Background: Esophageal squamous cell carcinoma (ESCC) develops through a multistage process in which normal epithelium transitions into intraepithelial neoplasia and ultimately into invasive carcinoma. Elucidating the molecular changes and functional roles of key genes during this progression is critical for understanding the mechanisms underlying this malignant transformation. Methods: Transcriptomic profiles of 12 normal esophageal tissues, 5 intraepithelial neoplasia tissues, and 7 ESCC tissues were analyzed via microarray. Stage-specific transcriptomic changes were systematically compared to delineate the phenotypic evolution that occurs during carcinogenesis, with a particular focus on identifying pivotal genes that regulate the precancerous-to-malignant transition. The candidate gene LINC01605 was further examined via the following approaches: (1) bioinformatics-based characterization of its tumor-associated functions using Genotype-Tissue Expression Project (GTEx) normal tissue and The Cancer Genome Atlas Program (TCGA) ESCC transcriptome; (2) functional validation in ESCC cell lines in which the gene was silenced or overexpressed in vitro; and (3) mechanistic exploration of RNA-binding partners via streptavidin bead-based RNA pull-down assays. Results: Multistage transcriptomic analysis revealed the progressive acquisition of cancer hallmarks during ESCC development. The transition from precancerous lesions to invasive carcinoma was characterized by epithelial dedifferentiation, extracellular matrix remodeling, and angiogenesis. LINC01605, which is a long noncoding RNA (lncRNA), was downregulated during this transition. GTEx revealed that LINC01605 was specifically expressed in the squamous epithelium of the esophagus and that its expression was negatively correlated with histological grade in the TCGA-ESCC dataset. Samples with high LINC01605 expression and those with low LINC01605 expression in the TCGA dataset exhibited significant functional differences in epithelial cell differentiation, proliferation, and migration, as well as in the extracellular matrix. Knocking down LINC01605 increased proliferation and migration in both the normal immortalized esophageal epithelial cell line NE3 and the ESCC cell line KYSE180. Conversely, the overexpression of LINC01605 isoforms suppressed these malignant phenotypes. RNA pull-down revealed potential interactions between LINC01605 and aurora kinase B (AURKB), which are components of the chromosomal passenger complex (CPC), suggesting its involvement in regulating the cell cycle. Conclusion: LINC01605 functions as a tumor suppressor in ESCC by maintaining squamous cell differentiation and inhibiting proliferation and migration. LINC01605 downregulation facilitates malignant transformation during esophageal carcinogenesis.
Cheng et al. (Thu,) studied this question.
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