Wang Yuyan, Gable Tyler, Ma Mark Z, Clark David, Zhao Jun, Zhang Yi, Liu Wei, Mao Li, Mei Yuping
Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, 650 W. Baltimore St., Baltimore, MD 21201, USA; Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Beijing Institute for Cancer Research, Beijing 100142, China.
Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, 650 W. Baltimore St., Baltimore, MD 21201, USA.
Mol Ther Nucleic Acids. 2017 Mar 17;6:269-278. doi: 10.1016/j.omtn.2017.01.003. Epub 2017 Jan 24.
Lung cancer is the leading cause of cancer-related death worldwide. Although advanced drugs have benefitted patients, therapeutic success has largely been hampered because of rapid development of resistance. Here we report that PIWI-interacting RNA likes (piR-Ls), a novel type of functional sncRNAs, play key roles in chemoresistance to cisplatin (CDDP)-based chemotherapy in lung squamous cell carcinoma (LSCC). piR-L-138 was upregulated upon CDDP-based chemotherapy both in LSCC cells and in patient-derived xenograft (PDX) LSCC models. Further, targeting upregulated piR-L-138 led to increased apoptosis in CDDP-treated LSCC cells and LSCC xenograft mice treated with CDDP. In addition, piR-L-138 directly interacted with p60-MDM2 and inhibited CDDP-activated apoptosis in p53-mutated LSCC. We identified the upregulated piR-L-138 upon CDDP-based chemotherapy, confirmed the enhanced sensitivity of LSCC to agents by targeting the upregulated piR-L-138 both in vitro and in vivo, and revealed mechanisms underlying piR-L-138 in chemoresistance, bolstering a new emerging clinical modality where novel functional piR-Ls provide potential strategies to overcome chemoresistance for patients with LSCC.
肺癌是全球癌症相关死亡的主要原因。尽管先进的药物使患者受益，但由于耐药性的快速发展，治疗成功在很大程度上受到了阻碍。在此，我们报告PIWI相互作用RNA样分子（piR-Ls），一种新型的功能性小非编码RNA，在肺鳞状细胞癌（LSCC）对基于顺铂（CDDP）的化疗的耐药性中起关键作用。在基于CDDP的化疗后，piR-L-138在LSCC细胞和患者来源的异种移植（PDX）LSCC模型中均上调。此外，靶向上调的piR-L-138导致经CDDP处理的LSCC细胞和经CDDP处理的LSCC异种移植小鼠的细胞凋亡增加。此外，piR-L-138直接与p60-MDM2相互作用，并抑制p53突变的LSCC中CDDP激活的细胞凋亡。我们鉴定了基于CDDP的化疗后上调的piR-L-138，在体外和体内通过靶向上调的piR-L-138证实了LSCC对药物的敏感性增强，并揭示了piR-L-138在耐药性中的潜在机制，支持了一种新出现的临床模式，即新型功能性piR-Ls为克服LSCC患者的化疗耐药性提供了潜在策略。
