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Tumor suppressor miR-145-5p sensitizes prolactinoma to bromocriptine by downregulating TPT1

Authors
  • Jian, M.1
  • Du, Q.1
  • Zhu, D.2
  • Mao, Z.2
  • Wang, X.1
  • Feng, Y.1
  • Xiao, Z.2
  • Wang, H.2
  • Zhu, Y.1
  • 1 Medical School of Sun Yat-sen University, Department of Histology and Embryology, No. 74, Zhongshan Road 2, Guangzhou, Guangdong, 510080, China , Guangzhou (China)
  • 2 The First Affiliated Hospital of Sun Yat-sen University, Department of Neurosurgery and Pituitary Tumor Center, No. 58, Zhongshan Road 2, Guangzhou, Guangdong, 510080, China , Guangzhou (China)
Type
Published Article
Journal
Journal of Endocrinological Investigation
Publisher
Springer-Verlag
Publication Date
Oct 28, 2018
Volume
42
Issue
6
Pages
639–652
Identifiers
DOI: 10.1007/s40618-018-0963-4
Source
Springer Nature
Keywords
License
Yellow

Abstract

PurposeProlactinoma is the most commonly seen secretory tumor of pituitary glands, which accounts for approximately up to 40% of total pituitary adenomas. Due to its high drug resistance, dopamine agonist, such as bromocriptine, has limited effect on the treatment of patients with prolactinoma. Recent discoveries have revealed that multiple miRNAs were involved in regulating drug resistance. In this research, we explored the relationship between miR-145-5p expression as well as bromocriptine sensitivity both in vitro and in vivo.MethodsTo study the role of miR-145-5p in drug resistance of prolactinoma, the expression levels of miR-145-5p in bromocriptine-resistant prolactinoma cell line MMQ/BRC and its parental cell line MMQ cells, 24 bromocriptine-resistant as well as eight sensitive clinical samples were measured by qRT-PCR. Moreover, CCK8, flow cytometry and immunofluorescence were performed to identify the biological characteristics of MMQ/BRC and MMQ. TPT1 was predicted as a direct target gene of miR-145-5p by bioinformatic methods. In addition, qRT-PCR, western blot and immunohistochemistry were used to detect the expression level of TPT1 in clinical specimens and cell lines. Xenograft mouse model was constructed to analyze whether miR-145-5p could reverse bromocriptine resistance in prolactinoma in vivo.ResultsIn our study, bromocriptine-resistant prolactinoma clinical samples and cell line had decreased miR-145-5p levels and expressed high levels of TPT1 compared with their sensitive counterparts. Bioinformatic methods and our preliminary dual luciferase reporter assay were utilized to elucidate that TPT1 was a direct target gene of miR-145-5p. Furthermore, introducing miR-145-5p mimic into MMQ cells led to a decrease of IC50 along with upregulation of TPT1; nevertheless, transfecting the corresponding inhibitor into MMQ cells resulted in an upregulation of IC50 as well as reduction of TPT1.ConclusionsCollectively, our findings elucidated the role of miR-145-5p as an important regulator of drug resistance in prolactinoma by controlling TPT1, and implicated the potential application of miR-145-5p in cancer therapy as well.

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