PTPRDis Homozygously Deleted and Epigenetically Downregulated in Human Hepatocellular Carcinomas

Abstract

PTPRD (protein tyrosine phosphatase, receptor type, D) is a tumor suppressor gene, frequently inactivated through deletions or epigenetic mechanisms in several cancers with importance for global health. In this study, we provide new and functionally integrated evidence on genetic and epigenetic alterations of PTPRD gene in hepatocellular carcinomas (HCCs). Importantly, HCC is the sixth most common malignancy and the third most common cause of cancer-related mortality worldwide. We used a high throughput single nucleotide polymorphism (SNP) microarray assay (Affymetrix, 10K2.0 Assay) covering the whole genome to screen an extensive panel of HCC cell lines (N = 14 in total) to detect DNA copy number changes. PTPRD expression was determined in human HCCs by Q-RT-PCR and immunohistochemistry. Promoter hypermethylation was assessed by combined bisulfite restriction analysis (COBRA). DNA methyl transferase inhibitor 5-azacytidine (5-AzaC) and/or histone deacetylase inhibitor Trichostain A (TSA) were used to restore the expression. We identified homozygous deletions in Mahlavu and SNU475 cells, in the 5¢UTR and coding regions, respectively. PTPRD mRNA expression was downregulated in 78.5% of cell lines and 82.6% of primary HCCs. PTPRD protein expression was also found to be lost or reduced in HCC tumor tissues. We found promoter hypermethylation in 22.2% of the paired HCC samples and restored PTPRD expression by 5-AzaC and/or TSA treatments. In conclusion, PTPRD is homozygously deleted and epigenetically downregulated in HCCs. We hypothesize PTPRD as a tumor suppressor candidate and potential cancer biomarker in human HCCs. This hypothesis is consistent with compelling evidences in other organ systems, as discussed in this article. Further functional assays in larger samples may ascertain the contribution of PTPRD to hepatocarcinogenesis in greater detail, not to forget its broader importance for diagnostic medicine and the emerging field of personalized medicine in oncology.

miR-135a-5p-mediated downregulation of protein tyrosine phosphatase receptor delta is a candidate driver of HCV-associated hepatocarcinogenesis

“…PTPRD is frequently inactivated and mutated in human cancers 26 27 including HCC. 28 In order to validate HCV-induced PTPRD downregulation, we measured mRNA expression in a second sample series of 24 liver biopsies of patients with chronic HCV and validated that PTPRD mRNA expression is significantly (p=0.0003, U-test) downregulated compared with 11 additional non-viral control biopsies ( figure 1 B).…”

“…PTPRD is a well-established tumour suppressor 27 whose chromosomal locus on 9p23–24.1 is regularly subject to genetic deletion or epigenetic inactivation in a broad spectrum of human malignancies including neuroblastoma, glioblastoma, 27 lung cancer, cutaneous squamous cell carcinoma, 38 laryngeal squamous cell carcinoma, 39 melanoma 40 and also HCC. 28 In addition, PTPRD copy number loss associates with a poor prognosis in breast cancer, colon cancer 41 and gastric adenocarcinoma. 42 Here, we demonstrate for the first time that PTPRD protein expression is downregulated in patients chronically infected with HCV.…”

PTPRT and PTPRD Deleterious Mutations and Deletion Predict Bevacizumab Resistance in Metastatic Colorectal Cancer Patients

“…PTPRD has also been found to be mutated in CRC and in various other cancer types [ 19 , 25 , 26 ] and is frequently inactivated by copy number loss in a broad range of cancer types [ 27 , 28 , 29 ]. Similar to TCGA data [ 30 ], copy number loss of PTPRD was more frequent than that of PTPRT in our cohort, in which no PTPRT loss was observed.…”

Recent updates of genetic and genomic alterations in hepatocellular carcinoma

“…[2] Protein tyrosine phosphatase, receptor type D, a tumor suppressor gene, which was previously identified to be frequently deleted in several cancers, [39][40][41] was also identified with homozygous deletion in human HCCs. [42] PROSPECTS In summary, multiple lines of evidence have shown that the genetic and genomic alterations play important roles in the development and progression of HCC. The next generation sequencing of genomic DNA provides the possibility that more novel genetic and genomic alterations may be discovered and may provide new insights for understanding of the pathogenesis of HCC.…”