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OBJECTIVE: AlkB homolog 5 (ALKBH5) has been proven to be closely related to tumors. However, the role and molecular mechanism of ALKBH5 in neuroblastomas have rarely been reported. METHODS: The potential functional single-nucleotide polymorphisms (SNPs) in ALKBH5 were identified by National Center for Biotechnology Information (NCBI) dbSNP screening and SNPinfo software. TaqMan probes were used for genotyping. A multiple logistic regression model was used to evaluate the effects of different SNP loci on the risk of neuroblastoma. The expression of ALKBH5 in neuroblastoma was evaluated by Western blotting and immunohistochemistry (IHC). Cell counting kit-8 (CCK-8), plate colony formation and 5-ethynyl-2’-deoxyuridine (EdU) incorporation assays were used to evaluate cell proliferation. Wound healing and Transwell assays were used to compare cell migration and invasion. Thermodynamic modelling was performed to predict the ability of miRNAs to bind to ALKBH5 with the rs8400 G/A polymorphism. RNA sequencing, N6-methyladenosine (m(6)A) sequencing, m(6)A methylated RNA immunoprecipitation (MeRIP) and a luciferase assay were used to identify the targeting effect of ALKBH5 on SPP1. RESULTS: ALKBH5 was highly expressed in neuroblastoma. Knocking down ALKBH5 inhibited the proliferation, migration and invasion of cancer cells. miR-186-3p negatively regulates the expression of ALKBH5, and this ability is affected by the rs8400 polymorphism. When the G nucleotide was mutated to A, the ability of miR-186-3p to bind to the 3’-UTR of ALKBH5 decreased, resulting in upregulation of ALKBH5. SPP1 is the downstream target gene of the ALKBH5 oncogene. Knocking down SPP1 partially restored the inhibitory effect of ALKBH5 downregulation on neuroblastoma. Downregulation of ALKBH5 can improve the therapeutic efficacy of carboplatin and etoposide in neuroblastoma. CONCLUSIONS: We first found that the rs8400 G>A polymorphism in the m(6)A demethylase-encoding gene ALKBH5 increases neuroblastoma susceptibility and determines the related mechanisms. The aberrant regulation of ALKBH5 by miR-186-3p caused by this genetic variation in ALKBH5 promotes the occurrence and development of neuroblastoma through the ALKBH5-SPP1 axis.

Supplemental Material, sj-pdf-1-ccx-10.1177_10732748211040009 for Association Between LIN28A Gene Polymorphisms and Glioma Susceptibility in Chinese Children by Huiqin Guo, Yuxiang Liao, Ao Lin, Huiran Lin, Xiaokai Huang, Jichen Ruan, Li Yuan and Zhenjian Zhuo in Cancer Control

Additional file 1: Table S1. Frequency distribution of selected variables in Wilms tumor patients and cancer-free controls.

Yi Zheng,* Zhenjian Zhuo,* Xiaoli Xie, Lifeng Lu, Qiuming He, Wei Zhong Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei ZhongDepartment of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, 9 Jinsui Road, Guangzhou 510623, Guangdong, People’s Republic of ChinaTel/Fax +86-18902268667Email zhongwei_gwcmc@163.comBackground: Hirschsprung disease (HSCR) is a congenital disease that arises from defective intestinal neural system. LncRNA HOTTIP is a critical gene in various diseases, including HSCR. No epidemiological studies have explored the correlation between lncRNA HOTTIP single nucleotide polymorphisms (SNPs) and HSCR risk. We here lead as a pioneer to explore whether SNPs in lncRNA HOTTIP impact the risk of HSCR and HSCR subtypes in an unrelated Chinese population.Methods: We used the TaqMan method to genotype rs3807598 C>G of the lncRNA HOTTIP gene using 1470 HSCR cases and 1473 healthy controls. Of them, 1441 cases and 1434 controls were successfully genotyped. We adopted odds ratios (ORs) and 95% confidence intervals (CIs) to quantify the relationship.Results: We got an unexpected outcome that lncRNA HOTTIP SNP rs3807598 C>G could not modify the risk of HSCR (CG vs. CC: adjusted OR=0.89, 95% CI=0.74– 1.07; GG vs. CC: adjusted OR=1.10, 95% CI=0.89– 1.37; GG/CG vs CC: adjusted OR=0.95, 95% CI=0.80– 1.13; and GG vs. CC/CG: adjusted OR=1.19, 95% CI=0.99– 1.43). What’s more, risk effect of lncRNA HOTTIP rs3807598 C>G is still not obvious in stratification analysis by HSCR subtype.Conclusion: Our studies did not provide statistical evidence of a correlation between lncRNA HOTTIP SNP rs3807598 C>G and susceptibility of HSCR in the Chinese population that is being studied. Further validation study with a larger sample size covering multi-ethnic groups is warranted.Keywords: Hirschsprung disease, HOTTIP, polymorphism, susceptibility, Chinese

