Dysplasia-Carcinoma Transition Specific Transcripts in Colonic Biopsy Samples

Galamb, Orsolya; Wichmann, Barnabás; Sípos, Ferenc; Spisák, Sándor; Krenács, Tibor; Tóth, Kinga; Leiszter, Katalin; Kalmár, Alexandra; Tulassay, Zsolt; Molnár, Béla

doi:10.1371/journal.pone.0048547

Cited by 44 publications

(46 citation statements)

References 33 publications

(31 reference statements)

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“…8). After normalization and removal of nonexpressed genes, we determined how the global dynamics of gene expression correlate with the different stages in carcinogenesis.…”

Section: Resultsmentioning

confidence: 99%

“…Raw expression data was acquired from the Gene Expression Omnibus (accession GSE37364; ref. 8). CEL files were processed using the rma function from the affy package (10) using curated annotations available from the Brainarray resource (11).…”

Section: Acquisition and Processing Of Expression Datamentioning

confidence: 99%

“…However, this study looked at the end point of carcinogenesis, the colon adenocarcinoma itself, and the question remains at what stage in carcinogenesis these pathways exert their effect. Only few studies have looked at the temporal dynamics of colon cancer progression, but even those studies were limited to the normal to adenoma transition or the adenoma to carcinoma transition (5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional Dynamics in Colorectal Carcinogenesis: New Insights into the Role of c-Myc and miR17 in Benign to Cancer Transformation

et al. 2014

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Colorectal cancer develops in a sequential, evolutionary process, leading to a heterogenic tumor. Comprehensive molecular studies of colorectal cancer have been previously performed; still, the process of carcinogenesis is not fully understood. We utilized gene expression patterns from 94 samples including normal, adenoma, and adenocarcinoma colon biopsies and performed a coexpression network analysis to determine gene expression trajectories of 8,000 genes across carcinogenesis. We found that the majority of gene expression changes occur in the transition from normal tissue to adenoma. The upregulated genes, known to be involved in cellular proliferation, included c-Myc along with its targets. In a cellular model system, we show that physiologic upregulation of c-Myc can lead to cellular proliferation without DNA replication stress. Our analysis also found that carcinogenesis involves a progressive downregulation of genes that are markers of colonic tissue and propose that this reflects a perturbed differentiation of colon cells during carcinogenesis. The analysis of miRNAs targets pointed toward the involvement of miR17 in the regulation of colon cell differentiation. Finally, we found that copy-number variations (CNV) enriched in colon adenocarcinoma tend to occur in genes whose expression changes already in adenoma, with deletions occurring in genes downregulated and duplications in genes upregulated in adenomas. We suggest that the CNVs are selected to reinforce changes in gene expression, rather than initiate them. Together, these findings shed new light into the molecular processes that underlie the transformation of colon tissue from normal to cancer and add a temporal context that has been hitherto lacking.

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“…8). After normalization and removal of nonexpressed genes, we determined how the global dynamics of gene expression correlate with the different stages in carcinogenesis.…”

Section: Resultsmentioning

confidence: 99%

Section: Acquisition and Processing Of Expression Datamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Transcriptional Dynamics in Colorectal Carcinogenesis: New Insights into the Role of c-Myc and miR17 in Benign to Cancer Transformation

et al. 2014

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“…GSE37364 set contains Affymetrix HGU133 Plus2.0 whole transcriptome data of 94 colonic biopsy samples (38 healthy normal, 27 colorectal adenocarcinoma, and 29 tubulovillous/villous adenoma) previously hybridized by our research group. 35 Five GEO data sets made by others on the same platform were also analyzed (GSE8671, 36 GSE18105, 37 GSE32323, 38 GSE22242, 39 GSE9348 40 ). Gene expression data of CRC and healthy normal (N)/ normal adjacent tissue (NAT) samples are available under serial accession numbers GSE18105, GSE32323 and GSE9348.…”

