Investigation of miRNA dysregulation and association with immune cell profile during malignant transformation of colorectal cells

Abstract

Background: Colorectal cancer (CRC) is one of the most prevalent and life-threatening cancer among the world. Accumulated somatic mutations during malignant transformation process endow cancer cells with increased growth, invasiveness and immunogenicity. These highly immunogenic cancer cells develop multiple strategies to evade immune attack. Through post-transcriptional regulation, microRNAs (miRNAs) not only participate in cancer development and progression but also manipulate anti-cancer immune response. This study aims to identify miRNAs associated with the colorectal cell malignant transformation process and their association with immune cell population using synchronous adjacent normal, polyp and CRC specimens.

Methods: We conducted a Low Density Array to compare the miRNA expression profile of synchronous colorectal adenoma, adenocarcinoma and adjacent normal colon mucosa collected from 8 patients, in order to identify candidate miRNAs involved in CRC progression. These findings were further validated in 14 additional patients and GEO dataset GSE41655. The relative abundance of dendritic cells, natural killer cells, neutrophil and macrophage was determined and correlated with dysregulated miRNA levels.

Results: MicroRNA microarray identified 39 miRNAs aberrantly expressed during the colorectal cell transformation process. Seven novel miRNAs were shortlisted, and dysregulation of miR-149-3p, miR-192-3p, miR-335-5p and miR-425 were further validated by the qPCR validation experiment and data retrieved from the GEO dataset. Furthermore, these miRNAs demonstrated certain associations with level of dendritic cells, natural killer cells, neutrophil and macrophage within the polyp or CRC specimens.

Conclusion: This study revealed miRNA dysregulated during stepwise malignant transformation of colorectal mucosal cells and their association with immune cell population.

Keywords: CRC; Dendritic cells; Natural killer cells; Neutrophil and macrophage; Polyp; miRNA.