Li Li, 1,* Zhenjian Zhuo, 2,* Zhen Yang, 1, 3,* Jinhong Zhu, 4 Xiaoli He, 1 Zhonghua Yang, 5 Jiao Zhang, 6 Yijuan Xin, 7 Jing He, 2 Tiesong Zhang 1 1Kunming Key Laboratory of Children’s Infection and Immunity, Yunnan Key Laboratory of Children’s Major Disease Research, Yunnan Institute of Pediatrics Research, Kunming Children’s Hospital, Kunming, Yunnan, 650228, People’s Republic of China; 2Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, People’s Republic of China; 3Department of Oncology, Kunming Children’s Hospital, Kunming 650228, Yunnan, People’s Republic of China; 4Department of Clinical Laboratory, Biobank, Harbin Medical University Cancer Hospital, Harbin 150040, Heilongjiang, People’s Republic of China; 5Department of Pediatric Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, People’s Republic of China; 6Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, People’s Republic of China; 7Clinical Laboratory Medicine Center of PLA, Xijing Hospital, Air Force Medical University, Xi’an 710032, Shaanxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tiesong ZhangKunming Key Laboratory of Children’s Infection and Immunity, Yunnan Key Laboratory of Children’s Major Disease Research, Yunnan Institute of Pediatrics Research, Kunming Children’s Hospital, 288 Qianxing Road, Kunming 650228, Yunnan, People’s Republic of ChinaTel/Fax +86 – 8713169969Email zts68420@sina.comJing HeDepartment of Pediatric, Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, 9 Jinsui Road, Guangzhou 510623, Guangdong, People’s Republic of ChinaTel/Fax +86 2038076560Email hejing198374@gmail.comBackground: Hepatoblastoma is a rare disease. Its etiology remains obscure. No epidemiological reports have assessed the relationship of High Mobility Group A2 (HMGA2) single nucleotide polymorphisms (SNPs) with hepatoblastoma risk. This case-control study leads as a pioneer to explore whether HMGA2 SNPs (rs6581658 A>G, rs8756 A>C, rs968697 T>C) could impact hepatoblastoma risk.Methods: We acquired samples from 275 hepatoblastoma cases and 1018 controls who visited one of five independent hospitals located in the different regions of China. The genotyping of HMGA2 SNPs was implemented using the PCR-based TaqMan method, and the risk estimates were quantified by odds ratios (ORs) and 95% confidence intervals (CIs).Results: In the main analysis, we identified that rs968697 T>C polymorphism was significantly related to hepatoblastoma risk in the additive model (adjusted OR=0.73, 95% CI=0.54– 0.98, P=0.035). Notably, participants carrying 2– 3 favorable genotypes had reduced hepatoblastoma risk (adjusted OR=0.71, 95% CI=0.52– 0.96, P=0.028) in contrast to those carrying 0– 1 favorable genotypes. Furthermore, stratification analysis revealed a significant correlation between rs968697 TC/CC and hepatoblastoma risk formales and clinical stage I+II. The existence of 2– 3 protective genotypes was correlated with decreased hepatoblastoma susceptibility in children ≥ 17 months old, males, and clinical stage I+II cases, when compared to 0– 1 protective genotype.Conclusion: To summarize, these results indicated that the HMGA2 gene SNPs exert a weak influence on hepatoblastoma susceptibility. Further validation of the current conclusion with a larger sample size covering multi-ethnic groups is warranted.Keywords: hepatoblastoma, HMGA2, polymorphism, susceptibility