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Purpose: The characteristic of RENT3B in cancer remains ambiguous. We aimed to study the relationship between RENT3B and immune infiltration in liver hepatocellular carcinoma (LIHC) and lung squamous cell carcinoma (LUSC). Patients and methods: We investigated the expression levels of RENT3B using ONCOMINE and TIMER databases, and assessed the interrelationship between RENT3B expression and survival using PrognoScan, GEPIA, and Kaplan–Meier plotter. Additionally, we examined the association between RENT3B and immune cells in the tumor microenvironment (TME), as well as markers of immune cells, using TIMER. Subsequently, we performed prognostic analysis based on the expression level of RENT3B within specific immune cell subgroups. Furthermore, we evaluated the promoter methylation profile of RENT3B between tumor and normal tissues in LIHC and LUSC using the DNMIVD database. Results: RENT3B exhibited increased levels in both in LIHC and LUSC. High RENT3B expression was associated with unfavorable prognosis in LIHC, whereas it indicated a beneficial prognosis in LUSC. In LIHC, the expression of RENT3B positively correlated with immune infiltration levels of B cells, CD4 + T cells, CD8 + T cells, neutrophils, macrophages, and dendritic cells. However, in LUSC, the expression of RENT3B showed a negative correlation with immune infiltration levels of B cells, CD8 + T cells, neutrophils, macrophages, and dendritic cells. RENT3B exhibited positive correlations with 42 immune markers in LIHC, while it displayed negative associations with 10 immune markers in LUSC. Despite variations in immune cell enrichment and reduction subgroups, high RENT3B expression consistently indicated poor prognosis in LIHC, whereas it remained favorable in LUSC. Additionally, there were no significant differences observed in RENT3B promoter methylation between tumor and normal tissues in both LIHC and LUSC. Conclusion: RENT3B can affect the overall tumor prognosis and is associated with immune infiltration, especially in LIHC and LUSC. Consequently, RENT3B can become a prognostic biomarker for LIHC and LUSC. [ABSTRACT FROM AUTHOR]

Objective: The gain of function (GOF) CTNNB1 mutations (CTNNB1 GOF ) in hepatocellular carcinoma (HCC) cause significant immune escape and resistance to anti-PD-1. Here, we aimed to investigate the mechanism of CTNNB1 GOF HCC-mediated immune escape and raise a new therapeutic strategy to enhance anti-PD-1 efficacy in HCC., Design: RNA sequencing was performed to identify the key downstream genes of CTNNB1 GOF associated with immune escape. An in vitro coculture system, murine subcutaneous or orthotopic models, spontaneously tumourigenic models in conditional gene-knock-out mice and flow cytometry were used to explore the biological function of matrix metallopeptidase 9 (MMP9) in tumour progression and immune escape. Single-cell RNA sequencing and proteomics were used to gain insight into the underlying mechanisms of MMP9., Results: MMP9 was significantly upregulated in CTNNB1 GOF HCC. MMP9 suppressed infiltration and cytotoxicity of CD8 + T cells, which was critical for CTNNB1 GOF to drive the suppressive tumour immune microenvironment (TIME) and anti-PD-1 resistance. Mechanistically, CTNNB1 GOF downregulated sirtuin 2 (SIRT2), resulting in promotion of β-catenin/lysine demethylase 4D (KDM4D) complex formation that fostered the transcriptional activation of MMP9. The secretion of MMP9 from HCC mediated slingshot protein phosphatase 1 (SSH1) shedding from CD8 + T cells, leading to the inhibition of C-X-C motif chemokine receptor 3 (CXCR3)-mediated intracellular of G protein-coupled receptors signalling. Additionally, MMP9 blockade remodelled the TIME and potentiated the sensitivity of anti-PD-1 therapy in HCC., Conclusions: CTNNB1 GOF induces a suppressive TIME by activating secretion of MMP9. Targeting MMP9 reshapes TIME and potentiates anti-PD-1 efficacy in CTNNB1 GOF HCC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Liver progenitor cells (LPCs) are a subpopulation of cells that contribute to liver regeneration, fibrosis and liver cancer initiation under different circumstances., Results: By performing adenoviral-mediated transfection, CCK-8 analyses, F-actin staining, transwell analyses, luciferase reporter analyses and Western blotting, we observed that TGF-β promoted cytostasis and partial epithelial-mesenchymal transition (EMT) in LPCs. In addition, we confirmed that TGF-β activated the Smad and MAPK pathways, including the Erk, JNK and p38 MAPK signaling pathways, and revealed that TGFβ-Smad signaling induced growth inhibition and partial EMT, whereas TGFβ-MAPK signaling had the opposite effects on LPCs. We further found that the activity of Smad and MAPK signaling downstream of TGF-β was mutually restricted in LPCs. Mechanistically, we found that TGF-β activated Smad signaling through serine phosphorylation of both the C-terminal and linker regions of Smad2 and 3 in LPCs. Additionally, TGFβ-MAPK signaling inhibited the phosphorylation of Smad3 but not Smad2 at the C-terminus, and it reinforced the linker phosphorylation of Smad3 at T179 and S213. We then found that overexpression of mutated Smad3 at linker phosphorylation sites intensifies TGF-β-induced cytostasis and EMT, mimicking the effects of MAPK inhibition in LPCs, whereas mutation of Smad3 at the C-terminus caused LPCs to blunt TGF-β-induced cytostasis and partial EMT., Conclusion: These results suggested that TGF-β downstream of Smad3 and MAPK signaling were mutually antagonistic in regulating the viability and partial EMT of LPCs. This antagonism may help LPCs overcome the cytostatic effect of TGF-β under fibrotic conditions and maintain partial EMT and progenitor phenotypes.