Downregulation of stomach cancer-associated protein tyrosine phosphatase-1 (SAP-1) in advanced human hepatocellular carcinoma

Nagano, Hidenobu; Noguchi, Tetsuya; Inagaki, Kenjiro; Yoon, Seitetsu; Matozaki, Takashi; Itoh, Hiroshi; Kasuga, Masato; Hayashi, Yoshitake

doi:10.1038/sj.onc.1206588

Cited by 27 publications

(16 citation statements)

References 38 publications

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“…The finding of PTPRH downregulation in colorectal tumors is consistent with the results from hepatocellular carcinoma where also a decreased expression was found (34). This suggests a suppressive rather than an oncogenic role as was previously proposed (35).…”

Section: Discussionsupporting

confidence: 91%

Downregulation of PTPRH (Sap-1) in colorectal tumors

Bujko

Kober

Statkiewicz

et al. 2017

International Journal of Oncology

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Tyrosine phosphorylation is one of the basic mechanisms for signal transduction in the cell. Receptors exhibiting tyrosine kinase activity are widely involved in carcinogenesis and are negatively regulated by receptor protein tyrosine phosphatases (RPTP). Genes encoding different RPTPs are affected by aberrant epigenetic regulation in cancer. PTPRH (SAP-1) has been previously described to be overexpressed in colorectal cancer (CRC) and classified as an oncogenic factor. Previous microarray-based mRNA expression comparison of colorectal adenomas (AD), CRC and normal mucosa samples (NM) demonstrated that PTPRH tumor expression is the most reduced of all RPTP genes. qRT-PCR validation revealed gene downregulation for CRC (7.6-fold-change; P<0.0001) and AD (3.4-fold-change; P<0.0001) compared to NM. This was confirmed by immunohistochemical staining of tumor and NM sections as pronounced decrease of protein expression was observed in CRCs compared to the corresponding normal tissue. DNA methylation of two PTPRH promoter fragments was analyzed by pyrosequencing in a group of CRC, and AD patients as well as NM samples and CRC cell lines. The mean DNA methylation levels of these two regions were significantly higher in CRC than in NM. Both regions were highly methylated in SW480 and HCT116 cell lines contrary to unmethylated HT29 and COLO205. Cell lines with highly methylated promoters notably showed lower PTPRH expression levels, lower RNA II polymerase concentrations and higher levels of H3K27 trimethylation in the promoter and gene body, measured by chromatin immunoprecipitation. Cells were cultured with 5-aza-deoxycitidine and an increase in PTPRH expression was observed in SW480 and HCT116, whereas this was unchanged in the unmethylated cell lines. The results indicate that PTPRH is downregulated in colorectal tumors and its expression is epigenetically regulated via DNA methylation and chromatin modifications.

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Section: Discussionsupporting

confidence: 91%

Downregulation of PTPRH (Sap-1) in colorectal tumors

Bujko

Kober

Statkiewicz

et al. 2017

International Journal of Oncology

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“…Kip1 (Tannapfel et al, 2000), p16 INK4 , cyclin D1, and cyclin E (Jung et al, 2001), pRb2/p130 (Huynh, 2004), SAP-1 (Nagano et al, 2003), PIN1 (Pang et al, 2004), LFIRE-1/HFREP-1 (Yan et al, 2004), MXR-7 (Hsu et al, 1997), and MAGE (Kobayashi et al, 2000). Many of them are involved in cell cycle checkpoint control; thus, the deregulation of these genes is likely to contribute to the tumor progression.…”

Section: Introductionmentioning

confidence: 99%

DDX3, a DEAD box RNA helicase, is deregulated in hepatitis virus-associated hepatocellular carcinoma and is involved in cell growth control

