# Differential Expression of MicroRNAs in the Colorectal Serrated Neoplasia Pathway and Adenoma–Carcinoma Sequence

## TL;DR

This study shows that different types of colorectal cancer develop through distinct patterns of microRNA activity, which could help in understanding and diagnosing these cancers.

## Contribution

The study identifies unique miRNA expression patterns in two colorectal cancer pathways, providing new insights into their molecular differences.

## Key findings

- miR-93 and miR-181b levels decrease as tumors progress in the serrated neoplasia pathway.
- miR-20a, miR-21, and miR-181b increase during tumor progression in the adenoma–carcinoma sequence.
- SSL-SC lesions show significantly lower levels of miR-20a, miR-93, and miR-181b compared to AD-SC.

## Abstract

Background and Aim: Colorectal carcinogenesis involves two distinct pathways, the serrated neoplasia pathway and adenoma (AD)–carcinoma sequence, whose precursors are sessile serrated lesion (SSL) and traditional AD, respectively. MicroRNAs (miRNAs) regulate gene expression and play a crucial role in colorectal tumorigenesis. This study investigated miRNA expression in the precursors and early invasive carcinomas of the two pathways.

Methods: Using real-time reverse transcription polymerase chain reaction, we quantified the expression of miR-20a, miR-21, miR-93, and miR-181b in 127 lesions, including 25 SSLs, 19 SSLs with high-grade dysplasia (SSL-HD), 13 SSLs with submucosal invasive carcinoma (SSL-SC), 19 ADs, 26 ADs with HD (AD-HD), and 25 ADs with SC (AD-SC).

Results: In the SSL series, miR-93 (SSL vs. SSL-SC, p = 0.038) and miR-181b (SSL vs. SSL-HD/SSL-SC, p = 0.013/p < 0.001, respectively) levels decreased with tumor progression. In the AD lineage, the expression of miR-20a (AD vs. AD-SC and AD-HD vs. AD-SC, p < 0.001), miR-21 (AD vs. AD-HD/AD-SC and AD-HD vs. AD-SC, p < 0.001), and miR-181b (AD-HD vs. AD-SC, p = 0.020) increased during carcinogenesis. Compared with normal mucosa (baseline), miR-93 expression showed a stepwise increase with tumor progression in the AD lineage, whereas the values did not change during SSL carcinogenesis. In the AD lineage, miR-20a expression increased in early invasive carcinoma but decreased in this phase of the SSL series. Overall, miR-20a, miR-93, and miR-181b levels were significantly lower in SSL-SC than in AD-SC (all p < 0.001).

Conclusions: These findings indicate that the SSL and AD pathways exhibit distinct miRNA expression dynamics during colorectal tumorigenesis, with the AD lineage showing a progressive increase in oncogenic miRNAs and the SSL series exhibiting selective downregulation or plateauing, particularly in invasive lesions. The differential expression of miR-20a, miR-21, miR-93, and miR-181b was presumed to be related to (epi)genetic alterations among serrated neoplasia and AD–carcinoma routes.