Abstract
BackgroundCircular RNAs (circRNAs) have been reported to play vital roles in colorectal cancer (CRC). However, only a few circRNAs have been experimentally validated and functionally described. In this research, we aimed to reveal the functional mechanism of circCSPP1 in CRC.Methods36 DOX sensitive and 36 resistant CRC cases participated in this study. The expression of circCSPP1, miR-944 and FZD7 were detected by quantitative real time polymerase chain reaction (qRT-PCR) and the protein levels of FZD7, MRP1, P-gp and LRP were detected by western blot. Cell proliferation, migration, invasion, and apoptosis were assessed by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay, transwell assay, or flow cytometry analysis, respectively. The interaction between miR-944 and circCSPP1 or frizzled-7 (FZD7) was predicted by Starbase 3.0 and verified by the dual luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA pull down assay. Xenograft tumor assay was performed to examine the effect of circCSPP1 on tumor growth in vivo.ResultsThe expression of circCSPP1 and FZD7 was upregulated while miR-944 expression was downregulated in doxorubicin (DOX)-resistant CRC tissues and cells. CircCSPP1 knockdown significantly downregulated enhanced doxorubicin sensitivity, suppressed proliferation, migration, invasion, and induced apoptosis in DOX-resistant CRC cells. Interestingly, we found that circCSPP1 directly downregulated miR-944 expression and miR-944 decreased FZD7 level through targeting to 3′ untranslated region (UTR) of FZD7. Furthermore, circCSPP1 mediated DOX-resistant CRC cell progression and doxorubicin sensitivity by regulating miR-944/FZD7 axis. Besides, circCSPP1 downregulation dramatically repressed CRC tumor growth in vivo.ConclusionOur data indicated that circCSPP1 knockdown inhibited DOX-resistant CRC cell growth and enhanced doxorubicin sensitivity by miR-944/FZD7 axis, providing a potential target for CRC therapy.
Highlights
Circular RNAs have been reported to play vital roles in colorectal cancer (CRC)
CircCSPP1 knockdown enhanced DOX sensitivity, suppressed cell proliferation, migration, and invasion, as well as promoted apoptosis in DOX‐resistant CRC cells In order to further investigate the function of circCSPP1 in DOX-resistant CRC cells, circCSPP1 knockdown was performed by transfection of si-circCSPP1
The decreased colony formation rate (Fig. 2e) in DOX-resistant CRC cells with circCSPP1 knockdown confirmed that cell proliferation ability of DOX-resistant CRC cells was inhibited by si-circCSPP1
Summary
Circular RNAs (circRNAs) have been reported to play vital roles in colorectal cancer (CRC). Despite many advances in the diagnosis and therapeutic improvements of this disease, the prognosis of CRC patients remains poor, owing to diagnosis is difficult in the earlier period. Doxorubicin (DOX), an anthracycline that inhibit nucleic acid synthesis [4], usually used to kill residual CRC cells after surgery and advanced colorectal cancer [5,6,7]. Despite the widely and long-term clinical application of DOX, current treatment effect is not very ideal on account of cell drug resistance [8]. A better understanding of the underlying mechanism of DOX resistance will has the enormous help for the treatment of CRC patients
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