Authors' Affiliations: University of Southampton Cancer Sciences Division, Somers Cancer Research Building; Department of Colorectal Surgery, Southampton University Hospital NHS Trust, Southampton; Bioinformatics Unit, London Research Institute, Cancer Research UK, London; and School of Cellular and Molecular Medicine, University of Bristol, Medical Sciences Building, Bristol, United Kingdom.
Cancer Res. 2013 Nov 1;73(21):6435-47. doi: 10.1158/0008-5472.CAN-12-3308. Epub 2013 Aug 15.
Although microRNAs (miRNA) have been broadly studied in cancer, comparatively less is understood about their role in progression. Here we report that miR-153 has a dual role during progression of colorectal cancer by enhancing cellular invasiveness and platinum-based chemotherapy resistance. miRNA profiling revealed that miR-153 was highly expressed in a cellular model of advanced stage colorectal cancer. Its upregulation was also noted in primary human colorectal cancer compared with normal colonic epithelium and in more advanced colorectal cancer stages compared with early stage disease. In colorectal cancer patients followed for 50 months, 21 of 30 patients with high levels of miR-153 had disease progression compared with others in this group with low levels of miR-153. Functional studies revealed that miR-153 upregulation increased colorectal cancer invasiveness and resistance to oxaliplatin and cisplatin both in vitro and in vivo. Mechanistic investigations indicated that miR-153 promoted invasiveness indirectly by inducing matrix metalloprotease enzyme 9 production, whereas drug resistance was mediated directly by inhibiting the Forkhead transcription factor Forkhead box O3a (FOXO3a). In support of the latter finding, we found that levels of miR-153 and FOXO3a were inversely correlated in matched human colorectal cancer specimens. Our findings establish key roles for miR-153 overexpression in colorectal cancer progression, rationalizing therapeutic strategies to target expression of this miRNA for colorectal cancer treatment.
虽然 microRNAs（miRNA）在癌症中已经得到广泛研究，但对其在进展过程中的作用了解较少。在这里，我们报告 miR-153 在结直肠癌进展过程中具有双重作用，可增强细胞侵袭性和铂类化疗耐药性。miRNA 谱分析显示，miR-153 在结直肠癌细胞模型的晚期阶段高表达。与正常结肠上皮相比，其在原发性人结直肠癌中上调，与早期疾病相比，在更晚期的结直肠癌阶段上调更为明显。在随访 50 个月的结直肠癌患者中，30 例 miR-153 高水平患者中有 21 例与该组中 miR-153 低水平患者相比出现疾病进展。功能研究表明，miR-153 的上调增加了结直肠癌细胞的侵袭性和对奥沙利铂和顺铂的耐药性，无论是在体外还是体内。机制研究表明，miR-153 通过诱导基质金属蛋白酶酶 9 的产生间接促进侵袭性，而耐药性则通过抑制叉头转录因子 Forkhead box O3a（FOXO3a）直接介导。支持后一种发现，我们发现匹配的人结直肠癌标本中 miR-153 和 FOXO3a 的水平呈负相关。我们的研究结果确立了 miR-153 过表达在结直肠癌进展中的关键作用，为针对这种 miRNA 表达的治疗策略提供了合理的依据，以用于结直肠癌的治疗。
