Uamous carcinoma cell by down-regulating ABCC4 (41). Interestingly, this study revealed that ABCC4 was upregulated in GC tissues, and mRNA expression of GlyT1 Inhibitor Molecular Weight HOXA13 was positively correlated with that of ABCC4. The unfavorable prognosis of GC individuals with higher ABCC4 expression was found in the case of 5-FU primarily based chemotherapy, suggesting that ABCC4 expression was linked with efficacy of 5-FU in GC individuals. To further investigate whether there was a regulatory relationship between HOXA13 and ABCC4, we examined the impact of HOXA13 expression alternation on ABCC4 in GC cells. The outcomes showed that ABCC4 expression was upregulated in HOXA13-overexpressing cells and downregulated in HOXA13 knockdown cells, prompting that HOXA13 might modulate the expression of ABCC4. Noticeably, the JASPAR database indicated the possibility of HOXA13 binding to the ABCC4 promoter. For that reason, we designed four primer sequences for ChIP assay and studied whether or not HOXA13 could bind to promoter region of ABCC4. The result showed that HOXA13 might enrich within the ABCC4 promoter region. Subsequent rescue experiments confirmed that inhibition of ABCC4 expression attenuated the capacity of HOXA13 overexpression enhanced 5-FU resistance of GC cells, even though upregulation of ABCC4 partly reversed the procedure of HOXA13 knockdown promoted GC cells sensitivity to 5-FU. These findingsFrontiers in Oncology | www.frontiersin.orgMay 2021 | Volume 11 | ArticleChen et al.HOXA13 Decreases Chemosensitivity in GCsuggested that HOXA13 upregulated ABCC4 expression possibly by binding to its promoter, and ABCC4 might play a vital role in HOXA13-mediated insensitivity of GC to 5-FU. Increasing evidences have demonstrated that miRNAs play an essential function in tumor progression through post-transcriptionally regulating functional mRNAs expression (42). In this study, miR139-5p, identified by GEO dataset and bioinformatics analyses, was downregulated in GC cells and negatively correlated with HOXA13 in GC tissues. Additionally, by mechanism experiments, we confirmed that miR-139-5p straight may well bind to HOXA13 3′-UTR to downregulate its expression. Even so, the part of miR-139-5p in chemoresistance of GC cells remains to further researched. In conclusion, our study shows that HOXA13 is upregulated in GC samples and linked with poor prognosis of GC individuals inside the case of 5-FU treatment. High HOXA13 expression enhances 5FU resistance and reduces 5-FU sensitivity, as well as alleviates the anti-proliferative effect of 5-FU and suppresses 5-FU-induced cell apoptosis. And ABC transporter pathway activation, especially ABCC4 upregulation, could play an essential part in HOXA13mediated 5-FU resistance. HOXA13 expression is directly suppressed by miR-139-5p in GC cells. Targeting the HOXA13/ ABCC4 axis is anticipated to become a prospective therapeutic tactic for decreasing resistance to chemotherapy.ETHICS STATEMENTThe studies involving human participants have been reviewed and authorized by Shanghai Basic Hospital. The patients/ participants supplied their HDAC4 Inhibitor web written informed consent to take part in this study. The animal study was reviewed and authorized by Shanghai Basic Hospital.AUTHOR CONTRIBUTIONSZC, ZQ, and XC developed and performed the experiments. LL and QW performed animal experiments. ZC and ZQ analyzed the information and wrote the manuscript. XC supervised the project. All authors contributed for the article and authorized the submitted version.Supplementary MATERIALThe Supplementary Material for this articl.
