Inhibition of KHSRP sensitizes colorectal cancer to 5-fluoruracil through miR-501-5p-mediated ERRFI1 mRNA degradation
Inhibition of KHSRP sensitizes colorectal cancer to 5-fluoruracil through miR-501-5p-mediated ERRFI1 mRNA degradation
复制标题
抑制KHSRP通过miR-501-5P介导的ERRFI1mRNA降解增敏结直肠癌对5-FU的敏感性
DOI：
10.1002/jcp.29076
复制
发表时间：
2019-07-16
影响因子：
5.6
通讯作者：
Zheng, Minhua
中科院分区：
文献类型：
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作者：
Pan, Ruijun;Cai, Wei;Zheng, Minhua
K-同源(KH)型剪接调节蛋白(KHSRP)是一种RNA结合蛋白，参与RNA的可变剪接和稳定性，并促进靶向mRNA的miRNAs的生物发生。然而，到目前为止，KHSRP在结直肠癌进展中的作用还没有报道。本研究探讨KHSRP在结直肠癌增殖和5-氟尿嘧啶(5-FU)耐药中的作用。KHSRP在结直肠癌患者组织和两个结直肠癌细胞系中的表达上调。KHSRP的表达改变了结直肠癌细胞的增殖和对5-FU的耐药性。ERRFI1是结直肠癌细胞中KHSRP的下游效应因子，它抑制了结直肠癌细胞的增殖。KHSRP基因敲除对5-FU的敏感性可被ERRFI1基因敲除逆转。我们发现KHSRP间接降低了ERRFI1mRNA的表达。通过筛选KHSRP调节的miRNAs，我们进一步发现miR-501-5p在CRC细胞中直接与KHSRP结合。从机制上讲，荧光素酶检测结果表明miR-501-5p直接与ERRFI13‘-非翻译区结合。综上所述，我们的数据表明KHSRP通过miR-501-5P修饰ERRFI1，这是导致CRC增殖和5-FU耐药的重要机制。深入了解这一机制可能为克服结直肠癌耐药提供新的靶点。
K-homology (KH)-type splicing regulatory protein (KHSRP) is an RNA binding protein that participates in RNA variable splicing and stability, and facilitates the biogenesis of miRNAs that target mRNA. However, to date, the role of KHSRP in colorectal cancer (CRC) progression has not been reported. In this study, the function of KHSRP in CRC proliferation and 5-fluoruracil (5-FU) resistance was investigated. The upregulation of KHSRP expression was confirmed in CRC patient tissues and two CRC cell lines. Manipulating KHSRP expression altered cell proliferation and 5-FU resistance in CRC cells. ERRFI1, a downstream effector of KHSRP in CRC cells, reduced CRC cell proliferation. Sensitivity to 5-FU mediated by KHSRP knockdown was reversed by ERRFI1 knockdown. We found that KHSRP decreased ERRFI1 mRNA expression indirectly. By screening KHSRP-regulated miRNAs, we further found that miR-501-5p directly combines with KHSRP in CRC cells. Mechanistically, the results of a luciferase assay suggested that miR-501-5p directly binds to the ERRFI1 3 '-untranslated region. Taken together, our data indicated that modification of ERRFI1 by KHSRP occurs through miR-501-5p, an essential mechanism driving CRC proliferation and 5-FU resistance. Insight into this mechanism may provide novel targets for overcoming drug resistance in CRC.