MicroRNAs (miRNAs) are key regulators of different human processes that represent a new promising class of cancer therapeutics or therapeutic targets. Indeed, in several tumor types, including non-small-cell lung carcinoma (NSCLC), the deregulated expression of specific miRNAs has been implicated in cell malignancy. As expression levels of the oncosuppressor miR-34c-3p are decreased in NSCLC compared to normal lung, we show that reintroduction of miR-34c-3p reduces NSCLC cell survival in vitro. Further, in order to deliver the miR-34c-based therapeutic selectively to tumor cells, we took advantage of a reported nucleic acid aptamer (GL21.T) that binds and inhibits the AXL transmembrane receptor and is rapidly internalized in the target cells. By applying methods successfully used in our laboratory, we conjugated miR-34c to the GL21.T aptamer as targeting moiety for the selective delivery to AXL-expressing NSCLC cells. We demonstrate that miR-34c-3p and the GL21.T/miR-34c chimera affect NSCLC cell proliferation and are able to overcome acquired RTK-inhibitor resistance by targeting AXL receptor. Thus, the GL21.T/miR-34c chimera exerts dual inhibition of AXL at functional and transcriptional levels and represents a novel therapeutic tool for the treatment of NSCLC.

微小RNA（miRNA）是不同人类过程的关键调节因子，代表了新的有前途的癌症治疗方法或治疗靶标。实际上，在包括非小细胞肺癌（NSCLC）在内的几种肿瘤类型中，特定miRNA的表达失调与细胞恶性肿瘤有关。与正常肺相比，NSCLC中抑癌药miR-34c-3p的表达水平降低了，我们证明了miR-34c-3p的重新引入降低了NSCLC细胞的体外存活率。此外，为了将基于miR-34c的治疗剂选择性地递送至肿瘤细胞，我们利用了已报道的核酸适体（GL21.T），该核酸适体结合并抑制AXL跨膜受体并在靶细胞中快速内在化。通过应用在我们实验室中成功使用的方法，我们将miR-34c偶联到GL21.T适体作为靶向部分，以选择性递送至表达AXL的NSCLC细胞。我们证明，miR-34c-3p和GL21.T / miR-34c嵌合体影响NSCLC细胞增殖，并能够通过靶向AXL受体克服获得的RTK抑制剂耐药性。因此，GL21.T / miR-34c嵌合体在功能和转录水平上都对AXL具有双重抑制作用，代表了一种用于治疗NSCLC的新型治疗工具。