title: 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 HIF-1α and HIF-2α-dependent manner. Given that exosomes have been shown to transport miRNAs to alter cellular functions, we performed miRNA sequencing of normoxic and hypoxic OSCC-derived 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-1α and HIF-2α-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-1α/HIF-2α 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. Cancer Res; 76(7); 1770-80. ©2016 AACR.
authors.affiliation: Department of Head and Neck Surgery, Sichuan Cancer Hospital & Institute, Sichuan, P.R. China. Department of Stomatology, Sichuan Cancer Hospital & Institute, Sichuan, P.R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Head and Neck Surgery, Sichuan Cancer Hospital & Institute, Sichuan, P.R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Head and Neck Surgery, Sichuan Cancer Hospital & Institute, Sichuan, P.R. China.
authors.forename: Shaoxin
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Head and Neck Surgery, Sichuan Cancer Hospital & Institute, Sichuan, P.R. China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Sichuan, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Head and Neck Surgery, Sichuan Cancer Hospital & Institute, Sichuan, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Head and Neck Surgery, Sichuan Cancer Hospital & Institute, Sichuan, P.R. China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Head and Neck Surgery, Sichuan Cancer Hospital & Institute, Sichuan, P.R. China.
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Head and Neck Surgery, Sichuan Cancer Hospital & Institute, Sichuan, P.R. China. Department of Stomatology, Sichuan Cancer Hospital & Institute, Sichuan, P.R. China.
authors.forename: Kun
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Head and Neck Surgery, Sichuan Cancer Hospital & Institute, Sichuan, P.R. China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Head and Neck Surgery, Sichuan Cancer Hospital & Institute, Sichuan, P.R. China. headnecksurg@foxmail.com.
authors.forename: Guiquan
authors.initials: G
authors.lastname: Zhu
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering