Hepatocellular carcinoma (HCC) poses a significant global health burden with limited therapeutic options, particularly for non-viral etiologies. The mitochondrial solute carrier SLC25A43 is implicated in cellular redox homeostasis, yet its role in HCC remains unclear. This study aimed to comprehensively investigate the expression pattern, clinical significance, biological function, and potential mechanisms of SLC25A43 in HCC. Utilizing multi-omics data from public databases (TCGA-LIHC, GEO, and HPA), we performed integrated bioinformatic analyses. SLC25A43 was consistently upregulated in HCC tissues compared with non-tumorous liver tissues and demonstrated strong diagnostic value (AUC = 0.861). High SLC25A43 expression was significantly associated with advanced tumor stage, metastasis, and adverse clinicopathological features. Survival analyses identified SLC25A43 as an independent prognostic risk factor for overall survival, progression-free interval, and disease-specific survival. Functional enrichment analyses suggested that SLC25A43 is involved in mitochondrial oxidative phosphorylation, energy metabolism, and immune-related pathways. Immune infiltration analyses using ssGSEA, xCell, and TIMER consistently revealed negative correlations between SLC25A43 expression and multiple antitumor immune cell populations, particularly CD8 + T cells. Experimental validation confirmed that SLC25A43 was significantly upregulated in HCC tissues at both mRNA and protein levels. Functional assays in Huh-7, Hep-LM3, MHCC97H, and LO2 cells demonstrated that SLC25A43 knockdown inhibited, whereas overexpression promoted, cell proliferation and migration. Rescue experiments further verified the specificity of these effects. Mechanistically, SLC25A43 regulated intracellular ATP production, ROS accumulation, and glutathione metabolism, indicating a role in redox homeostasis and energy metabolism. In addition, PBMC co-culture experiments showed that SLC25A43 suppressed CD8 + T-cell cytotoxic activity by reducing Granzyme B expression. A prognostic nomogram incorporating SLC25A43 exhibited favorable predictive performance and was successfully validated in two independent GEO cohorts. SLC25A43 is a novel diagnostic and prognostic biomarker for HCC. Its upregulation promotes tumor progression through metabolic reprogramming, redox homeostasis remodeling, and suppression of antitumor immune responses. These findings highlight SLC25A43 as a promising therapeutic target and provide new insights into the metabolic-immune regulatory network in hepatocellular carcinoma.
Solute carrier family 25 member 39 (SLC25A39) is crucial for regulating mitochondrial oxidative metabolism and homeostasis, linking to various physiological and pathological processes. Its expression landscape and mechanistic roles across cancer types remain largely unexplored. This study systematically profiled SLC25A39 in pan-cancer and assessed its prognostic relevance, molecular associations, and therapeutic potential. Multi-omics database resources were utilized to perform an integrated analysis of SLC25A39, including its expression profiles, prognostic value, molecular mechanisms, and associations with the immune microenvironment across diverse tumors. The oncogenic role of SLC25A39 was confirmed through in vitro gene knockdown in hepatocellular carcinoma. SLC25A39 was predominantly over expressed in nearly all types of cancer. SLC25A39 serves as an unfavorable prognosis marker. Its expression was primarily linked to immune cell infiltration, the cancer immunity cycle, major histocompatibility complex, immune checkpoints, tumor mutation burden, microsatellite instability, and RNA modifications like m1A, m5C, m6A, as well as DNA methylation sites. Functional enrichment analysis reveals that SLC25A39 is commonly associated with immune-related pathways and cell cycle-related pathways in the pan-cancer dataset. Knockdown of SLC25A39 in Huh-7 and HepG2 cells significantly inhibited hepatocellular carcinoma cell proliferation. SLC25A39 induces pro-tumorigenic effects across various cancer types. It serves as a potential biomarker.
