Abstract:Background & objectives:Loss of function of adenomatous polyposis coli (APC) has been reported in cancer. The two promoters of APC, 1A and 1B also have roles in cancer. But, the epigenetic role of APC promoters is not yet clear in gallbladder cancer (GBC) and gallstone diseases (GSD). We undertook this study to determine the epigenetic role of APC in GBC and GSD.Methods:Methylation-specific (MS)-PCR was used to analyze the methylation of APC gene. The expression of APC gene was studied by semi-quantitative PCR… Show more
“…This list includes well-known oncogenes, CTNNB1, ERBB2, ERBB3, KRAS, PIK3CA, BRAF , and NFE2L2 , tumor suppressors, TP53, ARID2, STK11, CDKN2A, SMAD4, SMARCA4, ARID1A, APC, NF1 , and MAP2K4 , and less well-established cancer-associated genes such as ELF3, EHF, ACVR2A, PSIP1, CHRM3, HIST1H2AG, KAT8 , and ZNF107 . Previous studies on GBC reported TP53, KRAS and ERBB3 as significantly mutated GBC genes (SMG) 6 , though low-frequency mutations were observed in other SMG GBC genes reported in this study 6 , 7 , 20 . Fig.…”
Gallbladder cancer (GBC) is an aggressive gastrointestinal malignancy with no approved targeted therapy. Here, we analyze exomes (
n
= 160), transcriptomes (
n
= 115), and low pass whole genomes (
n
= 146) from 167 gallbladder cancers (GBCs) from patients in Korea, India and Chile. In addition, we also sequence samples from 39 GBC high-risk patients and detect evidence of early cancer-related genomic lesions. Among the several significantly mutated genes not previously linked to GBC are ETS domain genes
ELF3
and
EHF
,
CTNNB1
,
APC
,
NSD1
,
KAT8
,
STK11
and
NFE2L2
. A majority of
ELF3
alterations are frame-shift mutations that result in several cancer-specific neoantigens that activate T-cells indicating that they are cancer vaccine candidates. In addition, we identify recurrent alterations in KEAP1/NFE2L2 and WNT pathway in GBC. Taken together, these define multiple targetable therapeutic interventions opportunities for GBC treatment and management.
“…This list includes well-known oncogenes, CTNNB1, ERBB2, ERBB3, KRAS, PIK3CA, BRAF , and NFE2L2 , tumor suppressors, TP53, ARID2, STK11, CDKN2A, SMAD4, SMARCA4, ARID1A, APC, NF1 , and MAP2K4 , and less well-established cancer-associated genes such as ELF3, EHF, ACVR2A, PSIP1, CHRM3, HIST1H2AG, KAT8 , and ZNF107 . Previous studies on GBC reported TP53, KRAS and ERBB3 as significantly mutated GBC genes (SMG) 6 , though low-frequency mutations were observed in other SMG GBC genes reported in this study 6 , 7 , 20 . Fig.…”
Gallbladder cancer (GBC) is an aggressive gastrointestinal malignancy with no approved targeted therapy. Here, we analyze exomes (
n
= 160), transcriptomes (
n
= 115), and low pass whole genomes (
n
= 146) from 167 gallbladder cancers (GBCs) from patients in Korea, India and Chile. In addition, we also sequence samples from 39 GBC high-risk patients and detect evidence of early cancer-related genomic lesions. Among the several significantly mutated genes not previously linked to GBC are ETS domain genes
ELF3
and
EHF
,
CTNNB1
,
APC
,
NSD1
,
KAT8
,
STK11
and
NFE2L2
. A majority of
ELF3
alterations are frame-shift mutations that result in several cancer-specific neoantigens that activate T-cells indicating that they are cancer vaccine candidates. In addition, we identify recurrent alterations in KEAP1/NFE2L2 and WNT pathway in GBC. Taken together, these define multiple targetable therapeutic interventions opportunities for GBC treatment and management.
Although great progress has been made in surgical techniques, traditional radiotherapy, and chemotherapy, gastric cancer (GC) is still the most common malignant tumor and has a high mortality, which highlights the importance of novel diagnostic markers. Emerging studies suggest that different microRNAs (miRNAs) are involved in tumorigenesis of GC. In this study, we found that miRNA-192 and -215 are significantly upregulated in GC and promote cell proliferation and migration. Adenomatous polyposis coli (APC), a well-known negative regulator in Wnt signaling, has been proved to be a target of miRNA-192 and -215. Inhibition of miRNA-192 or -215 reduced the Topflash activities and repressed the expression of Wnt signaling pathway proteins, while APC small interfering RNAs reversed the inhibitory effects, suggesting that miRNA-192 and -215 activate Wnt signaling via APC. In addition, APC mediates the cell proliferation and migration regulated by miRNA-192 and -215.Furthermore, APC is downregulated in GC tissues and negatively correlated with the expression of target APC and function as oncogenic miRNAs by activating Wnt signaling in GC, revealing to be potential therapeutic targets.Shiqi Deng and Xiaojing Zhang contributed equally to this study.
Promoter methylation in various tumor suppressor genes is reported to influence gallbladder carcinogenesis. Here, we aimed to identify methylation status in gallbladder cancer (GBC) by performing a comprehensive genome-wide DNA methylation profiling. The methylation status of 485,577 CpG sites were investigated using Illumina's Infinium Human Methylation 450 BeadChip array in 24 tissues (eight each of tumor, adjacent non-tumor, and gallstone). About 33,443 differentially methylated sites (DMRs) were obtained in the whole human genome, of which 24,188 (72 %) were hypermethylated and 9255 (28 %) were hypomethylated. The data also revealed that majority of the DMRs are localized on the proximal promoter region [Transcription start sites (TSS200, TSS1500) and 5' untranslated region (5'UTR)] and first exon. Exclusion of first exon detected a total of 10,123 (79 %) hypermethylated and 2703 (21 %) hypomethylated sites. Comparative analysis of the later with our differential proteomics data resulted in identification of 7 hypermethylated or down-regulated (e.g., FBN1, LPP, and SOD3) and 61 hypomethylated or up-regulated markers (e.g., HBE1, SNRPF, TPD52) for GBC. These genes could be further validated on the basis of their methylation/expression status in order to identify their utility to be used as biomarker/s for early diagnosis and management of GBC.
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