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BACKGROUND: Hepatocellular carcinoma (HCC) is a common cancer that is fatal and has a dismal prognosis. Obovatol (Ob), a novel lignan derived from the leaf and stem bark of Magnolia obovata Thunb, has exhibited anti-tumor effect on diverse tumors. However, its effect and mechanisms on HCC remain to be further explored. METHODS: Huh7 and Hep3B cells, as well as BALB/c nude mice were used to determine the function and mechanisms of Ob on growth, invasion and immune escape by cell counting kit-8, transwell, enzyme-linked immunosorbent assay (ELISA) and western blot experiments. RESULTS: Ob reduced the cell viability of Huh7 and Hep3B cells, with a IC50 value of 57.41 µM and 62.86 µM, respectively. Ob declined the invasion ability, the protein expression of N-cadherin and the concentrations of IL-10 and TGF-ß, whereas increased the E-cadherin expression and the contents of IFN-γ and IL-2 in Hep3B and Huh7 cells. Mechanically, Ob decreased the protein level of p-JAK/JAK, p-STAT3/STAT3 and PD-L1, which was partly restored with the treatment of RO8191, an activator of JAK/STAT3 axis. The effect of Ob on the cell viability, the invasion ability, the protein level of N-cadherin and E-cadherin, and the concentrations of IL-10, TGF-ß, IFN-γ and IL-2 in both Hep3B and Huh7 cells was reversed with the management of RO8191. In vivo, Ob reduced tumor volume and weight, the level of N-cadherin, PD-L1, p-JAK/JAK, and p-STAT3/STAT3, with an elevated expression of E-cadherin and IFN-γ. CONCLUSION: Ob downregulated the JAK/STST3/PD-L1 pathway to attenuate the growth, invasion and immune escape of HCC.
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BACKGROUND: Chronic hepatitis B virus (HBV) infection is a serious human health threat given its high morbidity and mortality. Timely and effective antiviral treatment can postpone liver disease progression and reduce the occurrence of HBV-related end-stage liver disease. At present, the antiviral treatment criteria are mainly based on alanine transaminase (ALT) levels, HBV DNA levels and HBV e antigen levels according to the American Association for the Study of Liver Diseases treatment guidelines. However, some chronic hepatitis B (CHB) patients not meeting the above criteria still experience liver disease progression without antiviral treatment. It is urgent to identify a more comprehensive tool to screen out more antiviral treatment candidates as soon as possible. METHODS: Considering the vital role of the immune response in the development of HBV infection and CHB cure, we collected data from 335 treatment-naïve CHB patients and comprehensively analysed their clinical and immune traits (including innate and adaptive responses). The immune parameters were obtained by flow cytometry. Finally, we established a model that can better distinguished CHB patients who need treatment through machine learning and LASSO regression of serological and immune parameters. RESULTS: Through a series of analyses, we selected four important clinical parameters (ALT, HBV DNA, the Fibroscan value, and the A/G ratio) and four immune indicators (NKbright + NKp44+, NKbright + NKG2A+, NKT+GranzymeB+, and CD3 + CD107a + ) from more than 200 variables and then successfully established a mathematical model with high sensitivity and specificity to better screen out antiviral treatment candidates from all CHB patients. CONCLUSIONS: Our results developed a refined model to better screen out antiviral treatment candidates from all CHB patients by combining common clinical parameters and important immune indicators, including innate and adaptive immunity. These findings provide more information for improving treatment guidelines and have potential implications for the timing of antiviral therapy to achieve better virus control and reduce the occurrence of end-stage liver disease.
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BACKGROUND: Liver cancer stem cells (CSCs) contribute to tumor initiation, progression, and recurrence in hepatocellular carcinoma (HCC). The Wnt/ß-catenin pathway plays a crucial role in liver cancer stemness, progression, metastasis, and drug resistance, but no clinically approved drugs have targeted this pathway efficiently so far. We aimed to elucidate the role of COLEC10 in HCC stemness. METHODS: The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases were employed to search for the association between COLEC10 expression and HCC stemness. Colony formation, sphere formation, side population, and limiting dilution tumor initiation assays were used to identify the regulatory role of COLEC10 overexpression in the stemness of HCC cell lines. Wnt/ß-catenin reporter assay and immunoprecipitation were performed to explore the underlying mechanism. RESULTS: COLEC10 level was negatively correlated with HCC stemness. Elevated COLEC10 led to decreased expressions of EpCAM and AFP (alpha-fetoprotein), two common markers of liver CSCs. Overexpression of COLEC10 inhibited HCC cells from forming colonies and spheres, and reduced the side population numbers in vitro, as well as the tumorigenic capacity in vivo. Mechanically, we demonstrated that overexpression of COLEC10 suppressed the activity of Wnt/ß-catenin signaling by upregulating Wnt inhibitory factor WIF1 and reducing the level of cytoplasmic ß-catenin. COLEC10 overexpression promoted the interaction of ß-catenin with the component of destruction complex CK1α. In addition, KLHL22 (Kelch Like Family Member 22), a reported E3 ligase adaptor predicted to interact with CK1α, could facilitate COLEC10 monoubiquitination and degradation. CONCLUSION: COLEC10 inhibits HCC stemness by downregulating the Wnt/ß-catenin pathway, which is a promising target for liver CSC therapy.
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BACKGROUND: The role of circRNAs in hepatocellular carcinoma (HCC) progression remains unclear. CircPIAS1 (circBase ID: hsa_circ_0007088) was identified as overexpressed in HCC cases through bioinformatics analysis. This study aimed to investigate the oncogenic properties and mechanisms of circPIAS1 in HCC development. METHODS: Functional analyses were conducted to assess circPIAS1's impact on HCC cell proliferation, migration, and ferroptosis. Xenograft mouse models were employed to evaluate circPIAS1's effects on tumor growth and pulmonary metastasis in vivo. Bioinformatics analysis, RNA immunoprecipitation, and luciferase reporter assays were utilized to elucidate the molecular pathways influenced by circPIAS1. Additional techniques, including RNA pulldown, fluorescence in situ hybridization (FISH), chromatin immunoprecipitation (ChIP), qPCR, and western blotting, were used to further explore the underlying mechanisms. RESULTS: CircPIAS1 expression was elevated in HCC tissues and cells. Silencing circPIAS1 suppressed HCC cell proliferation and migration both in vitro and in vivo. Mechanically, circPIAS1 overexpression inhibited ferroptosis by competitively binding to miR-455-3p, leading to upregulation of Nuclear Protein 1 (NUPR1). Furthermore, NUPR1 promoted FTH1 transcription, enhancing iron storage in HCC cells and conferring resistance to ferroptosis. Treatment with ZZW-115, an NUPR1 inhibitor, reversed the tumor-promoting effects of circPIAS1 and sensitized HCC cells to lenvatinib. CONCLUSION: This study highlights the critical role of circPIAS1 in HCC progression through modulation of ferroptosis. Targeting the circPIAS1/miR-455-3p/NUPR1/FTH1 regulatory axis may represent a promising therapeutic strategy for HCC.
