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Gene expression analysis of organoid model of human esophageal squamous cell carcinomas (ESCCs)

ABSTRACT: Esophageal squamous cell carcinoma (ESCC) is a serious cancer with a poor prognosis and a high recurrence rate after chemotherapy, which is a major clinical challenge. To elucidate the molecular basis of chemotherapy (chemo)-resistance and develop methods to effectively eliminate chemo-resistant tumor clones, we established a cancer organoid model from 24 ESCC patients of various stages, ages, and treatments. These ESCCOs recapitulated most oncogenic mutations of primary ESCC tissues and had tumorigenic properties upon xenografting. Each organoid line differs in its responsiveness to 5-fluorouracil (5-FU) and cisplatin (CDDP), chemotherapeutic agents commonly used to treat ESCC patients, with 7 lines exhibiting potent chemo-resistance. Importantly, these chemo-resistant ESCCOs had enhanced expression of genes involved in antioxidant stress response pathways and increased chromatin accessibility of their genomic loci, compared to chemo-sensitive ESCCOs, and these genes became useful biomarkers that can stratify chemo-resistant ESCC in histopathological specimens.

ORGANISM(S): Homo sapiens

PROVIDER: GSE269447 | GEO | 2025/02/25

REPOSITORIES: GEO

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Project description:Abstract Background: Sphingolipid transporter 1 (SPNS1) is a significant differentially expressed gene (DEGs) in esophageal squamous cell carcinoma (ESCC), but its role in cancer is unclear. This study aimed to investigate the role and potential mechanism of SPNS1 in ESCC. Methods: Transcriptomic data from 155 pairs of ESCC samples and GSE53624, and proteomic data from PXD021701 including 124 ESCC samples, were analyzed to determine the clinic relevance of SPNS1 in ESCC. The effects of SPNS1 on various phenotypes of ESCC cells, including proliferation, invasion, migration, apoptosis, and chemotherapy resistance, were assessed using MTT, Transwell, wound healing assay, and flow cytometry. Transcriptome sequencing was performed in ESCC cell lines with SPNS1 knockdown and DEGs correlated with SPNS1 were screened out and performed bioinformatics analysis. The correlation between NEU1, one of the identified DEG, and SPNS1 and the potential mechanism was validated. Results: SPNS1 was significantly higher in ESCC tissues compared to adjacent normal tissues. Patients with high SPNS1 had a significantly poorer clinical prognosis than those with low SPNS1. Knockdown of SPNS1 significantly inhibited proliferation, migration, and invasion of ESCC cells, while promoting apoptosis. And overexpression of SPNS1 exhibited opposite functions. Furthermore, ESCC cells became more sensitive to the chemotherapy drug 5-fluorouracil (5-Fu) after SPNS1 knockdown. Transcriptome sequencing revealed that NEU1 was one significant DEG affected by SPNS1 and positively correlated with SPNS1 expression. Oseltamivir phosphate (OP), one NEU1 inhibitor, markedly reversed 5-Fu resistance, migration, and proliferation induced by high expression of SPNS1 both in vitro and in vivo. Conclusion: Our findings indicated that SPNS1 may promote the progression of ESCC by upregulating NEU1 expression and influencing chemotherapy sensitivity. These results provide new insights into potential therapeutic targets for ESCC treatment.

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Gene expression analysis of organoid model of human esophageal squamous cell carcinomas (ESCCs)

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