Hypoxic BMSC-derived exosomal miRNAs promote metastasis of lung cancer cells via STAT3-induced EMT

Abstract

BackgroundMetastasis is the main cause of lung cancer mortality. Bone marrow-derived mesenchymal stem cells (BMSCs) are a component of the cancer microenvironment and contribute to cancer progression. Intratumoral hypoxia affects both cancer and stromal cells. Exosomes are recognized as mediators of intercellular communication. Here, we aim to further elucidate the communication between BMSC-derived exosomes and cancer cells in the hypoxic niche.MethodsExosomal miRNA profiling was performed using a microRNA array. Lung cancer cells and an in vivo mouse syngeneic tumor model were used to evaluate the effects of select exosomal microRNAs. Hypoxic BMSC-derived plasma exosomal miRNAs were assessed for their capacity to discriminate between cancer patients and non-cancerous controls and between cancer patients with or without metastasis.ResultsWe demonstrate that exosomes derived from hypoxic BMSCs are taken by neighboring cancer cells and promote cancer cell invasion and EMT. Exosome-mediated transfer of select microRNAs, including miR-193a-3p, miR-210-3p and miR-5100, from BMSCs to epithelial cancer cells activates STAT3 signaling and increases the expression of mesenchymal related molecules. The diagnostic accuracy of individual microRNA showed that plasma exosomal miR-193a-3p can discriminate cancer patients from non-cancerous controls. A panel of these three plasma exosomal microRNAs showed a better diagnostic accuracy to discriminate lung cancer patients with or without metastasis than individual exosomal microRNA.ConclusionsExosome-mediated transfer of miR-193a-3p, miR-210-3p and miR-5100, could promote invasion of lung cancer cells by activating STAT3 signalling-induced EMT. These exosomal miRNAs may be promising noninvasive biomarkers for cancer progression.Electronic supplementary materialThe online version of this article (10.1186/s12943-019-0959-5) contains supplementary material, which is available to authorized users.

Analysis of differential expression profile of miRNA in peripheral blood of patients with lung cancer

“…miRNAs can also affect the development and progression of tumors by intervening cell cycle, apoptosis, angiogenesis, and metastasis. 9,16,17 So far, only a very few of the miRNAs and their regulating target genes had been identified, and the functions of most miRNAs were still unclear. Further studies are needed on the functions of miRNAs to search for new miRNAs to accurately predict their target genes and correctly understand the interactions of miRNA and its target genes.…”

“…A total of 26 788 deaths were reported in 2017, and the reported mortality rate was 55.65/100 000. [6][7][8][9][10] However, the functions of miRNA remain unclear. The mortality of lung cancer increases with age; the mortality rate among the elderly (>65 years) reached 299.2/100 000.…”

“…In recent years, some studies reported that serum/plasma miRNA expression profile could effectively distinguish between cancer patients and healthy individuals and might be related to the development of lung cancer [3][4][5] or might have potential clinical value in the early diagnosis, prognostic, and therapeutic of lung cancer. [6][7][8][9][10] However, the functions of miRNA remain unclear. Therefore, we used a miRNA chip screening system for lung cancer, and then, real-time fluorescent quantitative PCR (RT-PCR) verification method to investigate the difference of plasma miRNA expression profile between lung cancer patients and healthy controls to predict target genes and to analyze the signal pathways, and to explore the relationship between miRNA and the genesis and the development of lung cancer.…”

Current Landscape of Epigenetics in Lung Cancer: Focus on the Mechanism and Application

“…Changes in these epigenetic factors result in the dysregulation of key oncogenes and tumor suppressor genes [18,19]. Many of the epigenetic events in lung cancer affect cancer hallmarks, such as proliferation [20][21][22][23], invasion [24][25][26], metastasis [27][28][29][30][31][32][33], apoptosis [34][35][36][37], and cell cycle regulation. In addition to cancer hallmarks, several important signaling pathways are affected by epigenetic deregulation in lung cancer, such as the ERK family, the NF-kB signaling pathway, and the Hedgehog signaling pathway [18].…”

Epstein‐Barr virus‐encoded latent membrane protein 1 promotes extracellular vesicle secretion through syndecan‐2 and synaptotagmin‐like‐4 in nasopharyngeal carcinoma cells

“…signaling pathways and performing a variety of important biological functions. [5][6][7] Nasopharyngeal carcinoma (NPC) is a malignant nasopharyngeal epithelial tumor that occurs mostly in Southeast Asia and southern China. 8 Epstein-Barr virus (EBV) has been confirmed to have a significant correlation with the progression of NPC.…”