OLFML2B promotes hepatocellular carcinoma malignancy via the PI3K/AKT-EMT axis and correlates with an immunosuppressive tumor microenvironment

CARS1 as a Prognostic Biomarker and Candidate Therapeutic Vulnerability in Hepatocellular Carcinoma: Insights Into Tumor Progression and the Immune Microenvironment.

BACKGROUND Cysteinyl-tRNA synthetase 1 (CARS1) has been included in ferroptosis-related prognostic signatures, but its clinicopathological relevance, cellular functions, and relationship with the immune microenvironment in hepatocellular carcinoma (HCC) remain incompletely characterized. METHODS Transcriptomic and clinical data from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset were integrated with corresponding data from an institutional HCC tissue cohort of 60 patients. CARS1 expression was evaluated by immunohistochemistry, and immune infiltration was examined using single-sample gene-set enrichment analysis (ssGSEA) and multiplex immunofluorescence, as well as by analyzing public single-cell datasets. The effects of CARS1 depletion were evaluated in MHCC97H and Hep3B cells using Cell Counting Kit-8 (CCK-8) assays, cell-cycle profiling, wound-healing assays, Transwell migration assays, western blotting, and erlotinib-sensitivity assays. RESULTS CARS1 expression was elevated in HCC and was associated with adverse clinicopathological features and poor overall survival. Quantitative immunohistochemistry confirmed elevated CARS1 protein expression in tumor tissues. CARS1 depletion inhibited cell proliferation, altered cell-cycle distribution, impaired migration, and enhanced in vitro sensitivity to erlotinib. High CARS1 expression was also associated with increased infiltration of Th2-like immune cells. CONCLUSIONS Elevated CARS1 expression is associated with an adverse biological and immune phenotype in HCC. These clinical, histopathological, and loss-of-function findings support further investigation of CARS1 as a prognostic marker and candidate therapeutic target in HCC, although additional mechanistic and in vivo validation is required.

IFIT1+ Tumor-Associated Macrophages Suppress Cancer Stemness and Enhance Chemosensitivity via the TNFSF10-TNFRSF10B Axis in Epithelial Ovarian Cancer.

BACKGROUND Epithelial ovarian cancer (EOC) is typically diagnosed at an advanced stage and is associated with high mortality due to metastasis and chemoresistance. Cancer stem cells (CSCs) are central to EOC progression, recurrence, and treatment resistance, with their functional behavior shaped by the tumor immune microenvironment. While M1 and M2 macrophages have been well-characterized, the role of interferon-stimulated gene-enriched subpopulations, particularly interferon-induced protein with tetratricopeptide repeats 1 tumor-associated macrophages (IFIT1+ TAMs), in regulating CSC properties in EOC remains largely unexplored. METHODS Single-cell RNA sequencing (scRNA-seq) was utilized to map the myeloid landscape and trace transcriptomic evolution in EOC. An in vitro indirect culture model utilizing unpolarized macrophage (M0)-conditioned medium (CM) was established to assess baseline phenotypic alterations. Furthermore, targeted siRNA silencing (si-TNFRSF10B) combined with recombinant human tumor necrosis factor ligand superfamily member 10 (TNFSF10) (rhTRAIL) treatments were employed to evaluate the specific impact of the TNF-related apoptosis-inducing ligand (TRAIL)-Death receptor 5 (DR5) signaling axis on multidrug resistance and CD44 expression. RESULTS High-resolution scRNA-seq analysis revealed a stage-dependent decline in IFIT1+ TAMs, an interferon-primed subset that robustly expresses the TNFSF10 ligand during early-stage disease. In vitro assays showed that conditioned medium from M0 macrophages suppresses CSC features and enhances expression of the tumor necrosis factor receptor superfamily member 10B (Death receptor 5) (TNFRSF10B/DR5) in EOC cells. Mechanistic studies confirmed that exogenous rhTRAIL treatment markedly diminished CD44+ cell populations and enhanced sensitivity to chemotherapeutic agents. Notably, these antitumor effects were largely abrogated following siRNA-mediated silencing of the DR5 receptor in EOC cell lines. CONCLUSIONS Our findings reveal that IFIT1+ tumor-associated macrophages intrinsically harbor anti-cancer stem cell potential through the TNFSF10 ligand. Activation of the TNFSF10-TNFRSF10B pathway suppresses cancer stemness and may enhance chemosensitivity. These insights shed light on the functional diversity of macrophages, highlighting that driving tumor-associated macrophages toward a sustained, interferon-primed IFIT1+ phenotype represents a promising therapeutic approach to target cancer stem cell populations in epithelial ovarian cancer.

AKR1B15 promotes hepatocarcinogenesis by activating the p53-PI3K-AKT-mTOR-E2F1 signaling pathway.

