Clinical significance and biological role of KLF17 as a tumour suppressor in colorectal cancer
Clinical significance and biological role of KLF17 as a tumour suppressor in colorectal cancer
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DOI：
10.3892/or.2019.7324
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发表时间：
2019-11-01
期刊：
影响因子：
4.2
通讯作者：
Wang, Feng
中科院分区：
文献类型：
--
作者：
Jiang, Xun;Shen, Tong-Yi;Wang, Feng
Kruppel样因子17（KLF17）在多种组织和癌细胞中具有抑癌作用，但其在结直肠癌（CRC）中的分子作用、机制及临床意义尚未完全阐明。在本研究中，KLF17蛋白表达检测在140个原发性CRC和配对的相邻的非肿瘤组织使用免疫组织化学与组织芯片。采用逆转录定量聚合酶链反应（RT-PCR）检测4种结直肠癌细胞系和20对上述组织中KLF17 mRNA的表达。分析KLF17表达与临床病理特征的关系。接下来，通过细胞增殖、集落形成、粘附、侵袭和小鼠异种移植试验来检查KLF17在CRC中的功能。采用甲基化特异性PCR和亚硫酸氢盐测序PCR检测结直肠癌细胞和组织中KLF17基因启动子甲基化状态，探讨慢病毒介导的UHRF1 RNAi对KLF17基因甲基化和表达的影响。结果显示，KLF17在大肠癌中的表达异常降低，并与淋巴结转移和不良的总生存率相关。此外，异位KLF17表达抑制CRC细胞的生长和侵袭在体外和体内。此外，KLF17的下调与KLF17启动子上CpG核苷酸的高甲基化有关。表观遗传调节因子UHRF1的敲低降低了KLF17启动子的甲基化水平，并通过上调KLF17来抑制CRC细胞粘附、侵袭和上皮-间质转化。目前的研究结果表明，KLF17可能作为一个肿瘤抑制基因在CRC和CRC患者的一个潜在的独立的预后生物标志物。UHRF1可通过其启动子的高甲基化抑制KLF17在结直肠癌中的表达。这些结果提供了深入了解KLF17在CRC中的表达调控，并表明KLF17对肿瘤发生具有抑制作用。
It has been reported that kruppel-like factor 17 (KLF17) acts as a tumour suppressor in several tissues and cancer cells, however, the molecular roles, the underlying mechanisms and clinical significance of KLF17 in colorectal cancer (CRC) have not been completely elucidated. In the present study, KLF17 protein expression was detected in 140 primary CRCs and paired adjacent non-tumour tissues using immunohistochemistry with tissue microarrays. The KLF17 mRNA expression was determined in 4 CRC cell lines and 20 pairs of the aforementioned tissues using reverse transcription quantitative polymerase chain reaction. The correlation between KLF17 expression and clinicopathologic characteristics was determined. Next, the functions of KLF17 in CRC were examined by cell proliferation, colony formation, adhesion, invasion and mouse xenograft assays. Methylation-specific PCR and bisulfite sequencing PCR were also carried out to investigate the promoter methylation status of KLF17 in CRC cells and tissues and explore the effects of lentiviral-mediated RNAi of UHRF1 on the methylation and expression of KLF17. The results revealed that KLF17 expression was abnormally decreased in CRC and associated with lymph node metastasis and unfavorable overall survival. Moreover, ectopic KLF17 expression suppressed CRC cell growth and invasion in vitro and in vivo. In addition, the downregulation of KLF17 was associated with the hypermethylation of the CpG nucleotides on the KLF17 promoter. The knockdown of the epigenetic regulator UHRF1 reduced the methylation level of the KLF17 promoter and inhibited CRC cell adhesion, invasion and epithelial-mesenchymal transition by upregulating KLF17. The present findings indicated that KLF17 may act as a tumour suppressor gene in CRC and a potential independent prognostic biomarker in CRC patients. UHRF1 can suppress KLF17 expression through the hypermethylation of its promoter in CRC. These results offer insights into the KLF17 expression regulation in CRC and suggest an inhibitory effect of KLF17 on tumourigenesis.