Uamous carcinoma cell by down-regulating ABCC4 (41). Interestingly, this study revealed that ABCC4 was upregulated in GC tissues, and mRNA expression of HOXA13 was positively correlated with that of ABCC4. The unfavorable prognosis of GC patients with high ABCC4 expression was located in the case of 5-FU primarily based IL-6 Inhibitor supplier chemotherapy, suggesting that ABCC4 expression was connected with efficacy of 5-FU in GC patients. To further investigate regardless of whether there was a regulatory relationship among HOXA13 and ABCC4, we examined the impact of HOXA13 expression alternation on ABCC4 in GC cells. The results showed that ABCC4 expression was upregulated in HOXA13-overexpressing cells and downregulated in HOXA13 knockdown cells, prompting that HOXA13 could modulate the expression of ABCC4. Noticeably, the JASPAR database indicated the possibility of HOXA13 binding to the ABCC4 promoter. Thus, we designed 4 primer sequences for ChIP assay and studied whether or not HOXA13 could bind to promoter area of ABCC4. The result showed that HOXA13 might enrich in the ABCC4 promoter region. Subsequent rescue experiments confirmed that inhibition of ABCC4 expression attenuated the capability of HOXA13 overexpression enhanced 5-FU resistance of GC cells, even though upregulation of ABCC4 partly reversed the course of action 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 essential function in HOXA13-mediated insensitivity of GC to 5-FU. Escalating evidences have demonstrated that miRNAs play a vital part in tumor progression via 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. Moreover, by mechanism experiments, we confirmed that miR-139-5p directly may possibly bind to HOXA13 3′-UTR to downregulate its expression. On the other hand, the function 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 associated with poor prognosis of GC patients in the case of 5-FU treatment. Higher HOXA13 expression enhances 5FU resistance and reduces 5-FU sensitivity, at the same time as alleviates the anti-proliferative effect of 5-FU and suppresses 5-FU-induced cell apoptosis. And ABC transporter pathway activation, specifically ABCC4 upregulation, may perhaps play a vital role in HOXA13mediated 5-FU resistance. HOXA13 expression is directly suppressed by miR-139-5p in GC cells. Targeting the HOXA13/ ABCC4 axis is expected to become a possible therapeutic tactic for lowering resistance to chemotherapy.ETHICS STATEMENTThe research involving human participants were reviewed and authorized by Shanghai Common Hospital. The patients/ participants provided their written informed consent to participate in this study. The Dopamine Receptor Agonist Formulation animal study was reviewed and approved by Shanghai Common Hospital.AUTHOR CONTRIBUTIONSZC, ZQ, and XC designed and performed the experiments. LL and QW performed animal experiments. ZC and ZQ analyzed the data and wrote the manuscript. XC supervised the project. All authors contributed for the short article and approved the submitted version.SUPPLEMENTARY MATERIALThe Supplementary Material for this articl.
