Methylation of PTCH1a gene in a subset of gastric cancers

Du, Peng; Ye, Hairong; Gao, Jun; Chen, Wei; Wang, Zhongchuan; Jiang, Honghua; Xu, Jianrong; Zhang, Ji-We; Zhang, Jiancheng; Cui, Long

doi:10.3748/wjg.15.3799

Cited by 21 publications

(11 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The presence of large rearrangements and/or deletions cannot be excluded as they cannot be detected by direct sequencing, although the detected 32 heterozygous changes provide some evidence against frequent and large PTCH1 deletions in the studied cancers. Alternative mechanisms for PTCH1 downregulation could include, e.g., epigenetic silencing of PTCH1 or constantly activated MAPK signaling [31,32]. We have recently observed that serrated adenocarcinomas are characterized by BRAF and KRAS mutations [30], and also in this study, 78% of the analyzed tumors carried a mutation in either gene (Table 3).…”

Section: Mutationmentioning

confidence: 74%

Downregulation of the hedgehog receptor PTCH1 in colorectal serrated adenocarcinomas is not caused by PTCH1 mutations

et al. 2011

View full text Add to dashboard Cite

Colorectal serrated adenocarcinoma forms about 15-20% of colorectal carcinomas. We have previously shown that downregulation of PTCH1 is distinctive for this type of colorectal cancer. In several other tumor types, somatic inactivating PTCH1 mutations have been shown to lead to aberrant Hedgehog signaling, but in colorectal cancer the role of PTCH1 mutations has not been thoroughly studied. Here, we have analyzed the mutation status of PTCH1 in a series of 33 colorectal serrated adenocarcinomas by sequencing all 23 coding exons. We detected 11 previously known SNPs and eight new alterations. The latter included five synonymous changes and two previously unknown missense variations, somatic M319V, and germline V1231A. V1231A was also present in population controls and likely represents polymorphism. The somatic M319V variant does not appear to be an attractive candidate for a disease-associated mutation because in silico analyses did not support the pathogenic nature of the change. A somatic, intronic 1-bp deletion was detected in a short poly(T) stretch in two microsatellite unstable tumors. None of the three changes had predicted effect on splicing when analyzed in silico. Our results did not reveal any clearly deleterious inactivating PTCH1 mutations in our collection of colorectal serrated adenocarcinomas. This suggests that other mechanisms are involved in the observed downregulation of the PTCH1 gene. These might include, e.g., constantly active MAPK signaling by KRAS or BRAF mutations or silencing of PTCH1 by hypermethylation, and further studies are needed to reveal these mechanisms.

show abstract

Section: Mutationmentioning

confidence: 74%

Downregulation of the hedgehog receptor PTCH1 in colorectal serrated adenocarcinomas is not caused by PTCH1 mutations

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Lack of methylation at the alternative exon 1B was reported for human medulloblastoma [ 31 , 32 ] whereas others showed methylation in exon 1A [ 33 ]. Methylation of exon 1A was also found in gastric cancer samples [ 34 ] and exon 1B was methylated in fibroma and dermoids [ 35 ], in basal cell carcinoma [ 36 ] but not in squamous cell cervical cancer or ovarian cancer [ 37 ]. Moreover it was reported that the Ptch promoter in medulloblastoma from Ptch heterozygous mice is not methylated [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of mutantPtchin rhabdomyosarcomas is associated with promoter hypomethylation and increased Gli1 and H3K4me3 occupancy

et al. 2015

View full text Add to dashboard Cite

Mice with heterozygous loss of the tumor suppressor Patched1 (Ptch) develop rhabdomyosarcoma (RMS)-like tumors. However, Ptch transcripts are consistently overexpressed in these tumors. We have recently shown that the upregulated transcripts are derived from the mutated Ptch allele thus leading to the hypothesis that the wild-type allele is repressed during RMS development. Here we describe epigenetic changes taking place at the Ptch locus during RMS development. We showed a lower degree of DNA-methylation in methylation-sensitive CpG regions of the Ptch promoter in RMS compared to normal muscle from heterozygous Ptch animals. In agreement with these results, treatment of heterozygous Ptch mice with the DNA demethylating agent 5-aza-2-deoxycytidine (5-aza-dC) between embryonic days E9.5–E11.5 significantly accelerated RMS formation. Since Ptch promoter methylation occurs after/around E13.5, the window for RMS initiation during embryogenesis, these results provide additional evidence that Ptch promoter hypomethylation may contribute to RMS formation. We have also demonstrated increased trimethylation of histone H3 lysine 4 (H3K4me3) and preferential binding of Gli1, a known Ptch activator, to the mutant locus in RMS. Together, these findings support an alternative model for RMS formation in heterozygous Ptch mice including loss of methylation and concomitant occupancy by activating histone marks of mutant Ptch.

show abstract

“…Thus, 5-aza-dc, a well-established promoter methylation inhibitor [31, 50], was employed. As shown, 5-aza-dc (1 µM) significantly inhibited HHIP promoter methylation in AGS cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of HHIP Promoter Methylation Suppresses Human Gastric Cancer Cell Proliferation and Migration

Zuo

Qian

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Human hedgehog-interacting protein (HHIP) is a negative regulator of the hedgehog (HH) signaling pathway. It is deregulated in gastric cancer. The underlying molecular mechanism of HHIP-induced inhibition of HH signaling remains to be determined. Methods: A lentiviral HHIP expression vector (“LV-HHIP”) was established to exogenously over-express HHIP in gastric cancer cells. HHIP protein and mRNA were tested by Western blotting assay and quantitative real-time PCR assay, respectively. Cell survival was tested by the Cell Counting Kit-8 (CCK-8) assay. Cell proliferation was examined by the BrdU ELISA assay and [H³] Thymidine DNA incorporation assay. Cell invasion and migration were tested by the phagokinetic track assay and the “Transwell” assay. The bisulfite-sequencing PCR was applied to test HHIP promoter methylation. Results: In the established (AGS cell line) and primary human gastric cancer cells, LV-HHIP transfection increased HHIP expression and inhibited cancer cell survival and proliferation as well as cell migration and invasion. Furthermore, LV-HHIP significantly attenuated promoter methylation of the endogenous HHIP gene in AGS cells, causing it upregulation. Inhibition of methylation by 5-aza-dc similarly induced HHIP expression in gastric cancer cells, which inhibited cancer cell proliferation and migration. Conclusions: Our results suggest that inhibition of HHIP promoter methylation can efficiently inhibit human gastric cancer cell proliferation and migration.

show abstract

Methylation of PTCH1a gene in a subset of gastric cancers

Cited by 21 publications

References 30 publications

Downregulation of the hedgehog receptor PTCH1 in colorectal serrated adenocarcinomas is not caused by PTCH1 mutations

Downregulation of the hedgehog receptor PTCH1 in colorectal serrated adenocarcinomas is not caused by PTCH1 mutations

Overexpression of mutantPtchin rhabdomyosarcomas is associated with promoter hypomethylation and increased Gli1 and H3K4me3 occupancy

Inhibition of HHIP Promoter Methylation Suppresses Human Gastric Cancer Cell Proliferation and Migration

Contact Info

Product

Resources

About