SIP1 is downregulated in hepatocellular carcinoma by promoter hypermethylation

Acun, Tolga; Öztaş, Emin; Yağcı, Tamer; Yakıcıer, Mustafa Cengiz

doi:10.1186/1471-2407-11-223

Cited by 29 publications

(24 citation statements)

References 45 publications

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“…5-AzaC, a pyrimidine ring analogue, had antiproliferation and anti-neoplasia activity in acute acute myeloid leukemia (Aimiuwu et al, 2012) and hepatocellular carcinoma (Acun et al, 2011). But the overall clinical utility of 5-AzaC was disappointing because of its activities of induce-neoplasia in mammalian cells.…”

Section: Discussionmentioning

confidence: 99%

Alteration of Runt-related Transcription Factor 3 Gene Expression and Biologic Behavior of Esophageal Carcinoma TE-1 Cells after 5-Azacytidine Intervention

Wang

Liu²,

Akhtar³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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5-Azacytidine (5-azaC) was originally identified as an anticancer drug (NSC102876) which can cause hypomethylation of tumor suppressor genes. To assess its effects on runt-related transcription factor 3 (RUNX3), expression levels and the promoter methylation status of the RUNX3 gene were assessed. We also investigated alteration of biologic behavior of esophageal carcinoma TE-1 cells. MTT assays showed 5-azaC inhibited the proliferation of TE-1 cells in a time and dose-dependent way. Although other genes could be demethylated after 5-azaC intervention, we focused on RUNX3 gene in this study. The expression level of RUNX3 mRNA increased significantly in TE-1 cells after treatment with 5-azaC at hypotoxic levels. RT-PCR showed 5-azaC at 50 µM had the highest RUNX3-induction activity. Methylation-specific PCR indicated that 5-azaC induced RUNX3 expression through demethylation. Migration and invasion of TE-1 cells were inhibited by 5-azaC, along with growth of Eca109 xenografts in nude mice. In conclusion, we demonstrate that the RUNX3 gene can be reactivated by the demethylation reagent 5-azaC, which inhibits the proliferation, migration and invasion of esophageal carcinoma TE-1 cells.

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Section: Discussionmentioning

confidence: 99%

Alteration of Runt-related Transcription Factor 3 Gene Expression and Biologic Behavior of Esophageal Carcinoma TE-1 Cells after 5-Azacytidine Intervention

Wang

Liu²,

Akhtar³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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“…HCC-derived cell lines; SNU449, Focus, SNU182, SNU475, Mahlavu (MV), SNU398, SNU423, SK-Hep1, SNU387, Hep40, Huh7, PLC/PRF5 (PLC), Hep3B and hepatoblastoma-derived cell line, HepG2, were maintained as described (Acun et al, 2011). 32 pairs of HCC and tumor-adjacent normal archival DNA samples had previously been described (Ozturk et al, 1991 Table S2).…”

Section: Cell Lines and Patient Samplesmentioning

confidence: 99%

“…TM realtime RT-PCR system (Stratagene, La Jolla, CA) as previously described (Acun et al, 2011). PTPRD-QRT-F/PTPRD-QRT-R primer pair was used with cDNAs from HCC cell lines and…”

Section: Quantitative Real-time Rt-pcr (Q-rt-pcr)mentioning

confidence: 99%

“…GAPDH and TBP (TATA box binding protein) genes were used as internal controls (Fu et al, 2009;Gur-Dedeoglu et al, 2009) (Supplementary Table S3). Modified DDCt formula was used to measure the relative levels of PTPRD transcripts (Acun et al, 2011;Pfaffl et al, 2001). Statistical analysis were performed by Student's t-test.…”

Section: Quantitative Real-time Rt-pcr (Q-rt-pcr)mentioning

confidence: 99%

“…5-AzaC (Sigma-Aldrich, St. Louis, MO) and TSA (SigmaAldrich) treatments were performed as described previously (Acun et al, 2011). In brief, 3 · 10 5 cells/well were seeded in 6-well plates.…”

Section: -Azacytidine (5-azac) and Trichostatin A (Tsa) Treatmentsmentioning

confidence: 99%

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PTPRDis Homozygously Deleted and Epigenetically Downregulated in Human Hepatocellular Carcinomas

Acun

Demir

Öztaş

et al. 2015

OMICS: A Journal of Integrative Biology

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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.

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The miR‐200b–ZEB1 circuit regulates diverse stemness of human hepatocellular carcinoma

Tsai

Lin

Shih

et al. 2017

Molecular Carcinogenesis

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Accumulating evidence suggests that human hepatocellular carcinoma (HCC) can be derived from cancer stem cells (CSCs), which contribute to tumor initiation, metastasis, chemoresistance, and recurrence. A great variety of HCC CSCs resulting in diverse clinical manifestations have been reported. However, how CSC diversity is regulated and generated remains unclear. Here we report that the miR-200b-ZEB1 circuit is closely involved with the induction and maintenance of a diverse group of CSCs. We found that miR-200b downregulation occurred in early HCC and associated with poor prognosis. The downregulation was attributable to genome deletion and promoter methylation of the miR-200a/b/429 gene. Ectopic expression of miR-200b or silencing of ZEB1 led to a decrease in CD13 and CD24 HCC CSCs and an increase in EpCAM HCC CSCs. Mechanistically, miR-200b directly suppressed BMI1 and ZEB1 expressions. ZEB1 recognized promoters of CD13, CD24, and EpCAM genes resulting in CD13 and CD24 upregulation and EpCAM downregulation. Neither miR-200b nor ZEB1 had obvious effects on CD133 or CD90 expression. Silencing CD13 or CD24 expression suppressed tumorigenicity of HCC cells. Ectopic expression of CD24 reversed the suppression of tumorigenicity by ectopic expression of miR-200b. Clinically, miR-200b downregulation was coupled with ZEB1 upregulation in approximately two-thirds of HCC patients. ZEB1 expression was positively correlated with CD13 and CD24 expressions in HCCs, while miR-200b expression was positively correlated with EpCAM. Our findings suggest that the miR-200b-ZEB1 circuit is a master regulator of diverse stemness of HCC, which differentiates HCCs into those containing CD13 /CD24 CSCs from those containing EpCAM CSCs.

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SIP1 is downregulated in hepatocellular carcinoma by promoter hypermethylation

Cited by 29 publications

References 45 publications

Alteration of Runt-related Transcription Factor 3 Gene Expression and Biologic Behavior of Esophageal Carcinoma TE-1 Cells after 5-Azacytidine Intervention

Alteration of Runt-related Transcription Factor 3 Gene Expression and Biologic Behavior of Esophageal Carcinoma TE-1 Cells after 5-Azacytidine Intervention

PTPRDis Homozygously Deleted and Epigenetically Downregulated in Human Hepatocellular Carcinomas

The miR‐200b–ZEB1 circuit regulates diverse stemness of human hepatocellular carcinoma

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