Section: Gene Expression Analysismentioning

confidence: 99%

Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer

et al. 2016

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The WNT signaling pathway has an essential role in colorectal carcinogenesis and progression, which involves a cascade of genetic and epigenetic changes. We aimed to analyze DNA methylation affecting the WNT pathway genes in colorectal carcinogenesis in promoter and gene body regions using whole methylome analysis in 9 colorectal cancer, 15 adenoma, and 6 normal tumor adjacent tissue (NAT) samples by methyl capture sequencing. Functional methylation was confirmed on 5-aza-2 0 -deoxycytidine-treated colorectal cancer cell line datasets. In parallel with the DNA methylation analysis, mutations of WNT pathway genes (APC, b-catenin/CTNNB1) were analyzed by 454 sequencing on GS Junior platform. Most differentially methylated CpG sites were localized in gene body regions (95% of WNT pathway genes). In the promoter regions, 33 of the 160 analyzed WNT pathway genes were differentially methylated in colorectal cancer vs. normal, including hypermethylated AXIN2, CHP1, PRICKLE1, SFRP1, SFRP2, SOX17, and hypomethylated CACYBP, CTNNB1, MYC; 44 genes in adenoma vs. NAT; and 41 genes in colorectal cancer vs. adenoma comparisons. Hypermethylation of AXIN2, DKK1, VANGL1, and WNT5A gene promoters was higher, while those of SOX17, PRICKLE1, DAAM2, and MYC was lower in colon carcinoma compared to adenoma. Inverse correlation between expression and methylation was confirmed in 23 genes, including APC, CHP1, PRICKLE1, PSEN1, and SFRP1. Differential methylation affected both canonical and noncanonical WNT pathway genes in colorectal normal-adenoma-carcinoma sequence. Aberrant DNA methylation appears already in adenomas as an early event of colorectal carcinogenesis.

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“…Detailed patients data were described previously. [33][34][35] For confirmation of exosome marker mRNA expression results revealed from our microarray data originate from all stages of colorectal adenoma-carcinoma sequence, four additional GEO data sets were also involved in the analysis, three of them includes HGU133 Plus2.0 microarray data of colorectal carcinoma (n = 99) and normal/normal adjacent tissue (NAT) (n = 39) tissue samples (GSE18105, 36 GSE4107 37 and GSE9348 38 ) and one of them with HGU133 Plus2.0 microarray data of adenoma (n = 32) and normal/NAT (n = 32) biopsy samples (GSE8671) 39 (Supplementary Table 1). …”

Section: In Silico Mrna Expression Analysis Of Exosome Markersmentioning

confidence: 99%

Exosomes in colorectal carcinoma formation: ALIX under the magnifying glass

et al. 2016

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Exosomes are small membrane vesicles that have important roles in transporting a great variety of bioactive molecules between epithelial compartment and their microenvironment during tumor formation including colorectal adenoma-carcinoma sequence. We tested the mRNA expression of the top 25 exosome-related markers based on ExoCharta database in healthy (n = 49), adenoma (n = 49) and colorectal carcinoma (n = 49) patients using Affymetrix HGU133 Plus2.0 microarrays. Most related genes showed significantly elevated expression including PGK1, PKM, ANXA5, ENO1, HSP90AB1 and MSN during adenoma-carcinoma sequence. Surprisingly, the expression of ALIX (ALG 2-interacting protein X), involved in multivesicular body (MVB) and exosome formation, was significantly reduced in normal vs adenoma (P = 5.02 × 10 − 13 ) and in normal vs colorectal carcinoma comparisons (P = 1.51 × 10 − 10 ). ALIX also showed significant reduction (Po 0.05) at the in situ protein level in the epithelial compartment of adenoma (n = 35) and colorectal carcinoma (n = 37) patients compared with 27 healthy individuals. Furthermore, significantly reduced ALIX protein levels were accompanied by their gradual transition from diffuse cytoplasmic expression to granular signals, which fell into the 0.6-2 μm diameter size range of MVBs. These ALIX-positive particles were seen in the tumor nests, including tumorstroma border, which suggest their exosome function. MVB-like structures were also detected in tumor microenvironment including α-smooth muscle actin-positive stromal cells, budding off cancer cells in the tumor front as well as in cancer cells entrapped within lymphoid vessels. In conclusion, we determined the top aberrantly expressed exosome-associated markers and revealed the transition of diffuse ALIX protein signals into a MVB-like pattern during adenoma-carcinoma sequence. These tumor-associated particles seen both in the carcinoma and the surrounding microenvironment can potentially mediate epithelial-stromal interactions involved in the regulation of tumor growth, metastatic invasion and therapy response.

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Dysplasia-Carcinoma Transition Specific Transcripts in Colonic Biopsy Samples

Cited by 44 publications

References 33 publications

Transcriptional Dynamics in Colorectal Carcinogenesis: New Insights into the Role of c-Myc and miR17 in Benign to Cancer Transformation

Transcriptional Dynamics in Colorectal Carcinogenesis: New Insights into the Role of c-Myc and miR17 in Benign to Cancer Transformation

Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer

Exosomes in colorectal carcinoma formation: ALIX under the magnifying glass

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