CircOMA1 Promotes Resistance in Prolactinoma by Regulating Dopamine Receptors
10.13471/j.cnki.j.sun.yat-sen.univ（med.sci）.2022.0306
- VernacularTitle:CircOMA1调控多巴胺受体促进泌乳素瘤耐药性
- Author:
Yi-yin ZHANG
1
;
Na WU
1
;
Xue-li LI
1
;
Bin HU
2
;
Xin-yi WU
2
;
Yong-hong ZHU
1
Author Information
1. Zhongshan School of Medicine， Sun Yat-sen University， Guangzhou 510080， China
2. Department of Neurosurgery， The First Affiliated Hospital of Sun Yat-sen University， Guangzhou 510080， China
- Publication Type:Journal Article
- Keywords:
circOMA1;
prolactinoma;
drug resistance;
miR-145-5p
- From:
Journal of Sun Yat-sen University(Medical Sciences)
2022;43(3):381-391
- CountryChina
- Language:Chinese
-
Abstract:
ObjectiveTo investigate whether hsa_circ_0002316 （circOMA1） is involved in drug resistance in prolactinoma and its mechanism. MethodsRT-qPCR was used to dectect the expression of circOMA1 in clinical prolactinoma specimens including 5 dopamine receptor agonists （DAs）-sensitive prolactinomas and 12 DAs-resistant prolactinomas. MMQ cell lines with stable expression of exogenous circOMA1 were constructed by lentivirus vector infection for in vitro experiment， and were divided into MMQ NC group and MMQ OMA1 group. Xenograft tumor models in nude mice were established for in vivo experiment， and were divided into MMQ NC+cabergoline （CAB） group， MMQ NC+bromocriptine （BRC） group， MMQ OMA1+CAB group and MMQ OMA1+BRC group. CCK8， Western blot and ELISA were performed to detect the effects of circOMA1 on cell proliferation and secretion of prolactin （PRL） in drug resistance mechanism. Western blot， ELISA and immunohistochemistry were used to examine the effect of circOMA1 on dopamine receptor expression. The mechanism of circOMA1 regulating dopamine receptor was explored by TargetScan， CircInteractome and microRNA-145-5p （miR-145-5p） minic remediation experiment. ResultsRT-qPCR showed that circOMA1 expression was increased in DAs-resistant prolactinomas （P < 0.01）. Compared with MMQ NC group， MMQ OMA1 group had lower DAs sensitivity and increased cell proliferation and prolactin secretion （P < 0.05） in vivo and in vitro. Western blot and immunohistochemical analysis showed that in MMQ OMA1 group， the expression of dopamine receptor type 2 （DRD2） was down-regulated， and the expression of dopamine receptor type 5 （DRD5）， the cyclic 3 'and 5' -adenosine monophosphine （cAMP） was up-regulated （P < 0.05）. In MMQ OMA1 group， miR-145-5p expression was down-regulated， kelch repeat sequence and BTB domain-containing protein 7 （KBTBD7） mRNA and protein expression was up-regulated （P < 0.05）. After transfected with miR-145-5p minic， MMQ OMA1 group exhibited down-regulated KBTBD7 expression and up-regulated DRD2 expression （P < 0.05）， which indicated that overexpression of miR-145-5p reversed the promoting effect of circOMA1 on KBTBD7. ConclusionCircOMA1 down-regulated DRD2 expression through miR-145-5p/KBTBD7 pathway to reduce the sensitivity of prolactinoma to DAs， and regulated the expression of dopamine receptors to activate the cAMP pathway and promote the synthesis and release of prolactin， thus promoting the drug resistance in prolactinoma.
