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PRSS8 Methylation and Its Significance in Esophageal Squamous Cell Carcinoma

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PRSS8 Methylation and Its Significance in Esophageal Squamous Cell Carcinoma www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 19 PRSS8 methylation and its significance in esophageal squamous cell carcinoma Yonghua Bao1, Qian Wang2, Yongchen Guo1, Zhiguo Chen3, Kai Li4, Yiqiong Yang1, Huijuan Zhang3, Huali Dong5, Kui Shen5, Wancai Yang1,5 1 Department of Pathology and Institute of Precision Medicine, Jining Medical University, Jining 272067, China 2 Department of Immunology, Xinxiang Medical University, Xinxiang 453003, China 3 Department of Pathology, Xinxiang Medical University, Xinxiang 453003, China 4 Department of Pathology, The First Affiliated Hospital, Xinxiang Medical University, Xinxiang 453003, China 5 Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612, USA Correspondence to: Wancai Yang, email: [email protected] Keywords: PRSS8, methylation, esophageal cancer, survival, cancer stroma Abbreviations: ESCC, esophageal squamous cell carcinoma; DAC, decitabine Received: December 20, 2015 Accepted: March 28, 2016 Published: April 11, 2016 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. INTRODUCTION be one of the major causes of esophageal carcinogenesis, in particular, promoter hypermethylation of tumor Esophageal cancer is one of the most common suppressor genes leads to silence and downregulation cancers worldwide [1], the incidence is increasing rapidly of gene expression, which is linked to tumor formation in recent years in China, and is the fourth most frequent and progression [5–8]. In the present study, we found that cause of cancer-related deaths in China, five-year survival PRSS8 (protease serine 8), a trypsin-like serine peptidase is very poor [2]. However, the underlying mechanisms are [9–11], is hypermethylated in ESCC tissues and ESCC cell largely unknown, although epidemiological and etiological lines. studies have shown the crucial roles of environmental and PRSS8, also known as Prostasin, was found genetic factors in esophageal carcinogenesis, resulting in highly expressed in normal prostate gland and seminal more than 95% of esophageal squamous cell carcinoma fluid. Further studies have demonstrated that PRSS8 is (ESCC) in China and more than 90% of esophageal overexpressed in epithelial cells of various tissues, is adenocarcinomas in the American and European [3, involved in epithelial differentiation and shows important 4]. Numerous studies have shown that the silence or roles in epidermal barrier function, skin phenotypes, and decreased expression of tumor suppressor genes could embryonic viability [10, 11]. Interestingly, recent studies www.impactjournals.com/oncotarget 28540 Oncotarget have reported that serum PRSS8 level is increased in of PRSS8 if the stroma did not present visible lymphocyte ovarian cancer patients [12], but PRSS8 expression was infiltration, the difference was statistically significant decreased in chemoresistant ovarian cancer patients and (p=0.001, Table 1). In addition, the stroma of cancer in situ chemoresistant cell line. Moreover, increased expression showed more expression of PRSS8 compared to that in of PRSS8 induced cells death in ovarian cancer cell invasive ESCC stroma (p=0.017, Table 1). It is worthy to lines [13]. In addition, PRSS8 expression was reduced be noted that the positive correlation of stromal expression in the cancers of prostate [14, 15], breast [16], bladder of PRSS8 and lymphocyte infiltration could be resulted [17] and stomach[18], showing tumor suppressive from a feedback or response, suggesting that PRSS8 acts roles. In prostate cancer, reduced PRSS8 was associated as a protector or suppressor to prevent cancer invasion and with hypermethylation of PRSS8 [17]. However, the progression. Actually, more lymphocyte infiltration in the methylation site was not clear and whether the methylation stroma is associated with better outcomes of the ESCC has biological functions is unknown either. Herein we patients (Bao, et al, unpublished data). found that PRSS8 was significantly reduced in ESCC We then determined the mRNA levels