KLF5 and MYC modulated LINC00346 contributes to gastric cancer progression through acting as a competing endogeous RNA and indicates poor outcome

• Published in: Cell death and differentiation Vol. 26; no. 11; pp. 2179 - 2193
• Main Authors: Xu, Tong-peng, Ma, Pei, Wang, Wen-yu, Shuai, You, Wang, Yan-fen, Yu, Tao, Xia, Rui, Shu, Yong-qian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2019; Nature Publishing Group
• Subjects: 13/1; 13/31; 13/44; 13/51; 13/89; 38/47; 38/61; 38/71; 38/90; 38/91; 59/5; 631/67/395; 631/80/79/2027; 64/60; 82/51; 82/80; Apoptosis; Argonaute 2 protein; Argonaute Proteins - genetics; Axl protein; Biochemistry; Biomedical and Life Sciences; CD44 antigen; Cell Biology; Cell cycle; Cell Cycle Analysis; Cell Line, Tumor; Cell migration; Cell Proliferation - genetics; Cell Transformation, Neoplastic - genetics; Disease Progression; Gastric cancer; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Gene set enrichment analysis; Humans; Hyaluronan Receptors - antagonists & inhibitors; Kruppel-Like Transcription Factors - genetics; Life Sciences; MicroRNAs - genetics; Myc protein; Next-generation sequencing; Notch1 protein; Phenotypes; Promoter Regions, Genetic - genetics; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins c-myc - genetics; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor, Notch1 - antagonists & inhibitors; Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; Stem Cells; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Transcription factors; Tumorigenesis
• ISSN: 1350-9047; 1476-5403; 1476-5403
• DOI: 10.1038/s41418-018-0236-y

It was found in this study that long intergenic non-protein coding RNA 346 (LINC00346) was an lncRNA aberrantly expressed in gastric cancer (GC) based on multiple Gene Expression Omnibus (GEO) databases of GC cohorts. The LINC00346 gene was recurrently amplified and upregulated in GC, and its expression was positively correlated with poor pathologic stage, large tumor size, and poor prognosis. In addition, the oncogenic transcription factors KLF5 and MYC could bind to the LINC00346 promoter and enhance its expression. Gene Set Enrichment Analysis (GSEA) in the GEO datasets revealed that cell cycle and focal adhesion genes were enriched in patients with high LINC00346 expression. In vitro and in vivo assays of LINC00346 alterations revealed a complex integrated phenotype affecting cell growth, migration and invasion. Strikingly, high-throughput sequencing analysis after LINC00346 alterations highlighted alterations in cell cycle and focal adhesion pathways in GC cells. Mechanistically, argonaute 2 (Ago2) was recruited by LINC00346, which functioned as a molecular sponge for miR-34a-5p by antagonizing its ability to repress CD44, NOTCH1, and AXL protein translation. Taken together, our findings support a model in which the KLF5, MYC/LINC00346/miR-34a-5p cross-talk served as critical effectors in GC tumorigenesis and progression, suggesting a new therapeutic direction in the treatment of GC.