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Exosomal miR-99a-5p is elevated in sera of ovarian cancer patients and promotes cancer cell invasion by increasing fibronectin and vitronectin expression in neighboring peritoneal mesothelial cells.
BMC Cancer. 2018 Nov 05; 18(1):1065.BC

Abstract

BACKGROUND

microRNAs (miRNAs) stably exist in circulating blood and are encapsulated in extracellular vesicles such as exosomes. The aims of this study were to identify which exosomal miRNAs are highly produced from epithelial ovarian cancer (EOC) cells, to analyze whether serum miRNA can be used to discriminate patients with EOC from healthy volunteers, and to investigate the functional role of exosomal miRNAs in ovarian cancer progression.

METHODS

Exosomes were collected from the culture media of serous ovarian cancer cell lines, namely TYK-nu and HeyA8 cells. An exosomal miRNA microarray revealed that several miRNAs including miR-99a-5p were specifically elevated in EOC-derived exosomes. Expression levels of serum miR-99a-5p in 62 patients with EOC, 26 patients with benign ovarian tumors, and 20 healthy volunteers were determined by miRNA quantitative reverse transcription-polymerase chain reaction. To investigate the role of exosomal miR-99a-5p in peritoneal dissemination, neighboring human peritoneal mesothelial cells (HPMCs) were treated with EOC-derived exosomes and then expression levels of miR-99a-5p were examined. Furthermore, mimics of miR-99a-5p were transfected into HPMCs and the effect of miR-99a-5p on cancer invasion was analyzed using a 3D culture model. Proteomic analysis with the tandem mass tag method was performed on HPMCs transfected with miR-99a-5p and then potential target genes of miR-99a-5p were examined.

RESULTS

The serum miR-99a-5p levels were significantly increased in patients with EOC, compared with those in benign tumor patients and healthy volunteers (1.7-fold and 2.8-fold, respectively). A receiver operating characteristic curve analysis showed with a cut-off of 1.41 showed sensitivity and specificity of 0.85 and 0.75, respectively, for detecting EOC (area under the curve = 0.88). Serum miR-99a-5p expression levels were significantly decreased after EOC surgeries (1.8 to 1.3, p = 0.002), indicating that miR-99a-5p reflects tumor burden. Treatment with EOC-derived exosomes significantly increased miR-99a-5p expression in HPMCs. HPMCs transfected with miR-99a-5p promoted ovarian cancer invasion and exhibited increased expression levels of fibronectin and vitronectin.

CONCLUSIONS

Serum miR-99a-5p is significantly elevated in ovarian cancer patients. Exosomal miR-99a-5p from EOC cells promotes cell invasion by affecting HPMCs through fibronectin and vitronectin upregulation and may serve as a target for inhibiting ovarian cancer progression.

Links

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Authors+Show Affiliations

Yoshimura A
Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Sawada K
Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. daasawada@gyne.med.osaka-u.ac.jp.
Nakamura K
Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
Kinose Y
Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Nakatsuka E
Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Kobayashi M
Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Miyamoto M
Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Ishida K
Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Matsumoto Y
Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Kodama M
Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Hashimoto K
Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Mabuchi S
Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Kimura T
Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

MeSH

AdultAgedCell Line, TumorEpitheliumExosomesFemaleFibronectinsGene Expression Regulation, NeoplasticHealthy VolunteersHumansMicroRNAsMiddle AgedNeoplasm InvasivenessNeoplasmsOvarian NeoplasmsPeritoneumVitronectin

