Tumor-derived exosomal lncRNA-MIR193BHG promotes bone metastasis of breast cancer by targeting the miR-489-3p/DNMT3A signaling axis in osteoclasts

AUTHORS

Xiaoya Liu, Rui Ma, Feng Wei, Maihuan Wang, Yiwei Jiang, Peng Zheng, Zhen Cao

ABSTRACT

Background

Breast cancer exhibits high incidence and mortality among women, with distant metastasis, especially bone metastasis, being the leading cause of death. Despite advances in adjuvant therapies, bone metastasis remains a challenge for patient survival and quality of life. Exosomes, small vesicles capable of mediating intercellular communication, play a crucial role in tumor metastasis.

Results

This study investigated the role of tumor-derived exosomal long noncoding RNA (lncRNA)-MIR193BHG in breast cancer bone metastasis. LncRNA-MIR193BHG was delivered to osteoclasts via exosomes and promoted osteoclast formation and activity by targeting the miR-489-3p/DNA methyltransferase 3A (DNMT3A) signaling axis, thereby accelerating breast cancer-induced osteolysis. Knockdown experiments demonstrated that reducing the levels of exosomal lncRNA-MIR193BHG significantly inhibited osteoclast differentiation and bone resorption, which was confirmed both in vitro and in vivo. Additionally, mechanistic studies revealed that lncRNA-MIR193BHG acted as a competitive endogenous RNA (ceRNA) interacting with miR-489-3p, regulating DNMT3A expression and subsequently affecting osteoclast differentiation.

Conclusions

These findings suggest that lncRNA-MIR193BHG plays a critical regulatory role in breast cancer bone metastasis, and the lncRNA-MIR193BHG/miR-489-3p/DNMT3A signaling axis could be a potential target for the treatment of breast cancer bone metastasis. Future studies should further explore the broader applicability of this mechanism and its clinical feasibility.

The Regulation of Hyperglycaemia-Induced Exosomal Mir-6499-3p Derived from Vascular Endothelial Cell on Calcification/Senescence of Vascular Smooth Muscle Cells

AUTHORS

Jiayu Zhong, MingHao Yuan, Shuo Hu, En Zhou

ABSTRACT

Diabetes is a prevalent metabolic condition that is closely linked to aging, and its biggest associated risk is vascular related complications. The calcification and aging of blood vessels in diabetes play a significant role in the development of diabetic vascular complications. Growing evidence links exosomal microRNA to the process of diabetic vascular complications. The present study aims to explore the expression, regulatory mechanisms and functions of exosomal miR-6499-3p in the process of diabetic vascular complications. VSMCs could take up exosomes isolated from HUVEC(ECs-exosome) treated with high glucose(HG). These exosomes induced the calcification and senescence of VSMCs through a paracrine mechanism. We then found that HG elevated the expression level of miR-6499-3p both in HUVECs and ECs-exosome. Calcification and senescence of VSMCs can be promoted by ECs-exosomes following overexpression of miR-6499-3p. Furthermore, we demonstrated that the effects of exosomes on the calcification and senescence of VSMCs is mediated by Sclerosin-containing domain SOSTDC1, the potential target of the miR-6499-3p. Our data has shown that a specific role of exosomes from HG-treated HUVEC in regulating the calcification and senescence of VSMCs in a paracrine manner through the miR-6499-3p/SOSTDC1 pathway. Modulation of exosomal miR-6499-3p may provide a novel perspective on the treatment of diabetic vascular complications.