Hypoxia‐induced tumor exosomes promote angiogenesis through miR‐1825/TSC2/mTOR axis in oral squamous cell carcinoma

Abstract

BackgroundOral squamous cell carcinoma (OSCC) is characterized by enhanced angiogenesis resulting in poor prognosis despite improvements in diagnostic/therapeutic techniques. Here, we aimed at investigating potential roles of miR‐1825 enclosed in OSCC‐derived exosomes on angiogenesis under hypoxic conditions.MethodsEffects of miR‐1825 mimic/inhibitor as well as hypoxia‐induced tumor derived exosomes on human umbilical vein endothelial cells (HUVECs) were evaluated using cell viability, migration/invasion, tube formation, and spheroid‐based 3D angiogenesis assays.ResultsHypoxic conditions caused significant increase in miR‐1825 levels in OSCC cells and hiTDEs. miR‐1825 alone and within hiTDEs promoted endothelial cell viability, migration, invasion, and angiogenic potential, which is reversed via inhibition of miR‐1825 expression. miR‐1825 within hiTDEs altered the angiogenesis potential of HUVEC cells via deregulation of TSC2/mTOR axis.ConclusionsWe showed that hypoxia led to OSCC‐derived exosome mediated transfer of miR‐1825 to HUVECs and enhanced angiogenesis in OSCC in vitro.

Tumor-derived hypoxic small extracellular vesicles promote endothelial cell migration and tube formation via ALS2/Rab5/β-catenin signaling

“…Increasing evidence indicates that extracellular vesicles (EVs) liberated by tumor cells induce endothelial cell events associated with angiogenesis (6)(7)(8)(9)(10)(11) and, most importantly, that these events are further increased under hypoxic conditions (12)(13)(14)(15). Specifically, EVs derived from hypoxic tumor cells, including multiple myeloma, oral squamous cell carcinoma, colorectal, leukemia, and lung cancer, among others, induce endothelial cell migration and angiogenesis in vitro, when compared with their counterpart released in normoxic conditions (15)(16)(17)(18)(19). The identity of cargo contained within hypoxic EVs and the consequences of such cargo in recipient endothelial cells remain to be elucidated.…”

“…In this context, EVs such as exosomes and microvesicles, which are smaller than 200 nm and defined as small EVs (sEVs) by the Minimal Information for Studies of Extracellular Vesicles (MISEV), play an important role in cell communication, because they can transport a plethora of cargo between cells, including proteins, nucleic acids, lipids and small molecules that converge in the activation of signaling pathways in recipient cells (20,21). In endothelial cells, tumor-derived EVs have been shown to activate different downstream signaling pathways associated with angiogenesis, including mTOR, ephrin reverse signaling, VEGF, and β-catenin (10,16,18,22). Intriguingly, the effects that hypoxia and other conditions of the tumor microenvironment have on EVs composition and EVs-dependent activation of such signaling pathways, remain poorly understood.…”

Tumor‐derived hypoxic small extracellular vesicles promote endothelial cell migration and tube formation via ALS2/Rab5/β‐catenin signaling

“…Increasing evidence indicates that extracellular vesicles (EVs) liberated by tumor cells induce endothelial cell events associated with angiogenesis 6–11 and, most importantly, that these events are further increased under hypoxic conditions 12–15 . Specifically, EVs derived from hypoxic tumor cells, including multiple myeloma, oral squamous cell carcinoma, colorectal, leukemia, and lung cancer, among others, induce endothelial cell migration and angiogenesis in vitro, when compared with their counterpart released in normoxic conditions 15–19 . The identity of cargo contained within hypoxic EVs and the consequences of such cargo in recipient endothelial cells remain to be elucidated.…”

“…In this context, EVs such as exosomes and microvesicles, which are smaller than 200 nm and defined as small EVs (sEVs) by the minimal information for studies of extracellular vesicles (MISEV), play an important role in cell communication because they can transport a plethora of cargo between cells, including proteins, nucleic acids, lipids, and small molecules that converge in the activation of signaling pathways in recipient cells 20,21 . In endothelial cells, tumor‐derived EVs have been shown to activate different downstream signaling pathways associated with angiogenesis, including mTOR, ephrin reverse signaling, VEGF, and β‐catenin 10,16,18,22 . Intriguingly, the effects that hypoxia and other conditions of the tumor microenvironment have on EVs composition and EVs‐dependent activation of such signaling pathways remain poorly understood.…”

Oncogenic miR‐1825 promotes head and neck carcinogenesis via targeting FREM1

“…Furthermore, 20q11.21 recurrent gain of function abnormality in human embryonic stem cells resulted in the acquisition of a gene‐expression signature enriched for cancer‐associated oncogenes 16,17 . These findings ascribe an oncogenic function with the power to induce stem cell characteristics to miR‐1825, which has been demonstrated to be a tumor inducer in several malignancies like cervical, gastric, pancreas, lung, and prostate tumors 16,18–22 . In recent years, innumerable research focused on understanding the functions of microRNAs and their targets as well as identification of their interaction with tumor suppressors or oncogenes during carcinogenic processes, however, the functions of miR‐1825, particularly in HNSCC, has not still been illuminated and further studies are needed.…”