Promoter hypomethylation and upregulation of trefoil factors in prostate cancer

Vestergaard, Else Marie; Nexø, Ebba; Tørring, Niels; Borre, Michael; Ørntoft, Torben F.; Sørensen, Karina Dalsgaard

doi:10.1002/ijc.25209

Cited by 49 publications

(52 citation statements)

References 47 publications

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“…GDF15 (alternatively MIC-1) expressed by PCa cells can disrupt cell adhesion and is associated with bone homeostasis (41,42). TFF3 is elevated in PCa, although its function is not clear (43). RUNX2, a transcription factor, has an anti-apoptotic effect in early cancer but contributes to subsequent bone metastasis (44).…”

Section: Discussionmentioning

confidence: 99%

SIGLEC12, a Human-specific Segregating (Pseudo)gene, Encodes a Signaling Molecule Expressed in Prostate Carcinomas

Mitra

Banda

Altheide

et al. 2011

Journal of Biological Chemistry

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The primate SIGLEC12 gene encodes one of the CD33-related Siglec family of signaling molecules in immune cells. We had previously reported that this gene harbors a human-specific missense mutation of the codon for an Arg residue required for sialic acid recognition. Here we show that this R122C mutation of the Siglec-XII protein is fixed in the human population, i.e. it occurred prior to the origin of modern humans. Additional mutations have since completely inactivated the SIGLEC12 gene in some but not all humans. The most common inactivating mutation with a global allele frequency of 58% is a single nucleotide frameshift that markedly shortens the open reading frame. Unlike other CD33-related Siglecs that are primarily found on immune cells, we found that Siglec-XII protein is expressed not only on some macrophages but also on various epithelial cell surfaces in humans and chimpanzees. We also found expression on certain human prostate epithelial carcinomas and carcinoma cell lines. This expression correlates with the presence of the nonframeshifted, intact SIGLEC12 allele. Although SIGLEC12 allele status did not predict prostate carcinoma incidence, restoration of expression in a prostate carcinoma cell line homozygous for the frameshift mutation induced altered regulation of several genes associated with carcinoma progression. These stably transfected Siglec-XII-expressing prostate cancer cells also showed enhanced growth in nude mice. Finally, monoclonal antibodies against the protein were internalized by Siglec-XII-expressing prostate carcinoma cells, allowing targeting of a toxin to such cells. Polymorphic expression of Siglec-XII in humans thus has implications for prostate cancer biology and therapeutics.Sialic acids (Sias) 5 are nine-carbon backbone sugar molecules typically found at terminal positions of glycan chains in Deuterostomes (vertebrates and some "higher" invertebrates), making them potentially important in recognition events (1-3). One class of intrinsic Sia recognition proteins in vertebrates are Siglecs (sialic acid-binding immunoglobulin-like lectins). Siglecs are single-pass transmembrane proteins, with a Siabinding site in the extracellular N-terminal Ig-like V-set domain (4 -9). Such V-set domains are followed by one or more C2-set Ig-like domains. Siglecs can signal through one or more tyrosine-based signaling motif(s) in the cytoplasmic tail (5,8,9).CD33-related Siglecs (CD33rSiglecs) are encoded by a subset of SIGLEC genes clustered on chromosome 19 in humans and chimpanzees. They are homologous in sequence and typically expressed on immune cells (10). Analyses of genomic SIGLEC sequences across humans, chimpanzees, baboons, rats, and mice showed that CD33rSiglecs are evolving rapidly (11). This is particularly pronounced in the Sia-recognizing V-set domain, suggesting that this domain is under the greatest selection pressure (11)(12)(13)(14).This study focuses on Siglec-12 (formerly Siglec-L1). We have shown previously that human Siglec-12 has an Arg 3 Cys (R122C) substitution m...

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Section: Discussionmentioning

confidence: 99%

SIGLEC12, a Human-specific Segregating (Pseudo)gene, Encodes a Signaling Molecule Expressed in Prostate Carcinomas

Mitra

Banda

Altheide

et al. 2011

Journal of Biological Chemistry

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“…Progressive increases in TFF1 expression in dysplasia and CCA in our study strongly argues for a role in the stepwise carcinogenesis of liver fluke-associated CCA. Moreover, Vestergaard et al [29] showed that TFF1 and TFF3 promoter hypomethylation correlates with increased mRNA expression in prostate cancer compared to benign prostatic hyperplasia. It is therefore conceivable that increased TFF1 expression in our CCA cohort was due to promoter hypomethylation.…”

Section: Discussionmentioning

confidence: 99%

Trefoil factors: Tumor progression markers and mitogens via EGFR/MAPK activation in cholangiocarcinoma

