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.