The chromosome 11q13.3 amplification associated lymph node metastasis is driven by miR-548k through modulating tumor microenvironment

Abstract

BackgroundThe prognosis for esophageal squamous cell carcinoma (ESCC) patients with lymph node metastasis (LNM) is still dismal. Elucidation of the LNM associated genomic alteration and underlying molecular mechanisms may provide clinical therapeutic strategies for ESCC treatment.MethodsJoint analysis of ESCC sequencing data were conducted to comprehensively survey SCNAs and identify driver genes which significantly associated with LNM. The roles of miR-548k in lymphangiogensis and lymphatic metastasis were validated both in vitro and in vivo. ESCC tissue and blood samples were analyzed for association between miR-548k expression and patient clinicopathological features and prognosis and diagnosis.ResultsIn the pooled cohort of 314 ESCC patients, we found 76 significant focused regions including 43 amplifications and 33 deletions. Clinical implication analysis revealed a panel of genes associated with LNM with the most frequently amplified gene being MIR548K harbored in the 11q13.3 amplicon. Overexpression of miR-548k remarkably promotes lymphangiogenesis and lymphatic metastasis in vitro and in vivo. Furthermore, we demonstrated that miR-548k modulating the tumor microenvironment by promoting VEGFC secretion and stimulating lymphangiogenesis through ADAMTS1/VEGFC/VEGFR3 pathways, while promoting metastasis by regulating KLF10/EGFR axis. Importantly, we found that serum miR-548k and VEGFC of early stage ESCC patients were significantly higher than that in healthy donators, suggesting a promising application of miR-548k and VEGFC as biomarkers in early diagnosis of ESCC.ConclusionsOur study comprehensively characterized SCNAs in ESCC and highlighted the crucial role of miR-548k in promoting lymphatic metastasis, which might be employed as a new diagnostic and prognostic marker for ESCC.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0871-4) contains supplementary material, which is available to authorized users.

Targeting p21-activated kinase 1 inhibits growth and metastasis via Raf1/MEK1/ERK signaling in esophageal squamous cell carcinoma cells

“…Metastasis is responsible for poor outcome of ESCC [29, 30]. We then investigated whether high expression of PAK1 confers ESCC cell abilities of migration and invasion, which are two of the most important processes in tumor metastasis.…”

Development of a Novel Serum Exosomal MicroRNA Nomogram for the Preoperative Prediction of Lymph Node Metastasis in Esophageal Squamous Cell Carcinoma

“…MiRNAs are believed to be produced by multiple cell types and could regulate target gene expressions, as well as associated cellular progression ( 53 ). Previous studies demonstrated that dysregulation of miRNA expression could modulate tumor metastasis due to the communication in different types of tumor microenvironments cells by exosomes ( 54 – 56 ). In this study, bioinformation analysis was performed to elucidate the functions and mechanisms of the four exosomal miRNAs by GO and KEGG pathway analyses.…”

APC/C-CDH1–Regulated IDH3β Coordinates with the Cell Cycle to Promote Cell Proliferation

“…Identified metabolism relative potential APC/C substrates Protein sequences of a previously curated list of 2,752 metabolic enzymes and transporters (26) were downloaded through the NCBI Batch Entrez tool (https://www.ncbi.nlm.nih.gov/sites/ batchentrez) and supplied for searching APC/C recognition motifs by R algorithm: those genes containing both destruction box (D box, RXXLXXXXN/D/E, where X indicates any amino acid) and the Lys-Glu-Asn box (KEN box, KENXXXN) were enrolled in Set 1. Next, according to our previous study (27), we extracted the copy number variation (copy number gain and loss) information of the 2,752 metabolism genes, and genes with variation frequency larger than 20% among all samples were placed into Set 2. Genes in the intersection of Set 1 and Set 2 were put forward for further study.…”

“…29). A total of 116 proteins containing both KEN box and D box were selected for further analysis (Set 1, Supplementary Table S1; (ii) copy number variation of these 2,752 genes were analyzed in our previous pooled ESCC sequencing cohort (27), with a variation frequency cutoff (larger than 20%) yielding 440 candidate genes (Set 2, Supplementary Table S2); (iii) genes overlapping of Set 1 and Set 2 were put forward for further study. Accordingly, we figured out 17 cell-cycle-related metabolic genes, including 10 CNV gain genes (ATP13A3, PIK3R4, PLCH1, TXNRD3, IDS, HS6ST2, RDH11, PLCG1, SLC12A5, and IDH3B) and 7 CNV loss genes (KCND1, AGPAT5, MOCOS, GALNT1, PDSS1, ATP10D, and LNPEP), suggesting their critical roles during ESCC progression (Fig.…”