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Review
. 2025 May 19;30(1):393.
doi: 10.1186/s40001-025-02618-z.

Dual role of miR-155 and exosomal miR-155 in tumor angiogenesis: implications for cancer progression and therapy

Affiliations
Review

Dual role of miR-155 and exosomal miR-155 in tumor angiogenesis: implications for cancer progression and therapy

Qusay Mohammed Hussain et al. Eur J Med Res. .

Abstract

Tumor angiogenesis facilitates cancer progression by supporting tumor growth and metastasis. MicroRNA-155 (miR-155) plays a pivotal role in regulating angiogenesis through both direct effects on tumor and endothelial cells and indirect modulation via exosomal communication. This review highlights miR-155's pro-angiogenic influence on endothelial cell behavior and tumor microenvironment remodeling. Additionally, exosomal miR-155 enhances intercellular communication, promoting vascularization in several cancers. Emerging therapeutic strategies include miR-155 inhibition using antagomirs, exosome-mediated delivery systems, and modulation of pathways such as JAK2/STAT3 and TGF-β/SMAD2. Targeting miR-155 represents a promising approach to hinder tumor angiogenesis and improve cancer therapy outcomes.

Keywords: Angiogenesis; Cancer; Exosome; MicroRNA-155.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The evolution of cancer through angiogenesis is driven by the fast proliferation of tumors, which has the effect of decreasing the oxygen supply. Angiopoietin, FGF, PDGF, and VEGF are among of the pro-angiogenic factors that are increased as a consequence of this. This leads in a low-oxygen tumor microenvironment (TME), which drives excessive blood vessel creation by boosting the levels of various pro-angiogenic proteins. An increase in the transport of oxygen and nutrients is made possible by the construction of new blood vessels, which in turn makes it easier for tumor cells to continue their growth, survival, and multiplication. As these cells become increasingly aggressive, they proliferate, expand, and promote the development of new blood vessels. Ultimately, they will penetrate and travel to distant regions via the bloodstream
Fig. 2
Fig. 2
miR-155 participates in multiple cellular functions. It is possible that hypoxic circumstances might lead to an increase in the production of miR-155 in cancer cells. This is because some response elements are present in the promoter region of miR-155. This particular microRNA has a strong connection to inflammation and exerts a major impact on lung cancer, ultimately having the capacity to alter the survival of cancer cells. In order to accomplish this objective, the levels of the tumor suppressor protein VHL are decreased, which in turn stimulates the development of new blood vessels. One-way TGF facilitates metastasis is by increasing miR-155 levels. This is accomplished through the action of Smad4. MiR-155 reduces RhoA protein levels, which breaks tight junctions and improves epithelial cell plasticity. This results in enhanced invasiveness and migration via enhancing epithelial–mesenchymal transition (EMT), which is triggered by transforming growth factor-beta 3. It is possible that lowering or inhibiting miR-155 could cause cells to halt in the G0/G1 phase of the cell cycle, which will signal the beginning of the process of programmed cell death. As a consequence of this, the growth of cancer cells in DLBCL and ccRC is restricted thanks to this. Another study showed that miR-155 inhibits Caspase 3 activity, which results in reduced cell death in nasopharyngeal cancer. Additionally, miR-155 has the potential to impact glucose metabolism by improving insulin sensitivity. This happens as a result of the suppression of C/EBPβ, which is a negative regulator in the insulin signaling pathway. This, in turn, leads to an increase in glycolysis. Ultimately, the presence of miR-155 is related with lowered levels of SOCS1 in non-small cell lung cancer (NSCLC), which might ultimately contribute to worse survival rates
Fig. 3
Fig. 3
Mechanistic overview of miR-155 in regulating insulin signaling and glucose metabolism. MiR-155 enhances insulin sensitivity by targeting key inhibitors of the insulin signaling pathway, including SOCS1, HDAC4, and C/EBPβ. Upon insulin binding to its receptor (IR), phosphorylation of insulin receptor substrates (IRS-1/2) activates PI3 K, leading to the conversion of PIP2 to PIP3. This cascade stimulates PDK1 and Akt, promoting GLUT4 translocation and increased glucose uptake. MiR-155 indirectly supports this process by enhancing AKT phosphorylation and glycolytic activity. Additionally, miR-155 counteracts TNF-α and JNK-mediated pathways that contribute to insulin resistance, thus playing a protective role in maintaining glucose homeostasis
Fig. 4
Fig. 4
Biogenesis and release of exosomes containing miR-155. Exosomes are nano-sized extracellular vesicles (40–100 nm) formed within multivesicular bodies (MVBs) through inward budding of endosomal membranes. Upon fusion of MVBs with the plasma membrane, exosomes are released into the extracellular space. They are enriched in lipids, proteins, and nucleic acids, including microRNAs such as miR-155. These vesicles can be taken up by nearby or distant recipient cells, enabling intercellular communication. The figure illustrates how exosomes derived from tumor or immune cells serve as carriers of miR-155, modulating gene expression in target cells and contributing to tumor angiogenesis and progression

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