外泌体传递lncRNA SNHG7调控自噬促进肺腺癌化疗耐药性播散的机制研究

Chemotherapy resistance is an important cause of clinical failure of lung adenocarcinoma. It has been found that the expression levels of autophagy-related genes ATG5 and ATG12 are increased in lung adenocarcinoma-resistant cells, and the increase in autophagy leads to chemotherapy failure, but the specific mechanism is unknown. In our previous experiments with docetaxel-resistant lung adenocarcinoma cells, we found that lncRNA SNHG7 was abnormally elevated in exosomes. Pre-experiment confirmed that HuR can bind to lncRNA SNHG7 and has a certain correlation with ATG5 and ATG12 elevation. Bioinformatics analysis also showed that the 3'-UTR sequences of lncRNA SNHG7 and ATG5/ATG12 distributed a large number of binding sites for chaperone HuR. Based on the previous studies, this study is to confirm that lncRNA SNHG7 is mediated by exosomes from drug-resistant cells into non-resistant cells in vitro and in vivo, and the stability of ATG5 and ATG12 mRNA is regulated by binding HuR to reveal exosomal delivery. lncRNA SNHG7 induced the autophagy of lung adenocarcinoma cells and triggered the mechanism of drug-resistant dissemination. This study will explore new clinical strategies for reversing chemoresistance in lung adenocarcinoma.

化疗耐药是影响肺腺癌临床疗效的重要原因。目前发现自噬相关基因ATG5及ATG12在肺腺癌耐药细胞中表达水平增加，并且引起自噬升高导致化疗失败，但其具体机制不明。我们前期通过对多西紫杉醇耐药肺腺癌细胞株的实验发现，lncRNA SNHG7在外泌体中异常升高。预实验证实HuR可与lncRNA SNHG7结合，并与ATG5、ATG12升高有一定的相关性。通过生物信息学分析也表明，lncRNA SNHG7和ATG5/ATG12的3’-UTR序列分布着大量伴侣蛋白HuR的结合位点。本课题拟在前期研究基础上,从体内外水平证实lncRNA SNHG7由外泌体介导由耐药细胞进入非耐药细胞，通过结合HuR对ATG5及ATG12 mRNA进行稳定性调控，揭示外泌体递送lncRNA SNHG7诱发肺腺癌细胞自噬增高并引发耐药性播散的机理。该研究将为逆转肺腺癌化疗耐药探索新的临床策略。

肺腺癌是肺癌中最常见的病理亚型。从基础医学到临床的各项研究探索为改善肺癌的诊断和治疗做出了巨大努力，但肺腺癌患者的总生存率仍不令人满意。多西他赛是一种用于治疗多项癌症的化疗药物，这其中包括肺腺癌。然而，肺腺癌对化疗有很强的抵抗力，易导致复发。因此，为了促进肺腺癌化疗的疗效，迫切需要探究肺腺癌中多西他赛耐药性背后的机制。. lncRNA SNHG7在各种癌症中被广泛报道，其中也包括肺腺癌。然而，lncRNA SNHG7与肺腺癌的多西他赛耐药性之间的关联尚未被报道。在本研究中，我们检测并确定了lncRNA SNHG7在多西他赛耐药细胞中的高表达。通过功能实验，我们确定沉默lncRNA SNHG7会降低多西他赛的IC50值，抑制肺腺癌细胞的增殖和自噬，并逆转巨噬细胞的M2极化。此外，lncRNA SNHG7通过招募HuR来稳定ATG5和ATG12来促进自噬。外泌体携带lncRNA SNHG7从多西他赛耐药的肺腺癌细胞传递到亲本肺腺癌细胞，促进肺腺癌多西他赛耐药。外泌体中携带的lncRNA SNHG7激活了PI3K/AKT途径，通过招募cullin 4A（CUL4A）促进PTEN泛素化和降解，进而促进巨噬细胞的M2极化。总之，外泌体携带lncRNA SNHG7通过促进肺腺癌细胞的自噬作用诱导多西他赛耐药性形成，并促进巨噬细胞的M2极化。. 本研究旨在揭示lncRNA SNHG7在调节肺腺癌细胞多西他赛耐药性和自噬以及巨噬细胞的M2极化方面的作用。我们的研究结果可能表明，lncRNA SNHG7是缓解肺腺癌多西他赛耐药性的一个新靶点。