Aberrant promoter�2 methylation‑mediated downregulation of protein tyrosine phosphatase, non‑receptor type�6, is associated with progression of esophageal squamous cell carcinoma

Abstract

The human protein tyrosine phosphatase, nonreceptor type 6 (PTPN6) gene is located on chromosome 12p13 and encodes an Mr 68,000 non-receptor type protein-tyrosine phosphatase. The PTPN6 gene has been considered as a candidate tumor suppressor in hematological and solid malignancies, and promoter methylation may be an epigenetic modification silencing its expression. However, the detailed role of PTPN6 and its promoter methylation status in the pathogenesis of esophageal squamous cell carcinoma (ESCC) has not been fully elucidated. The aim of the present study was to investigate PTPN6 expression in ESCC tissues and esophageal cancer cell lines, detect the effect of CpG hypermethylation on the activity of PTPN6, and additionally elucidate the role and prognostic significance of PTPN6 in ESCC tumorigenesis and progression. The expression of PTPN6 was identified to be significantly downregulated in esophageal cancer cell lines and ESCC tissues. Marked upregulation of PTPN6 was detected in 5-aza-2'-deoxycytidine-treated esophageal cancer cells, and frequent hypermethylation of the CpG sites within the P2 promoter (P2) was detected in ESCC tissues and esophageal cancer cell lines. The expression and methylation status of PTPN6 was associated with tumor node metastasis stage, pathological differentiation and lymph node metastasis in patients with ESCC. Aberrant hypermethylation of the P2 exhibited marked tumor specificity and was identified to be associated with the expression level of PTPN6. Downregulation and hypermethylation of PTPN6 were identified to be associated with poor ESCC patient survival. Furthermore, upregulation of PTPN6 inhibited the proliferation and invasion of esophageal cancer cells in vitro. The results of the present study suggest that PTPN6 may serve as a tumor suppressor in ESCC, and it may serve as a potential target for antitumor therapy.Abbreviations: P2, promoter 2; ESCC, esophageal squamous cell carcinoma; PTPs, protein tyrosine phosphatases; PTPN6, protein tyrosine phosphatase, non-receptor type 6

Comparative analysis of protein-protein interaction networks in metastatic breast cancer

“…Dowling et al demonstrated that this gene is among the best candidate biomarkers in breast cancer [ 57 ], as we discussed in this research. Several studies have shown that the DNA methylation-mediated down-regulation of protein tyrosin phosphatase non-receptor type 6 (PTPN6) was linked with the progression of esophageal squamous cell carcinoma [ 58 ] and gastric cancer [ 59 ]. Therefore, it seems down-regulation of this gene could potentially be a prognostic biomarker in breast cancer brain metastasis as well.…”

Multiomic Analysis of Methylation and Transcriptome Reveals a Novel Signature in Esophageal Cancer

“…Accumulating evidence suggests that DNA methylation is involved in the initiation and progression of EC and is associated with clinical outcomes. Promoter hypermethylation silences tumor suppressor genes, including coding genes (PTPN6, 18 RHCG, 19 and ZNF471 20 ) and noncoding genes (lncRNA ZNF667-AS1 and ZNF667, 21 microRNA-128, 22 and microRNA-10b-3p 23 ). Liu et al 18 indicated that PTPN6 expression was significantly downregulated in EC cell lines and tissues.…”

“…Promoter hypermethylation silences tumor suppressor genes, including coding genes (PTPN6, 18 RHCG, 19 and ZNF471 20 ) and noncoding genes (lncRNA ZNF667-AS1 and ZNF667, 21 microRNA-128, 22 and microRNA-10b-3p 23 ). Liu et al 18 indicated that PTPN6 expression was significantly downregulated in EC cell lines and tissues. The expression of PTPN6 in EC cells treated with DNA methyltransferase inhibitor was significantly upregulated, and frequent methylation of CpG sites in the P2 promoter was detected in esophageal squamous-cell carcinoma (ESCC) tissues and cell lines.…”

Shp1 in Solid Cancers and Their Therapy

“…As mentioned, Shp1 expression changes in different types of cancer. In the hematological malignancies and in some solid tumors Shp1 expression is reduced or absent as a result of PTPN6 promoter hypermethylation (59)(60)(61)(62)(63)(64)(65)(66)(67)(68). On the contrary, increased Shp1 levels are detected in a subset of high-grade breast tumors (70) and in ovarian cancers (71).…”

“…Several studies have been devoted to assess the prognostic and diagnostic value of Shp1 expression and promoter methylation, with the aim of identifying new biomarkers of cancer development. Shp1 decreased expression and PTPN6 hypermethylation are associated with tumor staging, pathological differentiation and poor survival in patients with esophageal squamous cell carcinoma (65). In endometrial carcinoma, PTPN6 hypermethylation is associated with age and tumor differentiation, while no correlation is found with muscular infiltration depth and lymphatic metastasis (68).…”