Oncotarget | https://doi.org/10.18632/oncotarget.13656 Lei Peng, Guanglin Chen, Zhongxian Zhu, Ziyang Shen, Chunxia Du, Rujin Zang, Yang Su, Hua Xie, Hongxing Li, Xiaoqun Xu, Yankai Xia, Weibing Tang Circular RNA ZNF609 functions as a competitive endogenous RNA to regulate AKT3 expression by sponging miR-150-5p in Hirschsprung’s disease

BACKGROUND This United States (U.S.) population study aimed to compare the incidence of neuroblastoma and outcomes in children, adolescents, and adults using the Surveillance, Epidemiology, and End Results (SEER) program database. MATERIAL AND METHODS Patients with neuroblastoma were identified in the SEER database from 1975 to 2013. According to the age at diagnosis, patients were divided into "Children" (≤14 years old) and "Adolescents/Adults" group (>14 years old). Then, comparisons in basic characteristics, incidence rates (IRs) and long-term survival outcomes between patients in 2 groups were made. RESULTS A total of 4280 patients were identified, including 3998 children and 282 adolescent/adult patients. Adolescent/adult patients were more likely to have localized diseases than children and to be diagnosed with ganglioneuroblastoma (all P<0.05). The IR of neuroblastoma presented with upward and downward trends in children and adolescent/adult populations, respectively. Adolescents/adults had worse overall survival (OS) than children despite the earlier tumor stage. Lastly, multivariate Cox proportional hazards analyses showed that tumor stage, histology, sequence of primary malignancy, primary site, the administration of surgery, and treatment era were prognostic factors for children, and sequence of primary malignancy, primary site, undergoing surgery, and treatment era were tightly related to OS in adolescent/adult patients. CONCLUSIONS Analysis of the SEER program database between 1975 to 2013 showed that in the U.S., the incidence of neuroblastoma in children increased, but the incidence decreased in adolescents and adults. There was a trend for improved overall survival in all age groups despite the increased stage at presentation in children.

Objectives: Emerged evidence demonstrates that long non‐coding RNAs (lncRNAs) may play quintessential regulatory roles in the cellular processes, tumourigenesis and the development of disease. Though focally amplified lncRNA on chromosome 1 (FAL1) has been identified to have crucial functions in many diseases, its biological mechanism in the development of Hirschsprung's disease (HSCR) still remains unknown.Materials and methods: The expression levels of FAL1 in HSCR aganglionic tissues and matched normal specimens were detected by quantitative real‐time PCR (qRT‐PCR). Cell proliferation and migration were detected by Cell Counting Kit‐8 (CCK‐8) assay, Ethynyl‐deoxyuridine (EdU) assay and transwell assay relatively. Cell cycle and apoptosis were assessed using flow cytometer analysis. Moreover, the novel targets of FAL1 were confirmed with the help of bioinformatics analysis and dual‐luciferase reporter assay. Western blot assay as well as RNA immunoprecipitation (RIP) assay was conducted to investigate the potential mechanism.Results: FAL1 expression was markedly down‐regulated in HSCR aganglionic tissues and decreased FAL1 expression was associated with the diagnosis of HSCR. Cell functional analyses indicated that FAL1 overexpressing notably promoted cell proliferation and migration, while down‐regulation of FAL1 suppressed cell proliferation and migration. Additionally, Flow cytometry assay demonstrated that knockdown of FAL1 induced markedly cell cycle stalled in the G0/G1 phase. Furthermore, FAL1 could positively regulate AKT1 expression by competitively binding to miR‐637.Conclusions: These results illuminated that FAL1 may work as a ceRNA to modulate AKT1 expression via competitively binding to miR‐637 in HSCR, suggesting that it may be clinically valuable as a biomarker of HSCR.

Hirschsprung disease (HSCR) is a birth defect with an approximate incidence of 1/5,000 live births, and up to one-third of HSCR patients develop Hirschsprung-associated enterocolitis (HAEC), the leading cause of HSCR-related death. Very little is known about the pathogenesis, prevention, and early diagnosis of HAEC. Here, we used a prospective study to investigate the enteric microbiome composition at the time of surgery as a predictor for developing postoperative HAEC. We identified a microbiome signature containing 21 operational taxonomic units (OTUs) that can potentially predict postoperative HAEC with ~85% accuracy. Furthermore, we identified exclusive breastfeeding as a novel protective factor for total HAEC (i.e., preoperative and postoperative HAEC combined). In addition, we discovered that breastfeeding was associated with a lowered risk for HAEC potentially mediated by modulating the gut microbiome composition characterized by a lower abundance of Gram-negative bacteria and lower LPS concentrations. In conclusion, modulating the gut microbiome by encouraging breastfeeding might prevent HAEC progression in HSCR patients.

Hirschsprung disease (HSCR) is a congenital disorder caused by the defective function of the embryonic enteric neural crest. The impaired migration of embryonic enteric neural crest plays an important role in the pathogenesis of this disease. Recent studies showed that the ARP2/3 complex and RAC isoforms had effects on actin cytoskeleton remodelling, which contributes to migration. Moreover, some regulatory relationships were identified between ARP2/3 complex and RAC isoforms. Although microRNAs (miRNAs) have been known to modulate target gene expression on the post‐transcriptional level, little is known about the regulation among miRNAs, ARP2/3 complex and RAC isoforms. Here, we report that down‐regulation of ARP2 and ARP3, two main subunits of ARP2/3 complex, suppressed migration and proliferation in 293T and SH‐SY5Y cell lines via the inhibition of RAC1 and RAC2. Meanwhile, as the target genes, ARP2 and ARP3 are reduced by increased miR‐24‐1* and let‐7a*, respectively, in 70 HSCR samples as compared with 74 normal controls. Co‐immunoprecipitation showed that aberrant reduction in ARP2 and ARP3 could weaken the function of ARP2/3 complex. Our study demonstrates that the miR‐24‐1*/let‐7a*‐ARP2/3 complex‐RAC isoforms pathway may represent a novel pathogenic mechanism for HSCR.