Halofuginone Affects the miR-34c-5p/MAP2K1 Axis Involved in the Development of Colorectal Cancer

Colorectal cancer (CRC) is highly heterogeneous and develops due to the accumulation of genetic and epigenetic alterations. MicroRNAs (miRNAs) are involved in various aspects of CRC, such as epithelial-mesenchymal transition (EMT), proliferation, migration, and metastasis. However, the complex mechanisms involved remain incompletely understood. This study identifies CRC-related differentially expressed miRNAs (with a focus on miR- 34c-5p), verifies its target, and explores the regulatory mechanism of halofuginone (HF) in CRC via the miR-34c-5p/MAP2K1 axis.

MiRNA sequencing (miRNA-Seq) identified differentially expressed miRNAs, which were verified by real-time quantitative PCR (RT-qPCR). miR-34c-5p expression was detected in HCT-15 cells and normal human primary colon epithelial cells; its effects on CRC cell proliferation, migration, and invasion were assessed in vitro and in vivo. Target prediction combined with dual-luciferase reporter assays validated the direct target of miR-34c-5p. Immunohistochemistry (IHC) was performed to analyse MAP2K1 expression in clinical samples and its correlation with the severity of precancerous lesions. The effect of HF on CRC via the miR-34c- 5p/MAP2K1 axis was examined in vitro and in vivo.

MiR-34c-5p was downregulated in HCT-15 cells compared with normal human primary colon epithelial cells and inhibited the malignant behaviours of CRC cells in vitro and in vivo. MAP2K1 was confirmed as the direct target of miR-34c-5p. MAP2K1 expression was positively correlated with the severity of colorectal precancerous lesions. HF suppressed CRC progression by regulating the miR-34c-5p/MAP2K1 axis in vitro and in vivo.

This study reveals that miR-34c-5p targets MAP2K1 to suppress colorectal cancer progression. HF upregulates miR-34c-5p and downregulates MAP2K1, exerting antitumour effects. The miR-34c-5p/MAP2K1 axis serves as a promising therapeutic target for CRC.

Taken together, our study revealed that the miR-34c-5p/MAP2K1 axis is involved in the development and progression of human CRC and may provide novel insights into the prevention and treatment of CRC. This work also provides a brief overview of several recently issued patents.