ArticleOncogene2020
SIX4 promotes hepatocellular carcinoma metastasis through upregulating YAP1 and c-MET.
Article in Oncogene, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 70 citations in OpenAlex.
- Efficacy and safety of multi-target tyrosine kinase inhibitor AL2846 combined with gemcitabine in pancreatic cancer.Investigational new drugs · 2025Trial
- Association of serum lactate dehydrogenase levels with the severity of microvascular invasion in hepatocellular carcinoma: a retrospective cross-sectional study.Journal of gastrointestinal oncology · 2026Article
- Fe-MOF loaded with capmatinib to reverse immunosuppressive microenvironment and inhibit tumor metastasis after radiofrequency ablation.Journal of nanobiotechnology · 2025Article
- Single-cell and bulk transcriptome sequencing identifies circadian rhythm disruption and cluster-specific clinical insights in colorectal tumorigenesis.Discover oncology · 2025Article
- Decoding Hepatocellular Carcinoma Metastasis: Molecular Mechanisms, Targeted Therapies, and Potential Biomarkers.Current issues in molecular biology · 2025Review
- Arid4a Suppresses Breast Tumor Metastasis by Enhancing MTSS1 Expression via mRNA Stability.Cancer medicine · 2025Article
- Sine oculis homeobox homolog family function in gastrointestinal cancer: Progression and comprehensive analysis.World journal of clinical oncology · 2025Review
- Targeting the Hippo/YAP1 signaling pathway in hepatocellular carcinoma: From mechanisms to therapeutic drugs (Review).International journal of oncology · 2024Review
- Metastasis and basement membrane-related signature enhances hepatocellular carcinoma prognosis and diagnosis by integrating single-cell RNA sequencing analysis and immune microenvironment assessment.Journal of translational medicine · 2024Article
- The Hippo-YAP signaling pathway drives CD24-mediated immune evasion in esophageal squamous cell carcinoma via macrophage phagocytosis.Oncogene · 2024Article
- Article
- Dual role of Nrf2 signaling in hepatocellular carcinoma: promoting development, immune evasion, and therapeutic challenges.Frontiers in immunology · 2024Review
- SIX4 Activation in Inflammatory Response Drives the Transformation of Colorectal Epithelium into Inflammation and Tumor via Feedback-Enhancing Inflammatory Signaling to Induce Tumor Stemness Signaling.International journal of biological sciences · 2024Article
- Multimodal Imaging-Guided Synergistic Photodynamic Therapy Using Carbonized Zn/Co Metal-Organic Framework Loaded with Cytotoxin Against Liver Cancer.International journal of nanomedicine · 2024Article
- SIX4 Controls Anti-PD-1 Efficacy by Regulating STING Expression.Cancer research communications · 2023Article
- Combination of SIX4-siRNA and temozolomide inhibits the growth and migration of A-172 glioblastoma cancer cells.Naunyn-Schmiedeberg's archives of pharmacology · 2023Article
- Transcription factor glucocorticoid modulatory element-binding protein 1 promotes hepatocellular carcinoma progression by activating Yes-associate protein 1.World journal of gastrointestinal oncology · 2023Article
- Comprehensive DNA methylation profiling of COVID-19 and hepatocellular carcinoma to identify common pathogenesis and potential therapeutic targets.Clinical epigenetics · 2023Article
- MESP2 binds competitively to TCF4 to suppress gastric cancer progression by regulating the SKP2/p27 axis.Cell death discovery · 2023Article
- Increased Platelet Distribution Width Predicts 3-Year Recurrence in Patients with Hepatocellular Carcinoma After Surgical Resection.Cancer management and research · 2023Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Metastasis is the main reason for high mortality in hepatocellular carcinoma (HCC) patients and the molecular mechanism remains unclear. Therefore, it is important to elucidate the mechanism underlying HCC metastasis. Here, we report a novel role of SIX homeobox 4 (SIX4), one of the SIX gene family, in promoting HCC metastasis. The elevated expression of SIX4 was positively correlated with loss of tumor encapsulation, microvascular invasion, higher TNM stage, and poor prognosis in human HCC. SIX4 expression was an independent and significant risk factor for the recurrence and survival in HCC patients. Upregulation of SIX4 promoted HCC invasion and metastasis, whereas downregulation of SIX4 decreased HCC invasion and metastasis. SIX4 transactivated Yes1 associated transcriptional regulator (YAP1) and MET proto-oncogene, receptor tyrosine kinase (MET) expression through directly binding to their promoters. Knockdown of YAP1 and c-MET inhibited SIX4-medicated HCC metastasis, while the stable overexpression of YAP1 and c-MET reversed the decreased metastasis induced by SIX4 knockdown. Hepatocyte growth factor (HGF), the specific ligand of c-MET, upregulated SIX4 expression through ERK/NF-κB pathway. Knockdown of SIX4 significantly decreased HGF-enhanced HCC metastasis. In human HCC tissues, SIX4 expression was positively correlated with nuclear YAP1, c-MET and HGF expression. Patients with positive coexpression of SIX4/ nuclear YAP1, SIX4/c-MET or HGF/SIX4 had the poorest prognosis. Moreover, the combination treatment of YAP1 inhibitor Verteporfin and c-MET inhibitor Capmatinib significantly suppressed SIX4-mediated HCC metastasis. In conclusion, SIX4 is a prognostic biomarker in HCC patients and targeting the HGF-SIX4-c-MET positive feedback loop may provide a promising strategy for the treatment of SIX4-driven HCC metastasis.
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