Abstract
The expression of monocyte chemotactic proteins (MCPs) in colorectal polyps and their suitability as targets for chemoprevention is unknown, although MCP expression and secretion can be modulated by non-steroidal inflammatory drugs. This study was designed to determine the expression patterns of MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7 at the protein (immunohistochemistry; n = 62) and transcriptional levels (RTqPCR; n = 173) in colorectal polyps with reference to the polyp malignancy potential. All chemokines were significantly upregulated in polyps at the protein level but downregulated at the transcriptional level by 1.4-(CCL2), 1.7-(CCL7), and 2.3-fold (CCL8). There was an inverse relation between the immunoreactivity toward chemokine proteins and the number of corresponding transcripts in polyps (CCL2 and CCL7) or in normal mucosa (CCL8). The downregulation of chemokine transcripts correlated with the presence of multiple polyps (CCL2 and CCL8), a larger polyp size (CCL2, CCL7, and CCL8), predominant villous growth patterns (CCL2, CCL7 and CCL8), and high-grade dysplasia (CCL2 and CCL8). In conclusion, MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7 chemokines are counter-regulated at the protein and transcriptional levels. Chemokine-directed chemopreventive strategies should therefore directly neutralize MCP proteins or target molecular pathways contributing to their enhanced translation or reduced degradation, rather than aiming at CCL2, CCL7 or CCL8 expression.
Highlights
As the risk of adenoma transformation to adenocarcinoma is higher in the case of larger and multiple polyps and those with dominant villous growth patterns and high-grade dysplasia, we summarized those risk factors by calculating a cumulative risk factor
Comparative RNAseq analysis of the colorectal transcriptome of patient-matched (n = 5) samples of normal mucosa, adenomas, and adenocarcinomas has shown that CCL2 expression is significantly upregulated in tumors compared with adenomas but downregulated in adenomas compared with normal mucosa [27]
We showed that CCL2 expression in polyps and the polyp-to-normal expression ratio were lower in patients with large and multiple polyps and adenomas with a dominant villous growth pattern and high-grade dysplasia
Summary
Colorectal cancer (CRC) is one of the most common malignancies worldwide, the incidence of which has recently been reduced, owing to improved screening. Chemoprevention, which is using chemicals to prevent, delay, or reverse the carcinogenesis, is another intensively studied strategy for reducing CRC risk in high-risk people as well as the general population [1]. Develop from polyps via the classic adenoma-carcinoma sequence or, less commonly, the serrated polyp pathway [3]. This well-known and relatively slow progression makes CRC open to chemoprevention. A better understanding of the molecular profile of polyps as premalignant lesions and recognition of the features distinguishing those with high potential for malignancy is considered a prerequisite for developing effective surveillance and chemopreventive strategies [3]
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