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide, with limited biomarkers available for early diagnosis and targeted therapy. AKR1B15, a lesser-studied member of the aldo-keto reductase family, shares high sequence similarity with AKR1B10, but its role in HCC remains unclear. Therefore, this study aimed to investigate the biological function of AKR1B15 in HCC and its involvement in oncogenic signaling pathways. Bioinformatic analysis of gene expression datasets and patient tissue samples was used to evaluate AKR1B15 expression and prognostic relevance. Functional assays were conducted following AKR1B15 knockdown, including CCK-8, colony formation, transwell, wound healing, flow cytometry, and xenograft models. Western blotting and immunofluorescence were employed to assess phosphorylation of key signaling molecules. AKR1B15 expression was significantly elevated in HCC tissues and associated with higher pathologic T stage and worse disease-specific survival (P < 0.05). AKR1B15 knockdown inhibited HCC cell proliferation, invasion, and migration (P < 0.01), and promoted apoptosis (P < 0.001). In vivo, AKR1B15 depletion suppressed tumor growth and reduced Ki-67 expression. Mechanistically, silencing AKR1B15 decreased phosphorylation of p53 (Ser15), PI3K (Tyr458/199), AKT (Ser473), mTOR (Ser2448), and E2F1 (S364), indicating inhibition of the p53-PI3K-AKT-mTOR-E2F1 axis. AKR1B15 promotes HCC progression and is associated with activation of the p53-PI3K-AKT-mTOR-E2F1 signaling pathway. It may serve as a novel diagnostic marker and therapeutic target in hepatocellular carcinoma.

IGF2BP3-Mediated m6A Modification of OLR1 mRNA Promotes Immune Evasion in CRC via the PI3K/AKT/mTOR Pathway.

Colorectal cancer (CRC) is a prevalent malignancy worldwide, with its immune evasion representing a pivotal barrier to effective immunotherapy. OLR1 is abnormally expressed in a variety of cancers, but its function in the CRC immune microenvironment and the upstream and downstream modulatory mechanisms remain unclear. Based on the TCGA-COAD data set, OLR1 was upregulated in colorectal cancer (CRC) and correlated with CD8+ T-cell infiltration. Functional assays (qRT-PCR, Western blotting, LDH, ELISA, CCK-8, CFSE, colony formation, Transwell, and flow cytometry) confirmed that OLR1 suppressed CD8+ T-cell function and promoted tumor malignancy. GSEA and inhibitor-based functional validation identified key pathways downstream of OLR1. Mechanistically, bioinformatics, RIP, RNA pull-down, MeRIP, and actinomycin D assays revealed that IGF2BP3 stabilized OLR1 mRNA. Rescue experiments further demonstrated that the IGF2BP3/OLR1 axis regulated the aforementioned pathways and CRC immune evasion. OLR1 was upregulated in CRC and negatively associated with CD8+ T-cell infiltration. Knockdown of OLR1 significantly enhanced the antitumor function of CD8+ T cells. Mechanistically, IGF2BP3 stabilized OLR1 mRNA and up-regulated its expression in an m6A modification-dependent manner, thereby activating the PI3K/AKT/mTOR pathway to inhibit the antitumor activity of CD8+ T cells. IGF2BP3 stabilized OLR1 through m6A modification and activated the PI3K/AKT/mTOR pathway, thereby repressing the antitumor activity of CD8+ T cells and promoting immune evasion in CRC.

DCUN1D5 as a New Biomarker and Regulator of Fatty Acid Metabolism in Hepatocellular Carcinoma

Background Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, with limited reliable biomarkers for early diagnosis and prognosis. In this study, we explored the role of DCUN1D5, a potential biomarker, in HCC. Methods We performed integrated bioinformatics analyses of publicly available HCC datasets, including TCGA, GEO, and ICGC, followed by in vitro experiments on HCC cell lines to validate our findings. Results DCUN1D5 expression was significantly elevated in HCC tissues compared to normal liver tissues. High DCUN1D5 levels were associated with poor prognosis and advanced tumor stage in HCC patients. Additionally, bioinformatics analysis revealed a correlation between DCUN1D5 expression levels and both immune infiltration and immunotherapy response in hepatocellular carcinoma. Functional assays revealed that DCUN1D5 knockdown inhibited cell proliferation, migration, and invasion in HCC cells. Mechanistically, Enrichment analysis revealed significant correlations between DCUN1D5 and multiple biological pathways; specifically, we observed a negative correlation between the expression level of DCUN1D5 and fatty acid metabolism. Further cellular experiments demonstrated that knockdown of DCUN1D5 can induce accumulation of free fatty acids in hepatocellular carcinoma cells. Conclusion In summary, our study identified DCUN1D5 as a potential biomarker for poor prognosis in HCC, high expression of DCUN1D5 are closely associated with tumor invasion and proliferation. Knockdown of DCUN1D5 was found to inhibit the proliferation, migration, and invasion of HCC cells and increases its free fatty acid accumulation. These studies suggest new possibilities for treatment strategies for HCC.

OLR1 drives gastric cancer progression through NF-κB activation and immunosuppressive macrophage polarization