Chang¹,

Chi²,

et al. 2005

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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide and is highly correlated with hepatitis virus infection. Our previous report shows that a DEAD box RNA helicase, DDX3, is targeted and regulated by hepatitis C virus (HCV) core protein, which implicates the involvement of DDX3 in HCV-related HCC development. In this study, the potential role of DDX3 in hepatocarcinogenesis is investigated by examining its expression in surgically excised human HCC specimens. Here we report the differential deregulation of DDX3 expression in hepatitis virus-associated HCC. A significant downregulation of DDX3 expression is found in HCCs from hepatitis B virus (HBV)-positive patients, but not from HCV-positive ones, compared to the corresponding nontumor tissues. The expression of DDX3 is differentially regulated by the gender and, moreover, there is a tendency that the downregulation of DDX3 expression in HCCs is more frequent in males than in females. Genetic knockdown of DDX3 with small interfering RNAs (siRNA) in a nontransformed mouse fibroblast cell line, NIH-3T3, results in a premature entry to S phase and an enhancement of cell growth. This enhanced cell cycle progression is linked to the upregulation of cyclin D1 and the downregulation of p21 WAF1 in the DDX3 knockdown cells. In addition, constitutive reduction of DDX3 expression increases the resistance of NIH-3T3 cells to serum depletion-induced apoptosis and enhances the ras-induced anchorage-independent growth, indicating the involvement of DDX3 in cell growth control. These findings together with the previous study suggest that the deregulation of DDX3, a DEAD box RNA helicase with cell growth-regulatory functions, is involved in HBV-and HCV-associated pathogenesis.

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“…mRNA expression levels obtained from qRT-PCR confirmed the microarray data. While PTPRH expression was found to be increased in human colon and pancreatic cancer ( 4 , 17 ) and reduced in advanced human hepatocellular carcinoma ( 7 ), to our knowledge no previous study has examined its expression in lung cancer. Our data from LC-C1 samples suggested that PTPRH may have a significant role in NSCLC and be associated with its clinicopathological features.…”

Section: Discussionmentioning

confidence: 88%

“…Although it has been suggested that PTPRH regulates intestinal tumorigenesis, the mechanism is unclear. In contrast, PTPRH was found to be downregulated in advanced human hepatocellular carcinoma ( 7 ) and inhibited the proliferation of cultured cells ( 8 , 9 ). Thus, the role of PTPRH is largely unknown and needs to be clarified in diseases including lung cancer.…”

Section: Introductionmentioning

confidence: 99%

Prognostic implication of PTPRH hypomethylation in non-small cell lung cancer

Sato

Soejima

Arai³

et al. 2015

Oncology Reports

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PTPRH is a receptor-type protein tyrosine phosphatase thought to be a potential regulator of tumorigenesis. The aim of the present study was to clarify the significance of PTPRH expression and its regulation by DNA methylation in non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma (LADC). PTPRH mRNA expression was examined in 89 NSCLC and corresponding non-cancerous tissues. The correlation between DNA methylation and PTPRH gene expression was investigated in another cohort that consisted of 145 patients with LADC, a major NSCLC subtype. Gene regulation by DNA methylation was assessed using a DNA methylation inhibitor. PTPRH mRNA expression was significantly upregulated in NSCLC. PTPRH DNA methylation was reduced in LADC samples and inversely correlated with mRNA expression. 5-Aza-2′-deoxycytidine treatment of lung cancer cell lines with low PTPRH expression, restored mRNA PTPRH expression levels. Furthermore, low PTPRH methylation was associated with shorter recurrence-free survival (P=1.64×10−4) and overall survival (P=5.54×10−5). Multivariate analysis revealed that PTPRH DNA methylation was an independent prognostic factor (P=6.88×10−3). It was confirmed that PTPRH is overexpressed in NSCLC. Furthermore, we determined that PTPRH is epigenetically regulated by DNA hypomethylation, with prognostic implications for LADC.

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Downregulation of stomach cancer-associated protein tyrosine phosphatase-1 (SAP-1) in advanced human hepatocellular carcinoma

Cited by 27 publications

References 38 publications

Downregulation of PTPRH (Sap-1) in colorectal tumors

Downregulation of PTPRH (Sap-1) in colorectal tumors

DDX3, a DEAD box RNA helicase, is deregulated in hepatitis virus-associated hepatocellular carcinoma and is involved in cell growth control

Prognostic implication of PTPRH hypomethylation in non-small cell lung cancer

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