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.

miR‐423‐3p activates FAK signaling pathway to drive EMT process and tumor growth in lung adenocarcinoma through targeting CYBRD1

“…Among them, microRNAs have been regarded as indispensible mediators in LUAD. For example, Yu F and colleagues demonstrated that exosomal miR‐31‐5p derived from hypoxic tumor targeted SATB2 and activated MEK/ERK signaling to facilitate tumor metastasis in LUAD, 32 and Zhan J et al demonstrated that miR‐3130‐5p could drive the growth, metastasis, and EMT progress in LUAD through directly mediating NDUFS1. 33 In addition, Liu H et al revealed the carcinogenic role of miR‐301b‐3p in inducing LUAD cell proliferation, migration, and invasion via inhibiting DLC1.…”

LncRNA-MCM3AP-AS1 Promotes the Progression of Infantile Hemangiomas by Increasing miR-138-5p/HIF-1α Axis-Regulated Glycolysis

“…Hypoxic microenvironment exists in the vast majority of tumors, including liver cancer ( Ma et al, 2021a ) and IH ( Wu et al, 2021 ). The hypoxic microenvironment promotes the metastasis of tumor cells ( Yu et al, 2021 ), enhances the tolerance of tumor cells to radiotherapy and chemotherapy ( Sun et al, 2021 ), and also changes the gene expression of tumor cells. HIF-1α is an important transcription factor in hypoxic microenvironment.…”

Integrative Molecular Analyses of an Individual Transcription Factor-Based Genomic Model for Lung Cancer Prognosis

“…For instance, SATB2 reduces NSCLC invasiveness through modulation of EMT-relevant proteins as well as histone methylation of G9a [ 31 ]. Further, hypoxic tumor-derived exosomal miR-31-5p triggers LUAD metastases through negative modulation of SATB2-reversed EMT as well as activation of the MEK/ERK pathway [ 32 ]. Downregulated HLF facilitates multiple-organ distant metastases of NSCLC via the PPAR/NF- κ b pathway NSCLC [ 33 ].…”