MiR-6872 host gene SEMA3B and its antisense lncRNA SEMA3B-AS1 function synergistically to suppress gastric cardia adenocarcinoma progression

• Published in: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 2019-07, Vol.22 (4), p.705-722
• Main Authors: Guo, Wei, Liang, Xiaoliang, Liu, Lei, Guo, Yanli, Shen, Supeng, Liang, Jia, Dong, Zhiming
• Format: Article
• Language: English
• Subjects: Abdominal Surgery; Adenocarcinoma; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adult; Aged; Antisense therapy; Biomarkers, Tumor - genetics; Cancer Research; Carcinoma; Cardia - metabolism; Cardia - pathology; Cell migration; Cell Movement; Cell Proliferation; Chromatin; Chromosome 5; CpG islands; Disease Progression; DNA Methylation; Drug Synergism; Female; Follow-Up Studies; Gastric cancer; Gastroenterology; Gene Expression Regulation, Neoplastic; Humans; Immunoprecipitation; Male; Medicine; Medicine & Public Health; Membrane Glycoproteins - genetics; MicroRNAs - genetics; Middle Aged; Oncology; Original Article; Prognosis; Ribonucleic acid; RNA; RNA, Antisense - genetics; RNA, Long Noncoding - genetics; Semaphorins - genetics; Sp1 protein; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Surgical Oncology; Survival Rate; Tumor Cells, Cultured; Tumorigenesis
• ISSN: 1436-3291; 1436-3305
• DOI: 10.1007/s10120-019-00924-0

Background Semaphorin 3B (SEMA3B) is frequently inactivated in several carcinomas. However, as the host gene of miR-6872, the roles of SEMA3B, antisense lncRNA SEMA3B-AS1, and miR-6872 in gastric cardia adenocarcinoma (GCA) tumorigenesis have not been clarified. Methods The expression levels of SEMA3B, SEMA3B-AS1, and miR-6872 were respectively detected by qRT-PCR, western blot, or immunohistochemical staining assays. The methylation status was determined by BGS and BS-MSP methods. In vitro assays were preformed to explore the biological effects of SEMA3B, SEMA3B-AS1, and miR-6872-5p in gastric cancer cells. Chromatin immunoprecipitation assay was used to detect the binding of protein to DNA. The interaction of SEMA3B-AS1 with MLL4 was identified by RNA immunoprecipitation and RNA pull-down assays. Results Frequent downregulation of SEMA3B, SEMA3B-AS1, and miR-6872 was detected in GCA tissues and gastric cancer cells. Aberrant hypermethylation of the promoter region was more tumor specific and was negatively correlated with the expression level of SEMA3B, SEMA3B-AS1, and miR-6872-5p. Transcription factor Sp1 activated SEMA3B or SEMA3B-AS1 transcription and CpG sites hypermethylation within promoter region eliminated Sp1 binding ability. Overexpression of SEMA3B and SEMA3B-AS1 inhibited gastric cancer cell proliferation, migration, and invasion in vitro. SEMA3B-AS1 induced the expression of SEMA3B by interacting with MLL4. ZNF143 might be the target gene of miR-6872-5p and miR-6872-5p functioning synergistically with SEMA3B to suppress cell invasion. Furthermore, SEMA3B, SEMA3B-AS1, and miR-6872-5p expression levels were associated with GCA patients’ survival. Conclusions SEMA3B, SEMA3B-AS1, and miR-6872 may act as tumor suppressors and may serve as potential targets for antitumor therapy.