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Molecular functions of microRNAs in colorectal cancer: recent roles in proliferation, angiogenesis, apoptosis, and chemoresistance

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Abstract

MiRNAs (microRNAs) constitute a group of diminutive molecules of non-coding RNA intricately involved in regulating gene expression. This regulation is primarily accomplished through the binding of miRNAs to complementary sequences situated in the 3′-UTR of the messenger RNA (mRNA) target; as a result, they are degraded or repressed. The multifaceted biogenesis of miRNAs is characterized by a meticulously orchestrated sequence of events encompassing transcription, processing, transportation, and decay. Colorectal cancer stands as a pervasive and formidable ailment, afflicting millions across the globe. Colorectal cancer is not well diagnosed early, and metastasis rates are high, which results in low survival rates in advanced stages. The genesis and progression of colorectal cancer are subject to the influence of genetic and epigenetic factors, among which miRNAs play a pivotal role. When it comes to colorectal cancer, miRNAs have a dual character, depending on the genes they target, functioning as either tumor suppressors or oncogenes and the prevailing cellular milieu. Their impact extends to modulating critical facets of colorectal cancer pathogenesis, including proliferation, angiogenesis, apoptosis, chemoresistance, and radiotherapy response. The discernible potential of miRNAs which are used as biomarkers to diagnose colorectal cancer, prognosis, and treatment response has come to the forefront. Notably, miRNAs are easily found and detected readily in a variety of biological fluids, including saliva, blood, urine, and feces. This prominence is attributed to the inherent advantages of miRNAs over conventional biomarkers, including heightened stability, specificity, sensitivity, and accessibility. Various investigations have pinpointed miRNA signatures or panels capable of differentiating colorectal cancer patients from their healthy counterparts, predicting colorectal cancer stage and survival, and monitoring colorectal cancer recurrence and therapy response. Although there has been research on miRNAs in various diseases, there has been less research on miRNAs in cancer. Moreover, updated results of preclinical and clinical studies on miRNA biomarkers and drugs are required. Nevertheless, the integration of miRNAs as biomarkers for colorectal cancer is not devoid of challenges and limitations. These encompass the heterogeneity prevalent among colorectal cancer subtypes and stages, the variability in miRNA expression across different tissues and individuals, the absence of standardized methodologies for miRNA detection and quantification, and the imperative for validation through extensive clinical trials. Consequently, further research is imperative to conclusively establish the clinical utility and reliability of miRNAs as colorectal cancer biomarkers. MiR-21 demonstrates carcinogenic characteristics by targeting several tumor suppressor genes, which encourages cell division, invasion, and metastasis. On the other hand, by controlling the Wnt/β-catenin pathway, the tumor suppressor miRNA miR-34a prevents CRC cell proliferation, migration, and invasion. Furthermore, in colorectal cancer, the miR-200 family increases chemotherapy sensitivity while suppressing epithelial-mesenchymal transition (EMT). As an oncogene, the miR-17–92 cluster targets elements of the TGF-β signaling pathway to encourage the growth of CRC cells. Finally, miR-143/145, which is downregulated in CRC, influences apoptosis and the progression of the cell cycle. These miRNAs affect pathways like Wnt, TGF-β, PI3K-AKT, MAPK, and EMT, making them potential clinical biomarkers and therapeutic targets. This review summarizes recent research related to miRNAs, their role in tumor progression and metastasis, and their potential as biomarkers and therapeutic targets in colorectal cancer. In addition, we combined miRNAs’ roles in tumorigenesis and development with the therapy of CRC patients, leading to novel perspectives on colorectal cancer diagnosis and treatment.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Faculty of Pharmacy for Girls, Al-Azhar University, Cairo, Egypt

    Doha El-Sayed Ellakwa

  2. Department of Biochemistry, Faculty of Pharmacy, Sinai University, Kantra Branch, Ismailia, Egypt

    Doha El-Sayed Ellakwa

  3. Department of Life Sciences, Lahore University of Management Sciences, Lahore, Pakistan

    Nadia Mushtaq

  4. Center for Applied Molecular Biology (CAMB), University of Punjab, Lahore, Pakistan

    Sahrish Khan

  5. Department of Veterinary Medicine, University of Veterinary and Animal Sciences, Lahore, Pakistan

    Abdul Jabbar

  6. Faculty of Pharmacy, Sinai University, Kantra Branch, Ismailia, Egypt

    Mohamed Ahmed Abdelmalek

  7. Faculty of Dentistry, Sinai University, Arish Branch, North Sinai, Egypt

    Al-Hassan Soliman Wadan

  8. Physical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt

    Takwa E. Ellakwa

  9. Department of Veterinary Microbiology, Faculty of Veterinary Medicine, Ataturk University, Erzurum, Turkey

    Ali Raza

Authors
  1. Doha El-Sayed Ellakwa
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  2. Nadia Mushtaq
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  3. Sahrish Khan
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  4. Abdul Jabbar
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  5. Mohamed Ahmed Abdelmalek
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  6. Al-Hassan Soliman Wadan
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  7. Takwa E. Ellakwa
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  8. Ali Raza
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All authors reviewed the manuscript equally. The authors confirm that no paper mill and artificial intelligence was used.

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Correspondence to Doha El-Sayed Ellakwa.

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Ellakwa, D.ES., Mushtaq, N., Khan, S. et al. Molecular functions of microRNAs in colorectal cancer: recent roles in proliferation, angiogenesis, apoptosis, and chemoresistance. Naunyn-Schmiedeberg's Arch Pharmacol (2024). https://doi.org/10.1007/s00210-024-03076-w

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