It is demonstrated that MCT4 drives HCC progression through two complementary mechanisms: enhancing MMP-mediated invasion and metastasis, and promoting immunosuppressive M2 macrophage polarization.
Abstract
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.
High MCT4 expression in TAMs may be associated with metabolic reprogramming toward glycolysis, and could promote M2 polarization of TAMs, thereby contributing to HCC progression and poor clinical outcomes.
Zhiying Li, Ni Zhang, Renjie Li et al.· Cell journal· 0 citations
Hepatocellular carcinoma (HCC) is a leading cause of global cancer-related mortality, highlighting the need for novel biomarkers and therapeutic targets.
The role of Olfactomedin-like 2B (OLFML2B) in HCC was investigated through multi-database analyses (The Cancer Genome Atlas, International Cancer Genome Consortium, Gene Expression Omnibus) and experimental validation.
OLFML2B was significantly upregulated in HCC tissues, correlated with poor overall and disease-specific survival, clinicopathological features (tumor grade, stage, age, gender), and robust diagnostic performance (AUC > 0.7 across 14/15 datasets). Transcriptomic and single-cell analyses further revealed that high OLFML2B expression was associated with an immunosuppressive tumor microenvironment, characterized by increased infiltration of M2 macrophages, cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs), as well as reduced abundance of cytotoxic T cells and NK cells. Knockdown of OLFML2B suppressed malignant phenotypes, including cell proliferation, migration, invasion, and angiogenesis, attenuated PI3K/AKT-EMT signaling, and enhanced sensitivity to sorafenib, cabozantinib, and regorafenib in Huh7 and HepG2 cells. Additionally, OLFML2B knockdown suppressed tumor growth and metastasis in zebrafish xenografts.
Collectively, these findings indicate that OLFML2B is required for HCC progression and represents a prognostic biomarker and potential therapeutic target.
Xiaoling Liu, Yonghong Wang, Jingjing Bai et al.· Frontiers in Immunology· 0 citations
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.
Dunzhen Chen, Li Yu, Xichang Zhou et al.· Scientific Reports· 0 citations
PURPOSE
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, with current therapies often limited by significant drug resistance. Owing to the Warburg effect, targeting cancer-specific metabolic vulnerabilities is a promising therapeutic strategy. This study aims to investigate the role of RNF114 in HCC progression and its regulatory mechanism, as well as its clinical translational potential as a therapeutic target.
METHODS
We evaluated the clinical significance of RNF114 using tissue microarrays and database analysis. RNF114 function in promoting HCC progression by regulating glucose uptake was investigated using knockdown experiments in cell lines and subcutaneous xenograft models. Furthermore, a therapeutic xenograft model was employed to assess the potential of RNF114 knockdown in overcoming Sorafenib resistance.
RESULTS
RNF114 was highly expressed in HCC and correlated with poor prognosis. Knockdown of RNF114 significantly suppressed HCC cell proliferation, migration, invasion, and glycolysis. Co-immunoprecipitation identified PACSIN3 as a key substrate of RNF114. RNF114 interacted with the SH3 domain of PACSIN3, promoting its ubiquitination and proteasomal degradation. Subcellular fractionation revealed that the F-BAR domain of PACSIN3 facilitated GLUT1 vesicular trafficking. Consequently, RNF114 impaired this process, leading to increased plasma membrane retention of GLUT1 and enhanced glycolytic flux. Consistently, in both HCC cells and subcutaneous xenograft models, RNF114 knockdown sensitized tumors to Sorafenib treatment.
CONCLUSIONS
Collectively, our findings reveal that the RNF114-PACSIN3-GLUT1 axis regulates glucose uptake and metabolic reprogramming in HCC, thereby promoting tumor progression and contributing to therapy resistance. Targeting this signaling axis provides a novel insight into metabolic therapy for HCC.
Yue Song, Yi-lu Lu, Qixiang Liu et al.· Cellular Oncology· 0 citations
The continuously rising incidence and persistently high mortality of hepatocellular carcinoma (HCC) have created an urgent need for a deeper understanding of the molecular mechanisms underlying this disease. In the present study, leveraging multiple HCC transcriptome databases, we employed expression analysis, correlation analysis, Gene Set Variation Analysis (GSVA), and cox regression analysis to identify that aberrant upregulation of PDIA6 represents a promising prognostic biomarker associated with adverse clinical outcomes in HCC. Using a series of in vitro oncology research approaches, as well as nude mouse models of subcutaneous tumor formation and lung metastasis, we experimentally validated that PDIA6 promotes the proliferation and metastasis of HCC cells. Through transcriptome sequencing analysis and subsequent rescue experiments, we further confirmed that PDIA6 enhances HCC cell proliferation and migration by activating the Wnt signaling pathway. Combined analysis via immunoprecipitation-mass spectrometry and proteomics revealed that PDIA6 significantly downregulates the expression of the tumor suppressor gene AKAP12. Subsequent rescue experiments demonstrated that PDIA6 drives HCC progression in a manner dependent on the reduced expression of AKAP12. Utilizing protein half-life assays, ubiquitination assays, and co-IP experiments, we uncovered the underlying mechanism: PDIA6 competitively binds to the UCH domain of USP24, which impairs the deubiquitinating activity of USP24 towards AKAP12. This ultimately leads to enhanced K48-linked ubiquitination of AKAP12 and its subsequent proteasomal degradation. We further verified, using specific activators, that AKAP12 inhibits the Wnt signaling pathway in a PKA-dependent manner. In vivo, targeted inhibition of PDIA6 exhibited a more potent therapeutic effect on Wnt-positive HCC tumors.Conclusion Collectively, our study demonstrates the HCC-promoting mechanism of the PDIA6-AKAP12-Wnt signaling axis and highlights its great potential for the development of therapeutic targets in HCC.
Rucheng Yao, Yuhan Yin, Xiaosong Li et al.· Cellular Oncology· 0 citations
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