MicroRNA-181a-mediated downregulation of AC9 protein decreases intracellular cAMP level and inhibits ATRA-induced APL cell differentiation

Abstract

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.

The epithelial-to-mesenchymal transition activator ZEB1 initiates a prometastatic competing endogenous RNA network

“…Two of the 4 genes (ADCY9 and ONECUT2) were expressed at significantly higher levels in mesenchymal than in epithelial KP cell lines (Supplemental Figure 7A). Activities of reporters driven by the 3′-UTRs of ADCY9 or ONECUT2 were lower in miR-181b-transfected 344SQ cells than in negative control transfectants, and loss of the miR-181b-binding sites in the ADCY9 and ONECUT2 3′-UTRs ablated the miR-181b-induced suppression of both reporters (Figure 5B), which is consistent with a prior report on ADCY9 (27).…”

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

“…sAC inhibition could be a strategy to achieve the elusive goal of a male contraceptive (Roth and Amory, 2016), but the proposed broad expression and function of sAC beyond the male reproductive system (Steegborn, 2014;Levin and Buck, 2015) would probably result in many side effects. It remains to be determined whether the recently introduced microRNA approach (Zhuang et al, 2014) constitutes a clinically useful approach to target mACs.…”

“…Reports for AC9 knockout phenotypes are lacking. However, microRNAs targeting AC9 (miR-142-3p, miR-181a, and miR-181b) point to a decrease in AC9 expression in sepsis (Risoe et al, 2011) and potential roles in regulating cell proliferation in cervical cancer cells and differentiation of promyelocytic leukemia Zhuang et al, 2014). Several reports suggest roles for AC9 in immune function.…”

“…miR-142-3p restricts cAMP production in regulatory T cells (Huang et al, 2009), whereas knockdown or overexpression of AC9 in human neutrophils alters chemotaxis (Liu et al, 2010). In newly diagnosed patients with acute myelogenous leukemia and in those with a disease relapse, AC9 expression is lower than in cases of remission (Zhuang et al, 2014), suggesting that AC9 could be used as biomarker for diagnosis and clinical course of certain leukemia forms. In cervical carcinoma cells, miR-181b downregulates AC9 and promotes proliferation , pointing to a more general role of AC9 in cancer biology.…”

MicroRNA‑143‑3p suppresses cell growth and invasion in laryngeal squamous cell carcinoma via targeting the k‑Ras/Raf/MEK/ERK signaling pathway

“…MicroRNAs (miRNAs or miRs) are a class of endogenous, non-coding, small, single-stranded RNAs consisting of 18-25 nucleotides, which mediate the post-transcriptional regulation of target genes via inhibiting translation or inducing RNA degradation (5,6). Increasing evidence has demonstrated that miRNAs can function as oncogenes or tumor suppressor genes in cancer, and can suppress cell signaling pathways to modulate various cancer cell processes, including cell proliferation, apoptosis, differentiation and migration (7,8). The ectopic expression of miRNAs is key in the development of LSCC (9), and certain miRNAs directly modulate the apoptosis, proliferation and invasion of LSCC cells (3,10).…”