Li Qin, Yuanqian Yao, Jianlin Lv· Discover Oncology· 0 citations
Introduction Hepatocellular carcinoma (HCC) is characterized by a complex tumor microenvironment and limited therapeutic options. Synaptogyrin-2 (SYNGR2), a transmembrane protein, has been implicated in cancer but its comprehensive role in HCC prognosis, immune regulation, and treatment response remains unclear. Methods Multiomics bioinformatics analysis was performed via RNA-seq data from the TCGA-LIHC cohort. Prognostic value was assessed via Cox regression and Kaplan‒Meier analysis. Immune cell infiltration was estimated via CIBERSORT, and drug sensitivity was predicted via the oncoPredict R package. In vitro validation was conducted using Hep3B and Huh7 cell lines. To establish causality, isogenic gain- and loss-of-function experiments were performed, followed by RT–qPCR, and CCK-8 assays. Results SYNGR2 expression was significantly elevated in HCC tissues and correlated with advanced tumor stage, poor differentiation, and poor overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) (all P<0.05). It served as an independent prognostic biomarker (AUC=0.923). High SYNGR2 expression was associated with an immunosuppressive microenvironment characterized by increased numbers of M0 macrophages and Tregs and strongly positively correlated with immune checkpoint genes (PD-1, CTLA-4, and PD-L1). Bioinformatic predictions revealed that SYNGR2-high tumors were more sensitive to MK-1775 (DNA damage inhibitor) and paclitaxel, whereas SYNGR2-low tumors were sensitive to JAK1/IAP inhibitors. In vitro, Hep3B cells (high endogenous SYNGR2) displayed a markedly lower IC50 for MK-1775 than Huh7 cells (low endogenous SYNGR2). Critically, plasmid-mediated overexpression of SYNGR2 in Huh7 cells significantly sensitized them to MK-1775, while siRNA-mediated knockdown of SYNGR2 in Hep3B cells conferred significant resistance, establishing a causal role for SYNGR2 in modulating sensitivity to this WEE1 inhibitor. Conclusion SYNGR2 has emerged as a multifaceted biomarker candidate in HCC, associated with prognosis, an immunosuppressive microenvironment, and differential therapeutic responses. Its integration into clinical models could enhance prognostic stratification and guide personalized treatment strategies, particularly in selecting patients for DNA damage-targeting agents.
Rong Wang, Dongmei Chen, Qiu Du et al.· Technology in Cancer Researc...· 0 citations
Background Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with a poor survival rate despite advances in therapy. Metabolic reprogramming, particularly involving lactate transport, plays a critical role in HCC progression. Monocarboxylate transporter 4 (MCT4) is a key lactate exporter often overexpressed in cancers, yet its precise role in HCC pathogenesis and immune modulation remains incompletely defined. Methods We integrated bioinformatic analyses of multiple datasets (TCGA-LIHC, GSE46408, GSE36411) with experimental validation in HCC cell lines (Huh7, MHCC97-H) and a murine xenograft model. Functional assays including wound healing, Transwell invasion, Western blot, and flow cytometry were employed. Immune cell infiltration and polarization were analyzed via CIBERSORT and single-cell RNA sequencing data (GSE282701). Results MCT4 was identified as a prognostic hub gene among lactate metabolism-related genes (LMRGs) and was significantly upregulated in HCC tissues, correlating with advanced tumor stage and poor survival. Gene Set Enrichment Analysis (GSEA) revealed a strong association between MCT4 expression and matrix metalloproteinase (MMP) pathways. In vitro, MCT4 knockdown downregulated MMP1, MMP2, and MMP9 expression and suppressed HCC cell migration and invasion. Furthermore, high MCT4 expression was linked to an immunosuppressive tumor microenvironment characterized by M2 macrophage polarization. In vivo, MCT4 knockdown inhibited tumor growth and reduced infiltration of CD206+ M2 macrophages. Conclusions Our findings demonstrate that MCT4 drives HCC progression through two complementary mechanisms: enhancing MMP-mediated invasion and metastasis, and promoting immunosuppressive M2 macrophage polarization. These results nominate MCT4 as a promising therapeutic target for restoring antitumor immunity and inhibiting metastasis in HCC.
Kaiyuan Zhang, Xiaochen Ni, Chuhang Wang et al.· Frontiers in Immunology· 0 citations
Aim: Hepatocellular carcinoma (HCC) remains a formidable worldwide health challenge, characterized by inadequate treatment efficacy and unsatisfactory clinical prognosis. Our previous study implicated LINC01607 in lenvatinib resistance, but its role in HCC progression and ferroptosis-associated vulnerability remains unclear. Methods: LINC01607 expression was examined in HCC patient samples and The Cancer Genome Atlas datasets. Cellular, animal, and patient-derived organoid (PDO) models were used to evaluate its biological function. RNA sequencing, ferroptosis-related assays, rescue experiments, and drug-sensitivity analyses were performed to explore associated downstream pathways. Results: LINC01607 was upregulated in HCC tissues and associated with aggressive clinicopathological features and poor survival. Functional assays showed that LINC01607 promoted HCC cell proliferation, migration, invasion, tumor growth, and metastasis. LINC01607 depletion induced ferroptosis-associated changes, including increased lipid peroxidation, glutathione depletion, and Fe2+ accumulation under ferroptotic stress, which were partially reversed by ferroptosis inhibitors. LINC01607 knockdown also enhanced sensitivity to RSL3 and sorafenib, while ferrostatin-1 partially rescued the increased sorafenib sensitivity. RNA sequencing and rescue experiments suggested involvement of the p62–Keap1–Nrf2 pathway. LINC01607 depletion was associated with reduced SQSTM1/p62, Nrf2, and ferroptosis-resistance proteins, whereas p62 overexpression partially reversed these effects and Nrf2 knockdown abrogated the rescue. In xenograft and PDO models, LINC01607 depletion improved the response to sorafenib. Conclusion: LINC01607 contributes to HCC progression and ferroptosis-associated therapy resistance, at least in part through the p62–Keap1–Nrf2 pathway, supporting further investigation of LINC01607 as a potential therapeutic target.
