Phosphorylation of RelA/p65 Ser536 inhibits the progression and metastasis of hepatocellular carcinoma by mediating cytoplasmic retention of NF-κB p65
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View abstract on PubMed
Summary
This summary is machine-generated.RelA/p65 Ser536 phosphorylation inhibits nuclear factor-κB (NF-κB) p65 translocation, hindering hepatocellular carcinoma (HCC) progression and metastasis. This finding highlights Ser536 as a potential therapeutic target for HCC treatment.
Area Of Science
- Oncology
- Molecular Biology
- Cancer Metastasis Research
Background
- Hepatocellular carcinoma (HCC) exhibits high recurrence and mortality rates, significantly influenced by intrahepatic and extrahepatic metastases.
- Constitutive activation of nuclear factor-κB (NF-κB), particularly the p50-p65 dimer, is a hallmark of HCC.
- The phosphorylation of RelA/p65 at Ser536 is critical, but its role in intermediate and advanced HCC progression and metastasis remains unelucidated.
Purpose Of The Study
- To investigate the effect of RelA/p65 Ser536 phosphorylation on hepatocellular carcinoma (HCC) progression and metastasis.
- To elucidate the underlying molecular mechanisms by which RelA/p65 Ser536 phosphorylation influences HCC.
- To evaluate the therapeutic potential of targeting RelA/p65 Ser536 phosphorylation in HCC.
Main Methods
- Immunohistochemical staining was employed to detect NF-κB p65 and its phosphorylated form (p-p65 Ser536) in HCC tissues.
- <i>In vivo</i> xenograft and metastasis models, alongside <i>in vitro</i> assays (proliferation, migration, invasion, epithelial-mesenchymal transition), were utilized to assess biological effects.
- Western blotting, chromatin immunoprecipitation, and various cell-based assays were performed to analyze NF-κB p65 nuclear translocation and promoter binding.
Main Results
- NF-κB p65 was highly expressed, but p-p65 Ser536 was poorly expressed in intermediate and advanced HCC tissues.
- A phosphorylation-mimetic mutant (p65/S536D) significantly inhibited tumor progression, metastasis, proliferation, migration, and invasion in both <i>in vivo</i> and <i>in vitro</i> models.
- RelA/p65 Ser536 phosphorylation was found to inhibit NF-κB p65 nuclear translocation and reduce its binding to the promoters of <i>BCL2</i>, <i>SNAIL</i>, and <i>MMP9</i>.
Conclusions
- RelA/p65 Ser536 phosphorylation impedes NF-κB p65 nuclear entry, thereby suppressing HCC progression and metastasis by downregulating <i>BCL2</i>, <i>SNAIL</i>, and <i>MMP9</i>.
- The RelA/p65 Ser536 phosphorylation site represents a promising therapeutic target for developing novel NF-κB-targeted therapies for HCC.
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