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30396333

Citation

Yoshimura, Akihiko, et al. "Exosomal miR-99a-5p Is Elevated in Sera of Ovarian Cancer Patients and Promotes Cancer Cell Invasion By Increasing Fibronectin and Vitronectin Expression in Neighboring Peritoneal Mesothelial Cells." BMC Cancer, vol. 18, no. 1, 2018, p. 1065.
Yoshimura A, Sawada K, Nakamura K, et al. Exosomal miR-99a-5p is elevated in sera of ovarian cancer patients and promotes cancer cell invasion by increasing fibronectin and vitronectin expression in neighboring peritoneal mesothelial cells. BMC Cancer. 2018;18(1):1065.
Yoshimura, A., Sawada, K., Nakamura, K., Kinose, Y., Nakatsuka, E., Kobayashi, M., Miyamoto, M., Ishida, K., Matsumoto, Y., Kodama, M., Hashimoto, K., Mabuchi, S., & Kimura, T. (2018). Exosomal miR-99a-5p is elevated in sera of ovarian cancer patients and promotes cancer cell invasion by increasing fibronectin and vitronectin expression in neighboring peritoneal mesothelial cells. BMC Cancer, 18(1), 1065. https://doi.org/10.1186/s12885-018-4974-5
Yoshimura A, et al. Exosomal miR-99a-5p Is Elevated in Sera of Ovarian Cancer Patients and Promotes Cancer Cell Invasion By Increasing Fibronectin and Vitronectin Expression in Neighboring Peritoneal Mesothelial Cells. BMC Cancer. 2018 Nov 5;18(1):1065. PubMed PMID: 30396333.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Exosomal miR-99a-5p is elevated in sera of ovarian cancer patients and promotes cancer cell invasion by increasing fibronectin and vitronectin expression in neighboring peritoneal mesothelial cells. AU - Yoshimura,Akihiko, AU - Sawada,Kenjiro, AU - Nakamura,Koji, AU - Kinose,Yasuto, AU - Nakatsuka,Erika, AU - Kobayashi,Masaki, AU - Miyamoto,Mayuko, AU - Ishida,Kyoso, AU - Matsumoto,Yuri, AU - Kodama,Michiko, AU - Hashimoto,Kae, AU - Mabuchi,Seiji, AU - Kimura,Tadashi, Y1 - 2018/11/05/ PY - 2018/04/04/received PY - 2018/10/19/accepted PY - 2018/11/7/entrez PY - 2018/11/7/pubmed PY - 2019/2/12/medline KW - Biomarker KW - Exosome KW - Fibronectin KW - Ovarian cancer KW - Vitronectin KW - microRNA SP - 1065 EP - 1065 JF - BMC cancer JO - BMC Cancer VL - 18 IS - 1 N2 - BACKGROUND: microRNAs (miRNAs) stably exist in circulating blood and are encapsulated in extracellular vesicles such as exosomes. The aims of this study were to identify which exosomal miRNAs are highly produced from epithelial ovarian cancer (EOC) cells, to analyze whether serum miRNA can be used to discriminate patients with EOC from healthy volunteers, and to investigate the functional role of exosomal miRNAs in ovarian cancer progression. METHODS: Exosomes were collected from the culture media of serous ovarian cancer cell lines, namely TYK-nu and HeyA8 cells. An exosomal miRNA microarray revealed that several miRNAs including miR-99a-5p were specifically elevated in EOC-derived exosomes. Expression levels of serum miR-99a-5p in 62 patients with EOC, 26 patients with benign ovarian tumors, and 20 healthy volunteers were determined by miRNA quantitative reverse transcription-polymerase chain reaction. To investigate the role of exosomal miR-99a-5p in peritoneal dissemination, neighboring human peritoneal mesothelial cells (HPMCs) were treated with EOC-derived exosomes and then expression levels of miR-99a-5p were examined. Furthermore, mimics of miR-99a-5p were transfected into HPMCs and the effect of miR-99a-5p on cancer invasion was analyzed using a 3D culture model. Proteomic analysis with the tandem mass tag method was performed on HPMCs transfected with miR-99a-5p and then potential target genes of miR-99a-5p were examined. RESULTS: The serum miR-99a-5p levels were significantly increased in patients with EOC, compared with those in benign tumor patients and healthy volunteers (1.7-fold and 2.8-fold, respectively). A receiver operating characteristic curve analysis showed with a cut-off of 1.41 showed sensitivity and specificity of 0.85 and 0.75, respectively, for detecting EOC (area under the curve = 0.88). Serum miR-99a-5p expression levels were significantly decreased after EOC surgeries (1.8 to 1.3, p = 0.002), indicating that miR-99a-5p reflects tumor burden. Treatment with EOC-derived exosomes significantly increased miR-99a-5p expression in HPMCs. HPMCs transfected with miR-99a-5p promoted ovarian cancer invasion and exhibited increased expression levels of fibronectin and vitronectin. CONCLUSIONS: Serum miR-99a-5p is significantly elevated in ovarian cancer patients. Exosomal miR-99a-5p from EOC cells promotes cell invasion by affecting HPMCs through fibronectin and vitronectin upregulation and may serve as a target for inhibiting ovarian cancer progression. SN - 1471-2407 UR - https://www.unboundmedicine.com/medline/citation/30396333/Exosomal_miR_99a_5p_is_elevated_in_sera_of_ovarian_cancer_patients_and_promotes_cancer_cell_invasion_by_increasing_fibronectin_and_vitronectin_expression_in_neighboring_peritoneal_mesothelial_cells_ DB - PRIME DP - Unbound Medicine ER -