Yuxin Zhang, Weiqi Xu, Fangling Cheng et al.· Cancer Drug Resistance· 0 citations
Hepatocellular carcinoma (HCC) is widely recognized as one of the leading causes of cancer‐related deaths worldwide. Although advances in screening, diagnosis, and treatment have been made, reliable biomarkers are urgently needed to monitor the disease. This study aims to investigate the association between spermidine synthase (SRM) and clinicopathological characteristics, inflammatory responses, and immune infiltration in HCC. RNA‐seq data and clinical information for liver HCC (LIHC) were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases to assess SRM expression. The correlation between SRM expression and immune infiltration was analyzed using the TIMER algorithm. Comprehensive analyses of immune checkpoints (ICPs), microsatellite instability (MSI), and tumor mutational burden (TMB) were performed using R‐based packages. KEGG analysis indicated SRM is involved in the IL‐17 signaling pathway. This association was further supported by experimental validation of key markers via qPCR and western blot. Functional studies, including in vivo experiments, are needed to establish a causal relationship. Our results show that SRM expression is significantly elevated in HCC tissues compared to adjacent nontumor tissues and associated with adverse clinicopathological features and poor prognosis. SRM expression was significantly correlated with immune infiltration levels in LIHC, involving 22 immune cell subtypes, particularly tumor‐associated macrophages (TAMs; CD86 and IL10). Moreover, SRM expression was closely associated with ICPs, TMB, and MSI. Based on transcriptomic data, KEGG pathway analysis of SRM‐associated differentially expressed genes revealed significant enrichment in the IL‐17 signaling pathway. These in vitro findings suggest a potential association among SRM, IL‐8 expression, and pathways related to tumor progression and immune modulation, although further in vivo studies are required to confirm these observations. However, in vivo studies using animal models are required to evaluate whether targeting SRM has therapeutic effects on HCC and to further validate these mechanistic findings.
Bo-Wen Wu, Feng-Hong Wang, Lei Zhang et al.· Mediators of Inflammation· 0 citations
AIM
Investigate FBXW8 expression levels in hepatocellular carcinoma (HCC), its biological roles and prognostic significance.
METHODS
Based on the analysis of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases, the expression level of FBXW8 was investigated. The results were verified in clinical samples using quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC). Functional experiments (Cell Counting Kit-8, wound healing, and Transwell) were conducted on Huh7 and MHCC-97 H cells. Immune infiltration and methylation status were also evaluated.
RESULTS
FBXW8 was significantly overexpressed in HCC tissues across multiple cohorts (TCGA, GSE25097, GSE54236; all p < 0.001), with consistent validation by qPCR and IHC in clinical specimens. Elevated FBXW8 expression correlated with aggressive clinicopathological characteristics, specifically, advanced tumor-node-metastasis staging, poor histological grade, and higher alpha-fetoprotein levels (all p < 0.05). High FBXW8 expression was associated with worse overall survival (hazard ratio [HR] = 1.52, p = 0.024), with Progression-free interval (HR = 1.45, p = 0.013) also adversely affected. Receiver operating characteristic analysis demonstrated that FBXW8 had diagnostic value. The areas under the curve in the TCGA, GSE25097 and GSE54236 datasets were 0.875, 0.837 and 0.716, respectively. The in vitro functional experiments demonstrated that FBXW8 overexpression promoted cell proliferation, migration, and invasion (all p < 0.05). The FBXW8 expression was positively correlated with T helper cells (r = 0.342), while it was negatively correlated with dendritic cells (r = - 0.379). Promoter hypermethylation of FBXW8 was observed in HCC, with three CpG sites associated with prognosis.
CONCLUSION
FBXW8 functions as a prognostic biomarker and promotes HCC progression, indicating its therapeutic potential.
Duanzhuo Li, Yanli Liao, S. Yao et al.· BMC Gastroenterology· 0 citations