HYPOTHESIS AND THEORY article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1552665
This article is part of the Research TopicCancer Metastases: Mechanisms of Tumor Dissemination, Formation of Metastatic Niche and Anti-metastatic TherapyView all 11 articles
CD44 knockdown alters miRNA expression and their target genes in colon cancer
Provisionally accepted
- 1Faculty of Biology and Biotechnologies, National Research University Higher School of Economics, Moscow, Russia
- 2Institute of Anatomy, University of Lübeck, Lübeck, Schleswig-Holstein, Germany
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Introduction: Metastasis formation poses a significant challenge to oncologists, as it severely limits the survival of colorectal cancer (CRC) patients. Recently, we demonstrated that CD44 promotes spontaneous distant metastasis in a CRC xenograft model. The depletion of CD44 was associated with reduction in hypoxia, EMT, as well as improved mitochondrial metabolism in primary tumor.Collectively, these effects decreased the metastatic potential of the CRC xenograft tumors under investigation. In this study we explore the molecular mechanisms by which CD44 knockdown (kd) leads to such substantial changes of tumor properties.Methods: Using miRNA-Seq data combined with bioinformatic analysis, we investigated the role of miRNA expression changes in the metastasis prevention observed with CD44 kd.Results: Among the differentially expressed miRNAs, three members of Let-7 family (let-7a-5p, let-7b-5p, and let-7c-5p), two isoforms of miR-203a (canonical miR-203a-3p and its +1 5'-isoform), miR-101-3p, miR-200b-3p|+1 5'-isoform, miR-125a-5p, and miR-185-5p were identified as potentially involved in regulating CD44-mediated metastasis. Gene set analysis of differentially expressed mRNA targets of these miRNAs, along with an examination of key regulators driving the observed changes in both mRNA and miRNA expression profiles, suggests that the CD44-STAT3- Let-7 miRNA axis as one of the most relevant in regulation of colon cancer metastasis via the CD44 receptor.Discussion: Our findings suggest a regulatory relationship between CD44, Let-7 miRNAs, and STAT3 in HT-29 tumors. Additionally, we propose the potential involvement of both isoforms of miR-203a (canonical and its +1 5'-isoform) in this regulatory network, and suggest a role for miR-101-3p and miR-125a-5p in metastasis regulation through CD44 kd.
Keywords: CD44, Let-7 miRNAs, MiR-203a-3p, miR-101-3p, MiR-125a-5p, miR-185-5p, miRNA 5'-isoform, colon cancer metastasis
Received: 28 Dec 2024; Accepted: 25 Apr 2025.
Copyright: © 2025 Tonevitsky, Maltseva, Zhiyanov and Lange. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Alexander Grigoryevich Tonevitsky, Faculty of Biology and Biotechnologies, National Research University Higher School of Economics, Moscow, Russia
Diana V. Maltseva, Faculty of Biology and Biotechnologies, National Research University Higher School of Economics, Moscow, Russia
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