MicroRNA-181a-mediated downregulation of AC9 protein decreases intracellular cAMP level and inhibits ATRA-induced APL cell differentiation.
AC9 is one of the adenylate cyclase (AC) isoforms, which catalyze the conversion of ATP to cAMP, an important second messenger. We previously found that the integration of cAMP/PKA pathway with nuclear receptor-mediated signaling was required during all-trans retinoic acid (ATRA)-induced maturation of acute promyelocytic leukemia (APL) cells. Here we showed that AC9 could affect intracellular cAMP level and enhance the trans-activity of retinoic acid receptor. Knockdown of AC9 in APL cell line NB4 could obviously inhibit ATRA-induced differentiation. We also demonstrated that miR-181a could decrease AC9 expression by targeting 3'UTR of AC9 mRNA, finally controlling the production of intracellular cAMP. The expression of miR-181a itself could be inhibited by CEBPα, probably accounting for the differential expression of miR-181a in NB4 and ATRA-resistant NB4-R1 cells. Moreover, we found that AC9 expression was relatively lower in newly diagnosed or relapsed APL patients than in both complete remission and non-leukemia cases, closely correlating with the leukemogenesis of APL. Taken together, our studies revealed for the first time the importance of miR-181a-mediated AC9 downregulation in APL. We also suggested the potential value of AC9 as a biomarker in the clinical diagnosis and treatment of leukemia.
State Key Laboratory of Medical Genomics, Faculty of Medical Laboratory Science and Shanghai Institute of Hematology, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
L K
LK
Zhuang
State Key Laboratory of Medical Genomics, Faculty of Medical Laboratory Science and Shanghai Institute of Hematology, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
G P
GP
Xu
State Key Laboratory of Medical Genomics, Faculty of Medical Laboratory Science and Shanghai Institute of Hematology, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
X R
XR
Pan
State Key Laboratory of Medical Genomics, Faculty of Medical Laboratory Science and Shanghai Institute of Hematology, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Y J
YJ
Lou
State Key Laboratory of Medical Genomics, Faculty of Medical Laboratory Science and Shanghai Institute of Hematology, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Q P
QP
Zou
State Key Laboratory of Medical Genomics, Faculty of Medical Laboratory Science and Shanghai Institute of Hematology, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
D
D
Xia
State Key Laboratory of Medical Genomics, Faculty of Medical Laboratory Science and Shanghai Institute of Hematology, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
W W
WW
Yan
State Key Laboratory of Medical Genomics, Faculty of Medical Laboratory Science and Shanghai Institute of Hematology, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Y T
YT
Zhang
State Key Laboratory of Medical Genomics, Faculty of Medical Laboratory Science and Shanghai Institute of Hematology, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
P M
PM
Jia
State Key Laboratory of Medical Genomics, Faculty of Medical Laboratory Science and Shanghai Institute of Hematology, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J H
JH
Tong
D020413:3' Untranslated Regions / Q000235:genetics; D000262:Adenylyl Cyclases / Q000235:genetics* / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*
D020413:3' Untranslated Regions; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C413923:adenylate cyclase 9