Hsa_circ_0038646 promotes cell proliferation and migration in colorectal cancer via miR-331-3p/GRIK3
Hsa_circ_0038646 promotes cell proliferation and migration in colorectal cancer via miR-331-3p/GRIK3
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DOI：
10.3892/ol.2020.11547
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发表时间：
2020-07-01
期刊：
影响因子：
2.9
通讯作者：
Zhang, Jiansheng
中科院分区：
文献类型：
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作者：
Du, Haipeng;He, Zhiguo;Zhang, Jiansheng
越来越多的证据支持环状rna （circRNAs）和微rna （miRNAs/miRs）在不同类型的人类癌症中的重要作用。例如，hsa_circ_0137008作为mi-338-5p的海绵，抑制结直肠癌的恶性表型。此外，hsa_circ_RNA_0011780通过靶向miR-554a并抑制非小细胞肺癌的进展下调FBXW7。到目前为止，只有一篇报道发现miRNA miR-331-3p在人类结直肠癌（CRC）的进化中发挥关键作用。然而，miR-331-3p的上下游调控机制尚不清楚。在本研究中，通过生物信息学分析预测circRNA、hsa_circ_0038646和谷氨酸受体嗜离子盐酸盐3 （GRIK3）基因含有可与miR-331-3p相互作用的结合位点。因此，hsa_circ_0038646/miR-331-3p/GRIK3可能是CRC的一种新的治疗途径。进行逆转录定量PCR和western blotting分析，以及细胞增殖、荧光素酶报告基因和Transwell迁移实验。Hsa_circ_0038646在CRC细胞和组织中均过表达，且这种异常表达与肿瘤分级的增加呈正相关。敲低hsa_circ_0038646显著削弱人结直肠癌细胞的增殖和迁移。结果表明，hsa_circ_0038646可以海绵miR-331-3p抑制其表达，抑制miR-331-3p可以逆转hsa_circ_0038646在CRC细胞中的抑制作用。我们确定GRIK3是miR-331-3p的下游靶点，hsa_circ_0038646可以通过抑制CRC细胞中的miR-331-3p来提高GRIK3的水平。在敲除hsa_circ_0038646后，恢复GRIK3的表达挽救了CRC细胞的增殖和迁移。本研究表明，hsa_circ_0038646通过海绵化miR-331-3p增加GRIK3的表达，从而在CRC中发挥肿瘤启动子的作用。hsa_circ_0038646/miR-331-3p/GRIK3轴可能是CRC的一个新的治疗和诊断靶点。
Increasing evidence supports the essential roles of circular RNAs (circRNAs) and microRNAs (miRNAs/miRs) in different types of human cancer. For example, hsa_circ_0137008 functions as a sponge for mi-338-5p and inhibits the malignant phenotype in colorectal cancer. Furthermore, hsa_circ_RNA_0011780 downregulates FBXW7 by targeting miR-554a and suppressing the progression of non-small cell lung cancer. Thus far, only a single report has identified that the miRNA miR-331-3p exerts a pivotal effect on human colorectal cancer (CRC) evolution. However, both the up- and downstream regulatory mechanisms of miR-331-3p are unclear. In the present study, it was predicted via bioinformatics analysis that the circRNA, hsa_circ_0038646, and the glutamate receptor ionotropic kainate 3 (GRIK3) gene contain binding sites that can interact with miR-331-3p. Thus, hsa_circ_0038646/miR-331-3p/GRIK3 may be a novel therapeutic pathway for CRC. Reverse transcription-quantitative PCR and western blotting analyses were performed, as well as cell proliferation, luciferase reporter and Transwell migration assays. Hsa_circ_0038646 was overexpressed in both CRC cells and tissues, and this aberrant expression was positively related with increasing tumor grade. Knockdown of hsa_circ_0038646 significantly weakened human CRC cell proliferation and migration. It was shown that hsa_circ_0038646 can sponge miR-331-3p to suppress its expression, and that suppression of miR-331-3p can reverse the effects of hsa_circ_0038646 inhibition in CRC cells. It was determined that GRIK3 is a downstream target of miR-331-3p, and that hsa_circ_0038646 could increase the levels of GRIK3 by suppressing miR-331-3p in CRC cells. Restoring GRIK3 expression rescued the weakened CRC cell proliferation and migration following hsa_circ_0038646 knockdown. The present study indicated that hsa_circ_0038646 functions as a tumor promoter in CRC by increasing GRIK3 expression via sponging of miR-331-3p. The hsa_circ_0038646/miR-331-3p/GRIK3 axis may be a novel therapeutic and diagnostic target of CRC.