Role of non-coding RNAs in radiosensitivity of colorectal cancer: A narrative review

Abstract

Colorectal cancer (CRC) is a global public health concern because of its high prevalence and mortality. Although radiotherapy is a key method for treating CRC, radioresistance is an obstacle to radiotherapy use. The molecular mechanisms underlying the radioresistance of CRC remain unclear. Increasing evidence has revealed the multiple regulatory functions of non-coding RNAs (ncRNAs) in numerous malignancies, including CRC. Several ncRNAs have been reported to be involved in the determination of radiosensitivity of CRC cells, and some have excellent potential to be prognostic biomarkers or therapeutic targets in CRC treatment. The present review discusses the biological functions and underlying mechanisms of ncRNAs (primarily lncRNA, miRNA, and circRNA) in the regulation of the radiosensitivity of CRC. We also evaluate studies that examined ncRNAs as biomarkers of response to radiation and as therapeutic targets for enhancing radiosensitivity.

Keywords: biomarkers; colorectal cancer; ncRNAs; radioresistance; radiosensitivity.

Figure 1

Mechanisms of ncRNAs contributing to CRC cell radiosensitivity. Radiation induces several types of DNA damage, and double-strand breaks (DSBs) are lethal. DNA damage activates the DNA damage repair pathway and the homologous recombination (HR) and the non-homologous end joining (NHEJ) are the most classic mechanisms for DSB repair. DNA damage repair results in two pathways: apoptosis and DNA repair, which lead to radiosensitivity or radioresistance. LncRNAs and circRNAs downregulate the expression levels of miRNA-targeted mRNAs by sponging their targeted miRNAs. mRNAs can directly regulate the DNA damage repair and indirectly modulate repair mechanisms through several onco-signaling pathways, such as Wnt/β-catenin, epithelial-mesenchymal transition (EMT), and DNA damage response. Taken together, the lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA interaction networks modulate the radiosensitivity of CRC cells by regulating DNA damage repair pathways.

Figure 2

Schematic depicting several pathways of ncRNAs in modulating radiation response to CRC cells. (A) Several ncRNAs regulate radiosensitivity by targeting insulin-like growth factor receptor signaling pathways. (B) A few ncRNAs modulate cell apoptosis by regulating anti-apoptotic pathways. (C) Some ncRNAs modulate response to irradiation by mediating autophagy pathways. (D) Many ncRNAs manipulate epithelial-mesenchymal transition (EMT) by enhancing EMT (e.g., TLCD2-1) or inhibiting EMT (e.g., miR-124). (E) Numerous ncRNAs regulate DNA damage response pathways (e.g., p53 pathways) to modulate radiosensitivity. (F) Specific ncRNAs control NF-κB signaling pathways to overcome radioresistance. (G) Some ncRNAs mediate cellular response to irradiation via targeting Wnt/β-catenin. (H) Several ncRNAs regulate radiosensitivity through mediating DNA damage repair pathways, such as non-homologous end joining (NHEJ).