THEMIS2 as a Novel Mediator of VEGFR2-driven Angiogenesis in Breast Cancer: Functional Suppression by miR-125b-5p

THEMIS2, a protein that plays a role in immune regulation, has recently been identified as a key factor in breast cancer progression. This study aimed to identify novel oncogenic regulators in circulating tumor cells (CTCs) that contribute to breast cancer metastasis and chemoresistance, elucidating the regulatory axis involving THEMIS2, VEGFR2 and microRNAs (miRNAs), specifically miR-125b-5p.

Using RNA-sequencing of breast cancer CTCs, THEMIS2 was identified as a significantly upregulated gene. miRNA target predictions and expression profiling in primary tumors and normal breast specimens were conducted to evaluate candidate regulators. Functional assays including sphere formation, migration, luciferase reporter activity, VEGFR phosphorylation analysis and in vivo tumor models were employed to investigate the roles of THEMIS2 and miR-125b-5p in metastasis and drug sensitivity.

THEMIS2 was found upregulated in CTCs and breast cancer cell lines with metastatic potential. miR-125b-5p, but not miR-125a-5p, was significantly down-regulated in metastatic models and identified as a direct post-transcriptional suppressor of THEMIS2. THEMIS2 enhanced VEGFR2 phosphorylation and promoted metastatic traits and resistance to docetaxel and bevacizumab. miR-125b-5p suppressed metastasis and restored chemosensitivity by targeting 3'UTR of THEMIS2, an effect reversible with anti-miR-125b or ectopic THEMIS2 expression.

We unraveled a novel miR-125b-5p-THEMIS2-VEGFR2 signaling axis as a key modulator of breast cancer metastasis and chemoresistance. These findings provide mechanistic insight and suggest that miR-125b-5p or THEMIS2 may serve as therapeutic targets or prognostic biomarkers in aggressive breast cancers.