Abstract
Esophageal cancer represent a major global health concern. Esophageal squamous cell carcinoma (ESCC) is the most prevalent histological subtype and exhibits pronounced population-specific variation in incidence. Unfortunately, the main cause of this geographical difference in disease prevalence is poorly understood. Therefore, it requires additional study on identifying main mechanisms in disease development and progression. In this study, RNAs and miRNAs were sequenced from tumor samples of 16 patients with ESCC to analyze transcriptomics signatures that might contribute in disease development and progression. RNA-seq and miRNA-seq data of the same patient were integrated to identify lncRNA-miRNA-mRNA regulatory axes. Differential expression analysis of miRNA-seq data revealed 38 highly dysregulated miRNAs across all patients samples, eight of them previously not reported in esophageal cancers (hsa-miR-3529-3p, hsa-miR-9985, hsa-miR-362-5p, hsa-miR-22-5p, hsa-miR-4531, hsa-miR-3907, hsa-miR-7704, hsa-miR-4770). Network analysis revealed bidirectional miRNA dysregulation: upregulated miRNAs suppress tumor suppressors including KMT2D, KMT2C, KMT2A, MAP3K1, TET2, and BCOR, while downregulated miRNAs are associated with upregulation of ribosomal proteins and metastasis-related genes. Competing endogenous RNA analysis identified NEAT1 and KCNQ1OT1 as hub lncRNAs regulating multiple miRNAs. Validation using The Cancer Genome Atlas data confirmed six survival-associated miRNAs and identified DDX6 and HOOK3 as novel prognostic genes in ESCC. This study provides the first comprehensive multi-omics characterization of ESCC in Central Asia, revealing population-specific regulatory networks and novel biomarker candidates with immediate translational potential.