摘要:miR520a在支气管上皮细胞和NSCLC中抑制Fzd9

Alex J. Smith, Paulina Do, K. Sompel, A. Elango
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引用次数: 0

摘要

非小细胞肺癌(NSCLC)仍然是世界上诊断最多的癌症类型,死亡率最高。治疗方法已得到高度研究,但5年生存率仍在20%左右。化学预防可以对抗肺癌高危人群的发展,比如前吸烟者。伊洛前列素是一种前列环素类似物,被证明可以减少前吸烟者支气管内发育不良的存在。Iloprost诱导卷曲蛋白9 (Fzd9)表达增加,导致过氧化物酶体增殖物激活受体γ (PPARγ)的激活和转化生长的抑制。本研究的目的是阐明吸烟、非小细胞肺癌和miRNA调控Fzd9表达的关系。我们假设,当非小细胞肺癌细胞暴露于香烟烟雾冷凝物(CSC)和Iloprost时,miRNA调节Fzd9的表达。通过计算机预测miR520a5p与Fzd9结合,并在永生化人支气管上皮细胞系(HBEC)和非小细胞肺癌细胞系中验证了miR520a5p模拟物与Fzd9 39UTR荧光素酶的结合。A549和H322 NSCLC细胞和HBEC暴露于香烟烟雾冷凝物(CSC)和伊洛前列素。CSC增加了miR520a的表达,而在Iloprost处理的细胞中则相反。我们还测量了Fzd9 39UTR活性,并证明CSC降低了Fzd9 39UTR和PPRE活性,而Iloprost则相反。我们研究了miR520a5p对Fzd9下游靶标的影响,包括PPARγ反应元件(PPRE), PPARγ活性的直接测量,以及上皮到间充质转化(EMT)基因表达,包括Cox2, E-cadherin和CRB3。我们发现当Fzd9被miR520a5p抑制时,PPRE活性和上皮基因表达受到抑制,而间充质基因表达受到刺激。将CSC与miR520a5p抑制剂或伊洛前列素与miR520a5p模拟物联合进行的拯救实验支持了miR-520a-5p在肺上皮细胞CSC致癌途径中抑制Fzd9的作用,这一作用被伊洛前列素治疗逆转。总的来说,这些发现提示了暴露于香烟烟雾的肺上皮细胞中miRNA调控Fzd9的机制和潜在的化学预防靶点。引文格式:Alex J. Smith, Paulina Do, Kayla M. Sompel, Alamelu Elango。miR520a在支气管上皮细胞和NSCLC中抑制Fzd9[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):摘要第2569期。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Abstract 2569: miR520a inhibits Fzd9 in bronchial epithelial cells and NSCLC
Non-small cell lung cancer (NSCLC) continues to be the most diagnosed cancer type worldwide and has the highest mortality rate. Treatment is highly researched, but 5 year survival remains around 20%. Chemoprevention could combat the development of lung cancer in individuals who are at high risk, such as former cigarette smokers. Iloprost is a prostacyclin analogue demonstrated to reduce the presence of endobronchial dysplasia in former smokers. Increased Frizzled-9 (Fzd9) expression is induced by Iloprost, resulting in activation of peroxisome proliferator activated receptor γ (PPARγ) and inhibition of transformed growth. The goal of this study is to elucidate the relationship of cigarette smoke, NSCLC, and miRNA regulation of Fzd9 expression. We hypothesized that miRNA regulate Fzd9 expression when NSCLC cells are exposed to both cigarette smoke condensate (CSC) and Iloprost. miR520a5p was predicted in silico to bind Fzd9 and we validated binding with a miR520a5p mimic and Fzd9 39UTR luciferase in an immortalized human bronchial epithelial cell line (HBEC) and NSCLC cell lines. A549 and H322 NSCLC cells and HBEC were exposed to cigarette smoke condensate (CSC) and Iloprost. CSC increased miR520a expression, while the opposite was observed in Iloprost treated cells. We also measured Fzd9 39UTR activity and demonstrated that CSC decreases both Fzd9 39UTR and PPRE activity, while Iloprost does the opposite. We investigated the effect of miR520a5p on targets downstream of Fzd9, including PPARγ response element (PPRE), a direct measure of PPARγ activity, and epithelial to mesenchymal transition (EMT) gene expression, including Cox2, E-cadherin, and CRB3. We found that when Fzd9 is inhibited by miR520a5p, PPRE activity and epithelial gene expression are inhibited, while mesenchymal gene expression is stimulated. Rescue experiments combining CSC with a miR520a5p inhibitor or iloprost with a miR520a5p mimic supported a role for miR-520a-5p in inhibition of Fzd9 in a CSC carcinogenic pathway in lung epithelial cells that is reversed with iloprost treatment. Overall, these findings suggest a mechanism for miRNA regulation of Fzd9 in lung epithelial cells exposed to cigarette smoke and a potential chemoprevention target. Citation Format: Alex J. Smith, Paulina Do, Kayla M. Sompel, Alamelu Elango. miR520a inhibits Fzd9 in bronchial epithelial cells and NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2569.
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