Unraveling the Regulatory Role of HuR/microRNA Axis in Colorectal Cancer Tumorigenesis

Abstract

Colorectal cancer (CRC) remains a significant global health burden with high incidence and mortality. MicroRNAs (miRNAs) are small non-protein coding transcripts, conserved throughout evolution, with an important role in CRC tumorigenesis, and are either upregulated or downregulated in various cancers. RNA-binding proteins (RBPs) are known as essential regulators of miRNA activity. Human antigen R (HuR) is a prominent RBP known to drive tumorigenesis with a pivotal role in CRC. In this review, we discuss the regulatory role of the HuR/miRNA axis in CRC. Interestingly, miRNAs can directly target HuR, altering its expression and activity. However, HuR can also stabilize or degrade miRNAs, forming complex feedback loops that either activate or block CRC-associated signaling pathways. Dysregulation of the HuR/miRNA axis contributes to CRC initiation and progression. Additionally, HuR-miRNA regulation by other small non-coding RNAs, circular RNA (circRNAs), or long-non-coding RNAs (lncRNAs) is also explored here. Understanding this HuR-miRNA interplay could reveal novel biomarkers with better diagnostic or prognostic accuracy.

Keywords: HuR; RNA-binding protein; circular RNA; colorectal cancer; lncRNA; microRNA.

Figure 1

Expression of HuR in colon and rectal adenocarcinoma patients. Box plots showing expression of (A), ELAVL1 (gene encoding human antigen R; HuR) in colon adenocarcinoma (COAD) and rectal adenocarcinoma (READ) patients in The Cancer Genome Atlas (TCGA) COAD and READ cohorts generated using the Gene Expression Profiling Interactive Analysis 2 (GEPIA2) http://gepia2.cancer-pku.cn/) [48]. Box plots showing expression of ELAVL1 expression in (B), TCGA-COAD and (C), TCGA-READ cohorts in patients grouped based on the microsatellite stability status into microsatellite instability-high or low (MSI-h, MSI-l) or microsatellite stable (MSS). Comparisons are performed between cancer tissue and normal tissue. The number of patients (n) is indicated in the figure. The log2 fold change and p-value cut-offs were according to the default settings of GEPIA2. T = Tumor, N = Normal.

Figure 2

Graphics showing the role of different microRNAs (miRNAs) regulating human antigen R (HuR) in cancers of various organs. The names of the miRNAs are mentioned in the graphics. The miRNAs involved in gallbladder cancer (miR-502-3p), thyroid cancer (mir-31 and miR-19), sarcoma (mir-29), bladder cancer (miR-494), and kidney cancer (miR-519) are not mentioned in the graphics due to space restrictions. Each mentioned miRNA is either a tumor promoter or tumor suppressor in the specific cancer. The image was created with the help of Biorender.com.

Figure 3

Schematics show the different functions of circular RNAs (circRNAs) involved in cancer. Briefly, the image shows how circRNAs are categorized and presented based on their function, ranging from transcriptional to translational regulation, miRNA sponging, alternative splicing, and RBP sponging. We have also shown examples of circRNA that are predicted to be probable biomarkers and signaling scaffolds. The black arrow shows the signaling pathway. The red arrow shows downregulation, and the green arrow shows upregulation. The other colors used in the graphics are only for better illustration and do not represent explicitly anything.