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.
Highlights
Esophageal cancer is one of the most common cancers worldwide [1], the incidence is increasing rapidly in recent years in China, and is the fourth most frequent cause of cancer-related deaths in China, five-year survival is very poor [2]
We found that PRSS8 was significantly reduced in esophageal squamous cell carcinomas (ESCC) cancer tissues and cancer cells at protein and mRNA levels, and the reduction of expression was associated with poor differentiation and shorter survival time and diseasefree time
PRSS8 was reduced in ESCC tissues and the reduction of PRSS8 was associated with poor differentiation and shorter survival time
Summary
Esophageal cancer is one of the most common cancers worldwide [1], the incidence is increasing rapidly in recent years in China, and is the fourth most frequent cause of cancer-related deaths in China, five-year survival is very poor [2]. We found that PRSS8 (protease serine 8), a trypsin-like serine peptidase [9,10,11], is hypermethylated in ESCC tissues and ESCC cell lines. Recent studies www.impactjournals.com/oncotarget have reported that serum PRSS8 level is increased in ovarian cancer patients [12], but PRSS8 expression was decreased in chemoresistant ovarian cancer patients and chemoresistant cell line. PRSS8 expression was reduced in the cancers of prostate [14, 15], breast [16], bladder [17] and stomach[18], showing tumor suppressive roles. We found that PRSS8 was significantly reduced in ESCC cancer tissues and cancer cells at protein and mRNA levels, and the reduction of expression was associated with poor differentiation and shorter survival time and diseasefree time. The PRSS8 methylation likely played a crucial roles in ESCC, evidenced by restoration of PRSS8 by de-methylation agent and knockdown the restoration of PRSS8 in ESCC cells exhibiting inverse functions
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