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.
Highlights
The prognosis for esophageal squamous cell carcinoma (ESCC) patients with lymph node metastasis (LNM) is still dismal
VGX-100, a VEGFC monoclonal antibody, has been evaluated efficacy in a phase I clinical trial for advanced or metastatic solid tumors (NCT01514123) [16]. These findings suggests that VEGFC/VEGFR3 axis plays a crucial role in lymphangiogenesis and lymphatic metastasis
The samples in our pooled cohort have not been examined the expression of Somatic copy number alteration (SCNA) harbored genes, we inferred the The Cancer Genome Atlas (TCGA) ESCC cohort as compromise for screening a panel of genes that SCNAs were in accord with the mRNA expression level
Summary
The prognosis for esophageal squamous cell carcinoma (ESCC) patients with lymph node metastasis (LNM) is still dismal. Disrupting the conversation of tumor cells and LECs by interferring RNA or neutralizing antibodies to VEGFC or VEGFR3, has been shown to reduce the rate of lymph node metastasis in vitro and in vivo [14, 15]. VGX-100, a VEGFC monoclonal antibody, has been evaluated efficacy in a phase I clinical trial for advanced or metastatic solid tumors (NCT01514123) [16]. These findings suggests that VEGFC/VEGFR3 axis plays a crucial role in lymphangiogenesis and lymphatic metastasis. Understanding the regulatory mechanisms of VEGFC in ESCC may provide clinically valuable predictive tools for effective anti–VEGFC treatments
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