Molecular mechanisms and clinical implications of miRNAs in drug resistance of colorectal cancer

Abstract

Systemic chemotherapy is identified as a curative approach to prolong the survival time of patients with colorectal cancer (CRC). Although great progress in therapeutic approaches has been achieved during the last decades, drug resistance still extensively persists and serves as a major hurdle to effective anticancer therapy for CRC. The mechanism of multidrug resistance remains unclear. Recently, mounting evidence suggests that a great number of microRNAs (miRNAs) may contribute to drug resistance in CRC. Certain of these miRNAs may thus be used as promising biomarkers for predicting drug response to chemotherapy or serve as potential targets to develop personalized therapy for patients with CRC. This review mainly summarizes recent advances in miRNAs and the molecular mechanisms underlying miRNA-mediated chemoresistance in CRC. We also discuss the potential role of drug resistance-related miRNAs as potential biomarkers (diagnostic and prognostic value) and envisage the future orientation and challenges in translating the findings on miRNA-mediated chemoresistance of CRC into clinical applications.

The Mechanistic Roles of ncRNAs in Promoting and Supporting Chemoresistance of Colorectal Cancer

“…In CRC, this pathway is critical for maintaining the balance between cell proliferation, apoptosis, and differentiation, and thus its dysregulation results in further progression of CRC [146]. In fact, dysregulation of the Notch signaling pathway contributed to CRC progression, metastasis, and inhibition of apoptosis [147]. Lastly, the EGFR-RAS-MAPK pathway participates in many cellular processes, including the growth, proliferation, and survival of normal cells.…”

“…Furthermore, most have been validated under both in vitro and in vivo conditions, although only by the respective research group performing the investigation, and thus will eventually have to be further investigated and validated. Besides the ones to be discussed here, there are various other miRNAs, lncRNAs and circRNAs which have been identified and reviewed in the literature and have also contributed to modulating sensitivity and chemoresistance in CRC for the aforementioned drugs [13,20,22,23,25,32,70,125,142,147,189,[191][192][193].…”

“…As explained in the previous sections, 5-FU resistance in CRC has been a problem researchers have faced for the past two decades or so. Resistance due to this drug tends to arise mostly due to different members of the multidrug transporters' family, EMT, specific targets such as TYMS and DPD, cell death related pathways (apoptosis, autophagy), cell cycle and several different signalling pathways (MAPK/ERK, PI3K/AKT, Wnt/B-catenin, Hippo, NF-κB, Notch) [17,147,194]. Based on the research carried out to date, the three ncRNAs being discussed here have been shown to play a part and contribute to 5-FU resistance via most of these mechanisms (Figure 2) as will be discussed below (Table 1).…”

“…Studies have shown that miRNAs can regulate members of the BCL-2 family, which are responsible for controlling cell death and in turn contribute to drug resistance in CRC [147]. In fact, in the study by Qu et al [279], the relationship between miRNAs and DOX resistance in CRC cell lines was investigated.…”

Systematic Elucidation of the Mechanism of Action of Curcumin Against Colorectal Cancer via Network Pharmacology Approach

“…Colorectal cancer (CRC) is a complex heterogeneous disease involving multiple genes and epigenetic factors (Duan et al 2020). According to a recent report, there are 147950 new CRC cases that resulted in 53200 deaths in the United States in 2020(Lamichhane et al 2020).…”