Transcriptomics-based analysis of key genes and potential mechanism and therapeutic agents in cadmium-induced esophageal squamous cell carcinoma progression
Chronic cadmium exposure is linked to esophageal squamous cell carcinoma (ESCC) progression, treatment resistance, and poor prognosis, but its molecular mechanisms remain unclear. Based on whole-transcriptome sequencing (RNA-seq) on chronic cadmium-treated (CCT) and untreated human EC109 ESCC cells, we performed lncRNA-mRNA co-expression and protein-protein interaction (PPI) network analyses to screen the hub genes related to cadmium exposure. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses depicted that these genes were mainly enriched in nucleocytoplasmic transport, ferroptosis, Huntington disease, and cellular senescence. On the basis of lncRNA-miRNA-mRNA potential interaction, 3 lncRNAs (AC107068.1, TTN-AS1, MAPKAPK5-AS1) and 10 mRNAs (IPO5, NUDCD1, OSTM1, CCNB1, FANCD2, TFRC, POLR2B, HTT, NUP43, NBN) were identified for competitive endogenous RNA (ceRNA) network construction. Connectivity map (CMap) analysis for the target mRNAs showed that JAK3-inhibitor-I was the most promising therapeutic drug for cadmium-induced ESCC progression. The prognostic value and abnormal expression of the candidate mRNAs were then validated in TCGA cohorts, cadmium-treated cancer cells and 41 ESCC specimens. Moreover, migration and invasion assays were performed to assess the effects of the identified gene on cell malignant phenotypes. As a result, IPO5 was identified as the pivotal gene and MAPKAPK5-AS1-hsa-miR-379-5p-IPO5 was deemed as a potential ceRNA regulatory mechanism for cadmium carcinogenesis in ESCC. Using TIMER and EPIC algorithms, IPO5 was correlated with increased infiltration of CD4+ T cells and macrophages, while negatively associated with CD8+ T cells and NK cells in ESCC tissues. Collectively, our study provides valuable information in understanding the molecular mechanisms involved in cadmium-induced ESCC progression and treatment resistance. Furthermore, we predict potential agents for cadmium carcinogenicity prevention and treatment.