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


METHODS
To 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.


RESULTS
In 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.


CONCLUSIONS
Collectively, 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.
['Jian|M|M|', 'Du|Q|Q|', 'Zhu|D|D|', 'Mao|Z|Z|', 'Wang|X|X|', 'Feng|Y|Y|', 'Xiao|Z|Z|', 'Wang|H|H|', 'Zhu|Y|Y|']
D000293:Adolescent D000328:Adult D000818:Animals D017209:Apoptosis D014408:Biomarkers, Tumor D001971:Bromocriptine D049109:Cell Proliferation D015536:Down-Regulation D019008:Drug Resistance, Neoplasm D005260:Female D015972:Gene Expression Regulation, Neoplastic D006727:Hormone Antagonists D006801:Humans D008297:Male D008819:Mice, Nude D035683:MicroRNAs D008875:Middle Aged D010911:Pituitary Neoplasms D011379:Prognosis D015175:Prolactinoma D014407:Tumor Cells, Cultured D000090324:Tumor Protein, Translationally-Controlled 1 D023041:Xenograft Model Antitumor Assays D055815:Young Adult
miR-145-5P Prolactinoma Bromocriptine TPT1 Resistance MMQ cell Apoptosis