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Published on: April 12, 2024
PRSS8 methylation and its significance in esophageal squamous cell carcinoma
Yonghua Bao1, Qian Wang2, Yongchen Guo1
1Department of Pathology and Institute of Precision Medicine, Jining Medical University, Jining 272067, China.
Abstract:
Esophageal cancer is one of the most common cancers worldwide, and the incidence and mortality is increasing rapidly in recent years in China, but the underlying mechanisms are largely unclear. Herein we found that the expression of PRSS8, a serine protease prostasin, is significantly decreased in esophageal squamous cell carcinomas (ESCC) at mRNA and protein levels. The reduction of PRSS8 was well correlated with poor differentiation and shorter survival time. Interestingly, ESCC stromal expression of PRSS8 was significantly correlated with stromal lymphocyte infiltration and cancer progression. Methylation specific PCR showed that PRSS8 was hypermethylated in ESCC tissues and ESCC cell lines, which was linked to the downregulation of PRSS8 expression and decreased activities of PRSS8 promoter. De-methylation agent decitabine was able to restore PRSS8 expression, leading to the inhibition of cancer cell proliferation, motility, migration and cell cycle arrest. However, the restored PRSS8 and its tumor inhibition could be reversed by small interfering RNA targeting PRSS8. Mechanistic study showed that tumor inhibition of PRSS8 may be associated with proliferation- and epithelial mesenchymal transition - related proteins in ESCC cells. In conclusion, our finding showed that PRSS8 methylation and its stromal expression had important clinical significance in ESCC.
Insights
Prostate specific membrane antigen (PSMA) is a transmembrane protein. PSMA is a validated target for imaging and therapy of prostate cancer. Herein, we report the development of a novel PSMA-targeted antibody-drug conjugate (ADC). Our ADC demonstrated potent and specific antitumor activity in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Esophageal squamous cell carcinoma (ESCC) incidence and mortality are rising globally, particularly in China.
- Underlying molecular mechanisms driving ESCC progression remain largely unclear.
Purpose of the Study:
- To investigate the role of serine protease prostasin (PRSS8) in ESCC.
- To explore the clinical significance of PRSS8 methylation and stromal expression in ESCC.
Main Methods:
- Quantitative analysis of PRSS8 mRNA and protein expression in ESCC tissues.
- Correlation analysis between PRSS8 levels, clinicopathological features, and survival.
- Methylation-specific PCR to assess PRSS8 promoter methylation.
- In vitro studies using decitabine to restore PRSS8 expression and assess its effects on ESCC cells.
- Assessment of PRSS8's impact on proliferation, motility, migration, cell cycle, and epithelial-mesenchymal transition (EMT).
Main Results:
- PRSS8 expression was significantly decreased in ESCC at both mRNA and protein levels.
- Reduced PRSS8 correlated with poor differentiation and shorter survival.
- PRSS8 hypermethylation was observed in ESCC tissues and cell lines, linked to reduced expression.
- Decitabine treatment restored PRSS8 expression and inhibited ESCC cell proliferation, motility, migration, and induced cell cycle arrest.
- PRSS8's tumor-inhibitory effects were associated with proliferation and EMT-related proteins.
Conclusions:
- PRSS8 downregulation, driven by hypermethylation, plays a crucial role in ESCC progression.
- PRSS8 methylation and stromal expression hold significant clinical value for ESCC prognosis and potentially therapeutic targeting.
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