Biochimica et biophysica acta. Molecular cell researchDec 4, 2024

Low oxygen increases IL-8 signaling by lowering miR-128-3p levels in aggressive brain tumors

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 31, 2026

Abstract

Lower levels of miR-128-3p in hypoxic glioblastoma multiforme are associated with reduced sensitivity to temozolomide treatment.

miR-128-3p is negatively correlated with hypoxia signaling and the epithelial-mesenchymal transition (EMT) in glioblastoma.
Hypoxic glioblastoma exhibits lower levels of miR-128-3p, which desensitizes the tumor to temozolomide (TMZ), a standard treatment.
Overexpression of miR-128-3p increases the sensitivity of hypoxic gliomas to TMZ both in laboratory and animal models.
HIF-1α suppresses the expression of miR-128-3p in the hypoxic microenvironment of glioblastoma.
Interleukin (IL)-8 shows a positive correlation with hypoxia and a negative correlation with miR-128-3p, and is linked to poor outcomes with TMZ treatment.
The interaction between HIF-1α, miR-128-3p, and IL-8 may regulate TMZ sensitivity and the EMT in hypoxic glioblastoma cells.

Simplified

Glioblastoma multiforme (GBM) is an aggressive type of brain tumor known for its hypoxic microenvironment. Understanding the dysregulated mechanisms in hypoxic GBM is crucial for its effective treatment. Through data mining of The Cancer Genome Atlas (TCGA) with hypoxia enrichment scores and in vitro experiments, miR-128-3p was negatively correlated with hypoxia signaling and the epithelial-mesenchymal transition (EMT). Additionally, lower miR-128-3p levels existed in hypoxic GBM, leading to desensitizing temozolomide (TMZ)'s efficacy, a first-line therapeutic drug for GBM. Overexpressing miR-128-3p enhanced both the in vitro and in vivo sensitivity of hypoxic gliomas to TMZ treatment. Mechanistically, HIF-1α suppressed miR-128-3p expression in hypoxic GBM. Through establishing miR-128-3p-mediated transcriptomic profiles and data mining, interleukin (IL)-8 was selected. IL-8 respectively showed positive and negative correlations with hypoxia and miR-128-3p, and was associated with poor TMZ therapeutic results in GBM. Elevated miR-128-3p, which targets both the 3'-untranslated region (UTR) and 5'UTR of IL-8, resulted in suppression of IL-8 expression. Moreover, IL-8 was validated to be involved in HIF-1α/miR-128-3p-regulated TMZ sensitivity and the EMT in hypoxic GBM cells. Collectively, the HIF-1α/miR-128-3p/IL-8 signaling pathway plays a critical role in promoting the progression of hypoxic GBM. Targeting this signaling pathway holds promise as a potential therapeutic strategy.

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Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

PubMed

Low oxygen increases IL-8 signaling by lowering miR-128-3p levels in aggressive brain tumors

Abstract

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