). METHODS: This three-center retrospective study involved 82 HTB-uHCC patients administered with TACE-HAIC followed by A+B. We characterized HTB-uHCC patients as those surpassing the up-to-11 criteria, exhibiting VP 3-4, or presenting extrahepatic metastases. The primary outcomes were the objective response rate (ORR) and progression-free survival (PFS). Secondary outcomes encompassed the incidence of treatment-related adverse events (TRAEs) and overall survival (OS). RESULTS: Employing the mRECIST criteria, the ORR was 62.2 %, wherein 18 (22.0 %) patients achieved complete response, 33 (40.2 %) demonstrated partial response, 21 (25.6 %) maintained stable disease, and 10 (12.2 %) exhibited disease progression. Impressively, 11 (13.4 %) patients were converted to resectable HCC and underwent curative hepatectomy. The median PFS was 10.1 months (95 % CI, 8.4 to NA), and the median OS was still pending. At the one-year mark, the OS and PFS rates were 92.8 % (95 % CI, 86.1 to 100.0) and 42.9 % (95 % CI, 31.3 to 58.7), respectively. 79 (96.3 %) experienced TRAEs, and 39 (47.6 %) had grade 3-4 TRAEs, though no treatment-related death was recorded. CONCLUSIONS: The findings underscore the potential of the A+B and TACE-HAIC combined treatment for HTB-uHCC patients, marking it as a viable therapeutic option, given its potent efficacy and tolerable safety profile.

PD-L1 inhibitor versus PD-1 inhibitor plus bevacizumab with transvascular intervention in unresectable hepatocellular carcinoma.

Both atezolizumab (a PD-L1 inhibitor) plus bevacizumab (A+B) and sintilimab (a PD-1 inhibitor) plus bevacizumab (S+B) are recommended as the first-line regimen for advanced hepatocellular carcinoma (HCC) in China. Different efficacy between the two regimens combined with transvascular intervention for unresectable HCC (uHCC) remain unknown. We retrospectively analyzed uHCC patients treated in three centers by simultaneous combination of A+B or S+B with transarterial chemoembolization (TACE) and FOLFOX-based hepatic arterial infusion chemotherapy (HAIC). Objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and treatment-related adverse events (TRAEs) were compared. Totally 188 patients were included, with 92 and 96 administered A+B+TACE-HAIC (ABTH) and S+B+TACE-HAIC (SBTH), respectively. ORRs (62.0 vs. 70.8%, respectively; P = 0.257) and disease control rates (88.0 vs. 93.8%, P = 0.267) were similar between groups by the mRECIST criteria. ABTH showed no survival advantage over SBTH, with median PFS times of 11.7 months and 13.0 months, respectively (HR = 0.81, 95% CI, 0.52-1.26, P = 0.35) and similar OS times (HR = 1.19, 95% CI, 0.32-4.39, P = 0.8). No significant differences were observed in grade 3-4 TRAEs between groups. Either PD-L1 or PD-1 inhibitor plus bevacizumab combined with TACE-HAIC have similarly excellent therapeutic efficacy with manageable adverse events, representing promising treatment options for uHCC.

Early recurrence of hepatocellular carcinoma in patients after ablation and resection: A propensity score analysis.

BACKGROUND: Early recurrence (ER, recurrence within 2 years) is common in hepatocellular carcinoma (HCC) patients after ablation and resection. We aimed to compare ER and assess the associated risk factors. METHODS: We collected data from patients underwent resection (1,235) or ablation (517) for early HCC (solitary tumor ≤5 â€‹cm). Baseline of patients were matched using propensity score matching. RESULTS: In the matched cohort of 690 patients, the ablation group had a higher ER rate (37.4% vs. 19.4%; P < .001) than the resection group. Patients with ER had worse overall survival (OS) than those without ER in both the ablation (5-year OS: 60.4% vs. 86.7%) and resection groups (5-year OS: 59.2% vs. 88.1%). Ablation treatment was identified as an independent adverse prognostic factor for ER (hazard ratio: 2.751, P < .001). Resection conferred a significant favorable OS than ablation (2-year: 95.4% vs. 90.9%; 5-years: 83.8% vs. 77.0%). CONCLUSIONS: Resection was superior to ablation in minimizing the risk of ER and offering a better OS for patients with early HCC.

METTL9-SLC7A11 axis promotes hepatocellular carcinoma progression through ferroptosis inhibition.

Methytransferase-like proteins 9 (METTL9) has been characterized as an oncogene in several cancers, however, its role in hepatocellular carcinoma (HCC) remains unknown. Here, we investigated the function and molecular mechanism of METTL9 in HCC. We showed that METTL9 expression was elevated in HCC, and its high expression was associated with poor survival outcomes. Knockdown of METTL9 observed a significant inhibition of HCC cell viability, migration, and invasion both in vitro and in vivo. By contrast, METTL9 overexpression HCC cells obtained stronger abilities in cell proliferation and migration. Mechanistically, we discovered that METTL9 knockdown led to a reduction in the expression level of SLC7A11, a key suppressor of ferroptosis, in turn, promoted ferroptosis in HCC cells, impeding the progression of HCC. Moreover, we have proved that targeting METTL9 could significantly restrain the growth of HCC patient-derived xenograft (PDX). Our study established METTL9 as a critical role in promoting HCC development and provides a foundation for further investigation and potential therapeutic interventions targeting ferroptosis in HCC.