miR-153 supports colorectal cancer progression via pleiotropic effects that enhance invasion and chemotherapeutic resistance.
miR-153 supports colorectal cancer progression via pleiotropic effects that enhance invasion and chemotherapeutic resistance.
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DOI：
10.1158/0008-5472.can-12-3308
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发表时间：
2013-11-01
期刊：
影响因子：
11.2
通讯作者：
Mirnezami AH
中科院分区：
文献类型：
--
作者：
Zhang L;Pickard K;Jenei V;Bullock MD;Bruce A;Mitter R;Kelly G;Paraskeva C;Strefford J;Primrose J;Thomas GJ;Packham G;Mirnezami AH
虽然microRNAs（miRNAs）在癌症中已被广泛研究，但对其在进展中的作用了解相对较少。在这里，我们报告了miR-153在结直肠癌（CRC）进展过程中具有双重作用，通过增强细胞侵袭力和铂类化疗耐药性。miRNA分析显示，miR-153在晚期CRC的细胞模型中高度表达。与正常结肠上皮相比，在原发性人CRC中也注意到其上调，并且与早期疾病相比，在更晚期的CRC阶段中也注意到其上调。在随访50个月的CRC患者中，与该组中具有低水平miR-153的其他患者相比，具有高水平miR-153的21/30患者具有疾病进展。功能研究显示，miR-153上调增加了CRC的侵袭性以及对奥沙利铂和顺铂的体外和体内耐药性。机制研究表明，miR-153通过诱导MMP 9的产生间接促进侵袭，而药物抗性通过抑制Forkhead转录因子FOXO 3a直接介导。为了支持后一个发现，我们发现miR-153和FOXO 3a的水平在匹配的人类CRC标本中呈负相关。我们的研究结果确立了miR-153过表达在CRC进展中的关键作用，合理化了针对该miRNA表达的治疗策略用于CRC治疗。
While microRNAs (miRNAs) 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 (CRC) 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 CRC. Its upregulation was also noted in primary human CRC compared to normal colonic epithelium, and in more advanced CRC stages compared to early stage disease. In CRC patients followed for 50 months, 21/30 patients with high levels of miR-153 had disease progression compared to others in this group with low levels of miR-153. Functional studies revealed that miR-153 upregulation increased CRC invasiveness and resistance to Oxaliplatin and Cisplatin both in vitro and in vivo. Mechanistic investigations indicated that miR-153 promoted invasiveness indirectly by inducing MMP9 production, whereas drug resistance was mediated directly by inhibiting the Forkhead transcription factor FOXO3a. In support of the latter finding, we found that levels of miR-153 and FOXO3a were inversely correlated in matched human CRC specimens. Our findings establishes key roles for miR-153 overexpression in CRC progression, rationalizing therapeutic strategies to target expression of this miRNA for CRC treatment.