Exosomes Derived from Hypoxic Oral Squamous Cell Carcinoma Cells Deliver miR-21 to Normoxic Cells to Elicit a Prometastatic Phenotype

Abstract

Hypoxia is a common feature of solid tumors and is associated with aggressiveness and poor patient outcomes. Exosomes, initially considered to be cellular "garbage dumpsters," are now implicated in mediating interactions with the cellular environment. However, the mechanisms underlying the association between exosomes and hypoxia during cancer progression remain poorly understood. In this study, we found that exosomes derived from hypoxic oral squamous cell carcinoma (OSCC) cells increased the migration and invasion of OSCC cells in a HIF1a and HIF-2a-dependent manner. Given that exosomes have been shown to transport miRNAs to alter cellular functions, we performed miRNA sequencing of normoxic and hypoxic OSCCderived exosomes. Of the 108 miRNAs that were differentially expressed, miR-21 stood out as one of the most significantly upregulated miRNAs under hypoxic conditions. miR-21 depletion in hypoxic OSCC cells led to decreased miR-21 levels in exosomes and significantly reduced cell migration and invasion. Conversely, restoration of miR-21 expression in HIF-1a and HIF2a-depleted exosomes rescued OSCC cell migration and invasion. Moreover, exosomal miR-21 markedly enhanced snail and vimentin expression, while significantly decreasing E-cadherin levels in OSCC cells, in vitro and in vivo. Finally, circulating exosomal miR-21 levels were closely associated with HIF-1a/ HIF-2a expression, T stage, and lymph node metastasis in patients with OSCC. In conclusion, our findings suggest that the hypoxic microenvironment may stimulate tumor cells to generate miR-21-rich exosomes that are delivered to normoxic cells to promote prometastatic behaviors and prompt further investigation into the therapeutic value of exosome inhibition for cancer treatment.

Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1

“…30,31 Secretory miRNAs are also involved in the remodelling of TME shaped and dominated by cancer cells. 19,32 miR-351b-and miR-210-enriched exosomes released by cancer cells increase tumour angiogenesis, thereby increasing cancer metastasis. 33 In this study, we found that exosomal miR-23a not only increases tumour angiogenesis during hypoxia, but also in normoxic conditions, suggesting that hypoxic lung cancer transmits genetic materials not only between cancer cells and endothelial cells within the hypoxic region, but also between cancer cells and distant endothelial cells located in normoxic regions.…”

“…16,17 They are capable of diffusing to neighbouring cells or being transported to distant anatomic locations where they can transduce signals or information in specific recipient cells. 18,19 Cancer-derived exosomes have been found to contribute to TME remodelling and premetastatic niche formation. 20,21 In this study, we have investigated the potential role of exosome vesicles in hypoxia-dependent signalling between lung cancer cells and endothelial cells.…”

Cisplatin-resistant lung cancer cell–derived exosomes increase cisplatin resistance of recipient cells in exosomal miR-100–5p-dependent manner

“…When tumors grew to 150-200 mm 3 , nude mice were administered with an intraperitoneal injection of DDP, 4 mg/kg, twice a week. At the same time, exosomes extracted with ultracentrifugation from the culture medium were directly injected into the implanted tumors at the dose of 100 μg per mouse every 3 days for 7 times.…”

Emerging Role of Exosomes in the Joint Diseases

“…MiRNA is commonly carried by exosomes and miRNA mimics are easily loaded into exosomes [49]. In many other fields, genetically engineered exosomes have been used, especially in the cancer therapy [47,[50][51][52]. Engineered exosomes in cancer therapy including drug-loading exosomes, surface-modifying exosomes, and contentmodifying exosomes [51] that may provide novel therapeutic strategies for joint diseases.…”