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In-depth proteomic analysis of paraffin-embedded tissue samples from colorectal cancer patients revealed TXNDC17 and SLC8A1 as key proteins associated to the disease.

ABSTRACT: A better understanding of the biology of colorectal cancer (CRC) would help identifying specific markers of the disease that could be used as diagnostic and/or prognostic biomarkers or become potential therapeutic targets of intervention. In this work, we aimed to analyze the differential protein expression of paraffin-embedded tissue colorectal adenocarcinoma in comparison to the surrounded original adenoma and healthy adjacent tissue by quantitative proteomics to identify early dysregulated key proteins in the disease. Two independent quantitative 10-plex tandem mass tag (TMT) experiments were performed using separately paired FFPE paired tissue samples from six different CRC patients. After protein extraction, trypsin digestion and labeling, proteins were identified and quantified by mass spectrometry using a Q Exactive. Data analysis and bioinformatics was then performed with MaxQuant and the R program to identify proteins differentially expressed in the adenoma to adenocarcinoma transition. More than 2500 proteins were identified and quantified, with 277 and 283 significantly upregulated or downregulated proteins (expression ratio ≥ 1.5 or ≤0.67, p-value ≤ 0.05), respectively, in adenoma and/or adenocarcinoma in comparison to healthy tissue. Ten altered proteins were then selected for further analyze their role in CRC by western blot, immunohistochemistry, tissue microarrays, and ELISA using tissue and plasma samples from CRC patients, individuals with premalignant lesions (low and high grade adenomas) and healthy individuals (controls), and by loss-of-function in vitro cell-based assays using three CRC cell lines with different metastatic properties. Among them, we found SLC8A1 and TXNDC17 associated to CRC survival and liver metastasis, and whose protein levels in plasma possessed diagnostic ability of early stages of the disease.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Colon

DISEASE(S): Colon Cancer

SUBMITTER: Ana Montero Calle

LAB HEAD: Rodrigo Barderas

PROVIDER: PXD039630 | Pride | 2025-05-04

REPOSITORIES: Pride

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Project description:Background. Most colorectal cancers (CRC) arise in a progression through adenoma to carcinoma phenotypes as a consequence of altered genetic information. Clinical progression of CRC may occur in parallel with distinctive signaling alterations. We designed multidirectional analyses integrating microarray-based data with biostatistics and bioinformatics to elucidate the signaling and metabolic alterations underlying CRC development in the adenoma-carcinoma sequence. Methodology/Principal Findings. Studies were performed on normal mucosa, adenoma, and CRC samples obtained during surgery or colonoscopy. Collections of cryostat sections prepared from the tissue samples were evaluated by a pathologist to control the relative cell type content. RNA was isolated from 105 macro- and 40 microdissected specimens. The measurements were done using Affymetrix GeneChip HG-U133plus2, and probe set data were generated using two normalization algorithms: MAS5 and GCRMA with LVS. The data were evaluated using pair-wise comparisons and data decomposition into SVD modes. The method selected for the functional analysis used the Kolmogorov-Smirnov test. Based on a consensus of the results obtained by two tissue handling procedures, two normalization algorithms, and two probe set sorting criteria, we identified six KEGG signaling and metabolic pathways (cell cycle, DNA replication, p53 signaling pathway, purine metabolism, pyrimidine metabolism, and RNA polymerase) that are significantly altered in both macro- and microdissected tumor samples compared to normal colon. On the other hand, pathways altered between benign and malignant tumors were identified only in the macrodissected tissues. Conclusion/Significance. Multidirectional analyses of microarray data allow the identification of essential signaling alterations underlying CRC development. Although the proposed strategy is computationally complex and labor–intensive, it may reduce the number of false results. Gene expression profiles of 40 tissue samples representing distant full-thickness normal colon, normal colon mucosa dissected from tumor, adenoma, and carcinoma. Gene expression profiles of 105 tissue samples representing colon carcinomas, adenocarcinomas, and normal colon samples.

			Action	DRS
	TMT-1_Raw_data.zip	Other
	TMT-1_SEARCH.zip	Other
	TMT-2_Raw_data.zip	Other
	TMT-2_SEARCH.zip	Other
	checksum.txt	Txt

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In-depth proteomic analysis of paraffin-embedded tissue samples from colorectal cancer patients revealed TXNDC17 and SLC8A1 as key proteins associated to the disease.

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