Elevated miRNA-222-3p may drive colorectal adenoma-to-carcinoma progression by modulating the PTEN/PI3K/AKT pathway

Abstract Objectives Colorectal cancer (CRC) is common, with the adenoma-carcinoma sequence being crucial, but the roles of the PTEN/PI3K/AKT pathway and miRNAs in it are unclear. This study aimed to observe the expression of related miRNAs and pathway molecules in this sequence, explore their role in adenoma carcinogenesis, and offer new ideas for CRC early diagnosis and treatment. Methods In this study, we observed the expression of miRNA-519α, miRNA-454, miRNA-222-3p, and related molecules of the downstream PTEN/PI3K/AKT/β-catenin pathway in colorectal adenoma-carcinoma sequence, and used Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR), transcriptomic analysis, and immunohistochemistry (IHC) to examine the expression of these miRNAs and molecules in colorectal adenoma and adenocarcinoma tissues. Results Clinical specimens showed miRNA-222-3p (Ct:17–31) was significantly higher than miRNA-519α (Ct: 37–45) and miRNA-454 (Ct: 31–39) in adenoma and adenocarcinoma; compared with normal tissues, it was upregulated in colorectal adenocarcinoma (p=0.040) and tubular adenoma (p<0.001, higher than tubular adenocarcinoma, p<0.001), and gradually increased in ascending colon villous tubular adenoma (2 L), early carcinoma (3 E Ca vs. 2 L, p=0.020), and adenocarcinoma (4Ca vs. 2 L, p=0.005). Transcriptomic analysis showed miRNA-222-3p upregulated in high-grade (HTG, p=0.021) and low-grade tumor adenoma (LTG, p=0.123) relative to the normal control group (NCG); plasma exosomal miRNA-222-3p was upregulated in LTG (p<0.001) and HTG (p=0.033; both vs. NCG), and KEGG analysis identified the PI3K-AKT pathway as key in adenoma-to-carcinoma progression. In the Azoxymethane/Dextran sodium sulfate (AOM/DSS) model, serum miRNA-222-3p (p=0.040), spleen weight (p=0.019), and intestinal weight (p=0.004) were higher in the model group. Based on IHC and transcriptomics results, the PTEN/PI3K/AKT pathway plays a role in colorectal adenoma carcinogenesis, with PIK3CA and GSK3B possibly involved in post-transcriptional translation. Conclusions These results indicated that miRNA-222-3p and the PTEN/PI3K/AKT pathway played an important role in colorectal adenoma-carcinoma sequence, especially in the ascending colon. MiRNA-222-3p may serve as a novel noninvasive diagnostic biomarker and therapeutic target for colorectal adenoma carcinogenesis.