of PRSS8 in cancer tissues and cancer cells at protein and mRNA ESCC tissues using available online data sets and found levels, and the reduction of expression was associated with that PRSS8 mRNA levels were also dramatically reduced poor differentiation and shorter survival time and disease- in ESCC tissues in comparison with their adjacent normal free time. More importantly, the PRSS8 methylation likely esophagus, evidenced by mining two sets of gene profile played a crucial roles in ESCC, evidenced by restoration data (Supplementary Figure S1, left panel (GDS3838) [19] of PRSS8 by de-methylation agent and knockdown the and middle panel from Oncomine [20]). Moreover, PRSS8 restoration of PRSS8 in ESCC cells exhibiting inverse mRNA levels were also reduced in Barrett’s Esophagus functions. (BE), a precancerous lesion of esophageal adenocarcinoma (EAC), and were reduced further in EAC (Supplementary RESULTS Figure S1, right panel from Oncomine [21] ). PRSS8 was reduced in ESCC tissues and the PRSS8 was differentially expressed in ESCC cell reduction of PRSS8 was associated with poor lines, and the reduction of PRSS8 was associated differentiation and shorter survival time with PRSS8 promoter hypermethylation To determine the expression levels of PRSS8, a We then determined PRSS8 expression levels in tissue microarray (TMA) containing 362 cases of ESCC ESCC cell lines. Four human ESCC cell lines (KYSE450, tissues was examined using immunohistochemical EC9706, TE1 and TE8) were screened for PRSS8 staining. As shown in Figure 1A, PRSS8 was highly expression. Immunoblotting results showed that PRSS8 expressed in normal esophageal epithelia mainly in protein levels were expressed in TE1 and TE8 cells, but membrane and cytoplasm and partially in nuclei. were almost undetectable in KYSE450 and EC9706 cells Importantly, PRSS8 expressed in epithelia was greatly (Figure 2A). The mRNA levels of PRSS8 in the four cell associated with cancer differentiation (Figure 1A and Table lines were similar as the protein levels assayed by semi- 1). For example, PRSS8 was overexpressed in cancer- RT-PCR (Figure 2B) and quantitative RT-PCR (Figure in-situ, and in well- and moderate-differentiated ESCC 2C). tissues, but the expression was dramatically reduced in To determine whether the reduction of PRSS8 the poorly differentiated ESCC tissues, the difference was in ESCC tissues and cell lines was caused by significant (p<0.001, Table 1 ). Moreover, 67% (12/18) of hypermethylation in PRSS8 promoter region, we used the less malignant cancers (i.e. cancer-in-situ) exhibited the methylation CpG island prediction software [22] and strong staining (score 3), but only 29% (100/344) of the identified one CpG island in PRSS8 promoter region invasive cancer showed strong staining (p=0.0017, Table (-4238 to -4116) (Figure 3A). Methylation specific 1). Further analysis revealed that the higher epithelial PCR (MS-PCR) was then used to amplify this region of PRSS8 expression in ESCC exhibited significantly longer some ESCC tissues and the four ESCC cell lines. Figure overall survival time (p=0.044) and disease-free period 3B showed the examples of PRSS8 promoter region (p=0.042, Figure 1B). hypermethylation in ESCC tissues (4 clones) and in 2 Moreover, ESCC stroma was also found positively ESCC cell lines (KYSE450 and EC9706) that showed stained (Figure 1A), although the staining intensity was undetectable PRSS8 level, but another 2 cell lines (TE1 not as strong as observed in the epithelia. Interestingly, and TE8) exhibited expression of PRSS8 and showed no cancer stromal staining of PRSS8 was well correlated with methylation in PRSS 8 promoter region. stromal lymphocyte infiltration, in which, 37% (77/207) To determine whether this CpG island at the of cancer stroma showed higher PRSS8 expression if the PRSS8 promoter region has biological function, we then stroma presented visible lymphocyte infiltration, whereas, constructed reporters with truncated PRSS8 promoter only 21% (33/155) of the stroma showed higher expression region into pGL4 vector (Promega, Madison, WI). As www.impactjournals.com/oncotarget 28541 Oncotarget shown in Figure 3C, a full length of PRSS8 promoter promoter)
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