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Oseltamivir enhances 5-FU sensitivity in esophageal squamous carcinoma with high SPNS1

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE245051 | GEO | 2024/01/01

REPOSITORIES: GEO

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Project description:SET (Su) and MYND (myeloid-Nervy-DEAF-1) domain-containing protein (SMYD) is a methyltransferase family, including five members of which SMYD1, SMYD2, SMYD3 and SMYD4, has been found to play critical roles in human carcinogenesis. It has been demonstrated that the altered expression of SMYD3 is associated with the progression of several solid tumors, including bladder cancer, glioma, gastric cancer, prostate cancer and colorectal cancer. Several trials have explored the effects of SMYD3 overexpression on proliferation, viability, cancer cells migration and invasion. The series of elegant experiments suggested that SMYD3 could serve as a potential biomarker for clinically aggressive disease and an attractive therapeutic target. In our previous study (PMID: 26980013), we found SMYD3 expression is frequently upregulated in human esophageal squamous cell carcinoma (ESCC) clinical tissues, correlating with overall survival of ESCC patients. RNAi-mediated knockdown of SMYD3 suppressed ESCC cell proliferation, migration and invasion in vitro, and inhibited local tumor invasion in vivo. To identify genes and biological pathways associated with SMYD3 functions and mechanism, SMYD3 was knockdowned bypGLV3/H1/GFP/+Puro Vector in ESCC cell line KYSE150 with an empty plasmid as a control, these two cells were applied for mRNA expression profile analyses to find the differentially expressed genes using GeneChipÂ® PrimeViewâ¢ Human Gene Expression Array. shRNA sequences targeting SMYD3 was ligated into the pGLV3/H1/GFP/+Puro Vector and transfected into ESCC cell line KYSE150 with an empty plasmid as a control. The mRNA expression profiles of SMYD3 knockdown was analyzed by GeneChipÂ®Â PrimeViewâ¢Â HumanÂ Gene Expression Array (Affymetrix,Â USA). The knockdown of SMYD3 was confirmed by QRT-PCR and Western blot. Total RNAs from SMYD3 knockdown cells and control cells were extracted for GeneChipÂ® PrimeViewâ¢ Human Gene Expression Array.

Project description:Background: Esophageal squamous cell carcinoma (ESCC) is a common invasive malignancy worldwide with poor clinical outcomes. Increasing amount of long non-coding RNAs (lncRNAs) have been reported to be involved in cancer development. However, lncRNAs that are functional in ESCC and the underlying molecular mechanisms remain largely unknown. Methods: Transcriptomic analysis was performed to identify dysregulated lncRNAs in ESCC tissue samples. The high expression of LINC00680 in ESCC was validated by RT-qPCR, and the oncogenic functions of LINC00680 was investigated by cell proliferation, colony formation, migration and invasion assays in ESCC cells in vitro and xenografts derived from ESCC cells in mice. RNA-seq, competitive endogenous RNA (ceRNA) network analysis, and luciferase reporter assays were carried out to identify LINC00680 target genes and the microRNAs (miRNAs) bound to LINC00680. Antisense oligonucleotides (ASOs) were used for in vivo treatment. Results: Transcriptome profiling revealed that a large number of lncRNAs was dysregulated in ESCC tissues. Notably, LINC00680 was highly expressed, and upregulation of LINC00680 was associated with large tumor size, advanced tumor stage, and poor prognosis. Functionally, knockdown of LINC00680 restrained ESCC cell proliferation, colony formation, migration, and invasion in vitro and inhibited tumor growth in vivo. Mechanistically, LINC00680 was found to act as a ceRNA by sponging miR-423-5p to regulate PAK6 (p21-activated kinase 6) expression in ESCC cells. The cell viability and motility inhibition induced by LINC00680 knockdown was significantly reversed upon PAK6 restoration and miR-423-5p inhibition. Furthermore, ASO targeting LINC00680 substantially suppressed ESCC both in vitro and in vivo. Conclusions: An oncogenic lncRNA, LINC00680, was identified in ESCC, which functions as a ceRNA by sponging miR-423-5p to promote PAK6 expression and ESCC. LINC00680/miR-423-5p/PAK6 axis may serve as promising diagnostic and prognostic biomarkers and therapeutic targets for ESCC.

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Oseltamivir enhances 5-FU sensitivity in esophageal squamous carcinoma with high SPNS1

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