Hypoxic tumor-derived exosomal miR-31-5p promotes lung adenocarcinoma metastasis by negatively regulating SATB2-reversed EMT and activating MEK/ERK signaling.

Abstract

BACKGROUND:

Exosomes have emerged as critical mediators of intercellular communication. Hypoxia is widely recognized as a key regulator of tumor aggressiveness, and significantly affects exosome release by tumor cells. However, the effects of exosomes derived from hypoxic lung adenocarcinoma (LUAD) cells are poorly understood.

METHODS:

Samples of miRNA isolated from hypoxic LUAD cell-derived exosomes (HExo) and normoxic LUAD cell-derived exosomes (NExo) were sequenced to identify miRNAs that might mediate tumor progression. Exosomal miRNA was co-cultured with LUAD cells to assess its biological effects on cell migration and metastasis both in vitro and in vivo. The cellular target of exosomal miRNA was confirmed by dual-luciferase assays. Western blot studies showed that exosomal miRNA regulated the related pathway. The availability of circulating exosomal miRNA derived from plasma was also evaluated.

RESULTS:

We found that HExo could significantly enhance the migration and invasion of normoxic LUAD cells. MiRNA sequencing results suggested that miR-31-5p was largely internalized within HExo and could be taken up by normoxic LUAD cells. Exosomal miR-31-5p was found to directly target Special AT-Rich Sequence-Binding Protein 2 (SATB2)-revered epithelial mesenchymal transition and significantly increase activation of MEK/ERK signaling, thereby contributing to tumor progression both in vitro and in vivo. Furthermore, higher levels of circulating exosomal miR-31-5p were detected in LUAD patients, especially in patients with metastatic disease.

CONCLUSIONS:

Our findings demonstrate that exosomal miR-31-5p exerts a crucial role in LUAD progression, and could serve as a diagnostic biomarker for LUAD.

• Authors: Fengqiang Yu, Mingqiang Liang, Yu Huang, Weidong Wu, Bin Zheng, Chun Chen
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 40 Issue 1 Pg. 179 (Jun 01 2021) ISSN: 1756-9966 [Electronic] England
• PMID: 34074322 (Publication Type: Journal Article)

Chemical References

• MIRN31 microRNA, human
• Matrix Attachment Region Binding Proteins
• MicroRNAs
• SATB2 protein, human
• Transcription Factors

Topics

• A549 Cells
• Adenocarcinoma of Lung (genetics, pathology)
• Animals
• Cell Movement (genetics)
• Cell Proliferation (genetics)
• Coculture Techniques
• Epithelial-Mesenchymal Transition (genetics)
• Exosomes (genetics)
• Gene Expression Regulation, Neoplastic (genetics)
• Heterografts
• Humans
• MAP Kinase Signaling System (genetics)
• Matrix Attachment Region Binding Proteins (genetics)
• Mice
• MicroRNAs (genetics)
• Neoplasm Invasiveness (genetics, pathology)
• Neoplasm Metastasis
• Transcription Factors (genetics)
• Tumor Hypoxia (genetics)