Ectopic Overexpression of COTE1 Promotes Cellular Invasion of Hepatocellular Carcinoma

Hai, Zhang; Huang, Changjun; Tian, Yuan; Wang, Yuping; Han, Ze‐Guang; Li, Xiangcheng

doi:10.7314/apjcp.2012.13.11.5799

Cited by 13 publications

(17 citation statements)

References 25 publications

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“…We discover replicating evidence for association of a rare variant burden with triglyceride levels at a locus not previously linked with the trait. FAM189B (Family With Sequence Similarity 189 Member B), also known as COTE1 or C1orf2, codes for a membrane protein that is widely expressed, including in adult liver tissue 13 . Expression of FAM189B has been found to be correlated with endogenous SREBP-1 activation in vitro 14 .…”

Section: Discussionmentioning

confidence: 99%

Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits

Gilly

Süveges

Kuchenbaecker

et al. 2018

Preprint

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The role of rare variants in complex traits remains uncharted. Here, we conduct deep whole genome sequencing of 1,457 individuals from an isolated population, and test for rare variant burdens across six cardiometabolic traits. We identify a role for rare regulatory variation, which has hitherto been missed. We find evidence of rare variant burdens overlapping with, and mostly independent of established common variant signals (ADIPOQ and adiponectin, P=4.2x10 -8 ; APOC3 and triglyceride levels, P=1.58×10 -26 ; GGT1 and gamma-glutamyltransferase, P=2.3x10 -6 ; UGT1A9 and bilirubin, P=1.9×10 -8 ), and identify replicating evidence for a burden associated with triglyceride levels in FAM189A (P=2.26x10 -8 ), indicating a role for this gene in lipid metabolism.The role of rare sequence variants in the genetic architecture of medically-relevant complex traits is not well-understood. Population-scale deep whole genome sequencing can capture genetic variation across the entire allele frequency spectrum traversing the coding and noncoding genome. Here, to improve our understanding of the role of rare variants, we perform cohort-wide deep whole genome sequencing of 1,457 individuals from a deeplyphenotyped, isolated population from Crete, Greece (the HELIC-MANOLIS cohort 1-3 ) at an average depth of 22.5x ( Supplementary Figure 1), capturing 98% of true single nucleotide variants (SNVs) (Online Methods and Supplementary Figure 2). We address open questions on whole genome sequencing study design, analysis and interpretation, and identify burdens of coding and regulatory rare variants associated with cardiometabolic traits. RESULTS Effect of sequencing depthComparing whole genome sequencing at various depths ranging from 15x to 30x (Online Methods), we find that 96.4% of singletons, 97.9% of doubletons and 97.6% of variants called using 30x sequencing are recapitulated at 22.5x depth. Genotype accuracy (as measured by r 2 ) is 99.7% for 22.5x depth and 98.5% for 15x depth, suggesting that increases between 15x and 30x translate into marginal improvements in both call rate and quality of very rare SNVs (Figure 1, Supplementary Figure 3 and Methods). We find that false discovery rates and genotype accuracy are substantially more dependent on sequencing depth for INDELs than for SNVs (Figure 1). Landscape of sequence variationFollowing quality control (QC), we call 24,163,896 non-monomorphic SNVs and INDELs, 97.9% of which are biallelic. 14,281,180 (60.31%) of the biallelic SNVs are rare (minor allele frequency [MAF]<0.01); 3,103,273 (13.1%) are low-frequency (MAF 0.01-0.05); and 6,292,726 (26.57%) are common (MAF>0.05). We call 8,294 non-monomorphic variants annotated as loss-of-function (LoF) with low-confidence (LC) 4 , and 438 variants annotated as LoF with high-confidence (HC) ( Supplementary Figure 4). On average, each individual carries 405 (s=19) LC LoF variants and 31 (s=6) HC LoF variants, compared to 149 LoF variants per sample in a whole genome sequencing study of 2,636 Icelanders 5 . 0.6% and 1% of HC and LC LoF c...

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Section: Discussionmentioning

confidence: 99%

Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits

Gilly

Süveges

Kuchenbaecker

et al. 2018

Preprint

View full text Add to dashboard Cite

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“…60 Two PPXY-containing proteins, TMEM207 and COTE1, interact with WWOX and counteract WWOX-mediated inhibition of cell invasion. 36,37 Alteration of subcellular localization may be another way leading to dysfunction of WWOX. For example, overexpressed Zfra sequesters WWOX in the cytoplasm and blocks TNFa/UV light-induced nuclear translocation of WWOX, thus disturbing the proapoptotic functions of WWOX and p53.…”

Section: How Cancer Cells Dodge or Overcome Wwox-mediated Tumor Supprmentioning

confidence: 99%

Strategies of oncogenic microbes to deal with WW domain-containing oxidoreductase

Chang

Lan

Hsiao

et al. 2014

Exp Biol Med (Maywood)

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WW domain-containing oxidoreductase (WWOX) is a well-documented tumor suppressor protein that controls growth, survival, and metastasis of malignant cells. To counteract WWOX's suppressive effects, cancer cells have developed many strategies either to downregulate WWOX expression or to functionally inactivate WWOX. Relatively unknown is, in the context of those cancers associated with certain viruses or bacteria, how the oncogenic pathogens deal with WWOX. Here we review recent studies showing different strategies utilized by three cancer-associated pathogens. Helicobactor pylori reduces WWOX expression through promoter hypermethylation, an epigenetic mechanism also occurring in many other cancer cells. WWOX has a potential to block canonical NF-κB activation and tumorigenesis induced by Tax, an oncoprotein of human T-cell leukemia virus. Tax successfully overcomes the blockage by inhibiting WWOX expression through activation of the non-canonical NF-κB pathway. On the other hand, latent membrane protein 2A of Epstein-Barr virus physically interacts with WWOX and redirects its function to trigger a signaling pathway that upregulates matrix metalloproteinase 9 and cancer cell invasion. These reports may be just "the tip of the iceberg" regarding multiple interactions between WWOX and oncogenic microbes. Further studies in this direction should expand our understanding of infection-driven oncogenesis.

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“…We discover replicating evidence for association of a rare variant burden with triglyceride levels at a locus not previously linked with the trait. FAM189B (Family With Sequence Similarity 189 Member B), also known as COTE1 or C1orf2 , codes for a membrane protein that is widely expressed, including in adult liver tissue 17 . Expression of FAM189B has been found to be correlated with endogenous SREBP-1 activation in vitro 18 .…”

Section: Discussionmentioning

confidence: 99%

Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits

et al. 2018

View full text Add to dashboard Cite

The role of rare variants in complex traits remains uncharted. Here, we conduct deep whole genome sequencing of 1457 individuals from an isolated population, and test for rare variant burdens across six cardiometabolic traits. We identify a role for rare regulatory variation, which has hitherto been missed. We find evidence of rare variant burdens that are independent of established common variant signals (ADIPOQ and adiponectin, P = 4.2 × 10−8; APOC3 and triglyceride levels, P = 1.5 × 10−26), and identify replicating evidence for a burden associated with triglyceride levels in FAM189B (P = 2.2 × 10−8), indicating a role for this gene in lipid metabolism.

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Ectopic Overexpression of COTE1 Promotes Cellular Invasion of Hepatocellular Carcinoma

Cited by 13 publications

References 25 publications

Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits

Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits

Strategies of oncogenic microbes to deal with WW domain-containing oxidoreductase

Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits

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