Kosriwong

Menheniott²,

Giraud³

et al. 2011

WJG

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AIM:To investigate trefoil factor (TFF ) gene copy number, mRNA and protein expression as potential biomarkers in cholangiocarcinoma (CCA). METHODS:TFF mRNA levels, gene copy number and protein expression were determined respectively by quantitative reverse transcription polymerase chain reaction (PCR), quantitative PCR and immunohistochemistry in bile duct epithelium biopsies collected from individuals with CCA, precancerous bile duct dysplasia and from disease-free controls. The functional impact of recombinant human (rh)TFF2 peptide treatment on proliferation and epidermal growth factor receptor (EGFR)/mitogenactivated protein kinase (MAPK) signaling was assessed in the CCA cell line, KMBC, by viable cell counting and immunoblotting, respectively. RESULTS: TFF1 , TFF2 and TFF3 mRNA expression was significantly increased in CCA tissue compared to disease-free controls, and was unrelated to gene copy number. TFF1 immunoreactivity was strongly increased in both dysplasia and CCA, whereas TFF2 immunoreactivity was increased only in CCA compared to diseasefree controls. By contrast, TFF3 immunoreactivity was moderately decreased in dysplasia and further decreased in CCA. Kaplan-Meier analysis found no association of TFF mRNA, protein and copy number with age, gender, histological subtype, and patient survival time. Treatment of KMBC cells with rhTFF2 stimulated proliferation, triggered phosphorylation of EGFR and downstream extracellular signal related kinase (ERK), whereas co-incubation with the EGFR tyrosine kinase inhibitor, PD153035, blocked rhTFF2-dependent proliferation and EGFR/ERK responses.CONCLUSION: TFF mRNA/protein expression is indicative of CCA tumor progression, but not predictive for histological sub-type or survival time. TFF2 is mitogenic in CCA via EGFR/MAPK activation.

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“…Bisulfite sequencing (biSeq) was performed as described previously (27,28 0 -BHQ1. All reactions were run in triplicates in 384-well plates using the Applied Biosystems 7900HT Sequence Detection System and TaqMan Universal PCR Master Mix without AmpErase UNG (Applied Biosystems).…”

Section: Dna Extraction and Methylation Analysismentioning

confidence: 99%

Hypermethylation of theGABRE∼miR-452∼miR-224Promoter in Prostate Cancer Predicts Biochemical Recurrence after Radical Prostatectomy

Kristensen

Haldrup

Strand

et al. 2014

Clinical Cancer Research

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Purpose: Available tools for prostate cancer diagnosis and prognosis are suboptimal and novel biomarkers are urgently needed. Here, we investigated the regulation and biomarker potential of the GABRE$miR-452$miR-224 genomic locus.Experimental Design: GABRE/miR-452/miR-224 transcriptional expression was quantified in 80 nonmalignant and 281 prostate cancer tissue samples. GABRE$miR-452$miR-224 promoter methylation was determined by methylation-specific qPCR (MethyLight) in 35 nonmalignant, 293 prostate cancer [radical prostatectomy (RP) cohort 1] and 198 prostate cancer tissue samples (RP cohort 2). Diagnostic/prognostic biomarker potential of GABRE$miR-452$miR-224 methylation was evaluated by ROC, Kaplan-Meier, uni-and multivariate Cox regression analyses. Functional roles of miR-224 and miR-452 were investigated in PC3 and DU145 cells by viability, migration, and invasion assays and gene-set enrichment analysis (GSEA) of posttransfection transcriptional profiling data.Results: GABRE$miR-452$miR-224 was significantly downregulated in prostate cancer compared with nonmalignant prostate tissue and had highly cancer-specific aberrant promoter hypermethylation (AUC ¼ 0.98). Functional studies and GSEA suggested that miR-224 and miR-452 inhibit proliferation, migration, and invasion of PC3 and DU145 cells by direct/indirect regulation of pathways related to the cell cycle and cellular adhesion and motility. Finally, in uni-and multivariate analyses, high GABRE$miR-452$miR-224 promoter methylation was significantly associated with biochemical recurrence in RP cohort 1, which was successfully validated in RP cohort 2.Conclusion: The GABRE$miR-452$miR-224 locus is downregulated and hypermethylated in prostate cancer and is a new promising epigenetic candidate biomarker for prostate cancer diagnosis and prognosis. Tumor-suppressive functions of the intronic miR-224 and miR-452 were demonstrated in two prostate cancer cell lines, suggesting that epigenetic silencing of GABRE$miR-452$miR-224 may be selected for in prostate cancer. Clin Cancer Res; 20(8); 2169-81. Ó2014 AACR.

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Promoter hypomethylation and upregulation of trefoil factors in prostate cancer

Cited by 49 publications

References 47 publications

SIGLEC12, a Human-specific Segregating (Pseudo)gene, Encodes a Signaling Molecule Expressed in Prostate Carcinomas

SIGLEC12, a Human-specific Segregating (Pseudo)gene, Encodes a Signaling Molecule Expressed in Prostate Carcinomas

Trefoil factors: Tumor progression markers and mitogens via EGFR/MAPK activation in cholangiocarcinoma

Hypermethylation of theGABRE∼miR-452∼miR-224Promoter in Prostate Cancer Predicts Biochemical Recurrence after Radical Prostatectomy

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