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Linc00673-V3 通过促进 Smad3 介导的 NSCLC 中转录来正向调控自噬。

Linc00673-V3 positively regulates autophagy by promoting Smad3-mediated transcription in NSCLC.

机构信息

https://ror.org/00a2xv884 Department of Toxicology of School of Public Health and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.

https://ror.org/00a2xv884 Department of Thoracic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

出版信息

Life Sci Alliance. 2024 Mar 25;7(6). doi: 10.26508/lsa.202302408. Print 2024 Jun.

DOI:10.26508/lsa.202302408
PMID:38527804
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10963591/
Abstract

Since its first discovery, long noncoding RNA Linc00673 has been linked to carcinogenesis and metastasis of various human cancers. Linc00673 had five transcriptional isoforms and their biological functions remained to be explored. Here we have reported that Linc00673-V3, one of the isoforms of Linc00673, promoted non-small cell lung cancer chemoresistance, and increased Linc00673-V3 expression level was associated with enhanced autophagy. Mechanistically, we discerned the existence of a stem-loop configuration engendered by the 1-100-nt and 2200-2275-nt fragments within Linc00673-V3. This structure inherently interacted with Smad3, thereby impeding its ubiquitination and subsequent degradation orchestrated by E3 ligase STUB1. The accumulation of Smad3 contributed to autophagy via up-regulation of transcription and ultimately conferred chemoresistance in NSCLC. Our results revealed a novel transcriptional regulation network between Linc00673-V3, Smad3, and , which provided an important insight into the interplay between autophagy regulation and non-canonical function of Smad3. Furthermore, the results from in vivo experiments suggested Linc00673-V3 targeted antisense oligonucleotide as a promising therapeutic strategy to overcome chemotherapy resistance in NSCLC.

摘要

自首次发现以来，长链非编码 RNA Linc00673 一直与各种人类癌症的致癌作用和转移有关。Linc00673 有五个转录异构体，其生物学功能仍有待探索。在这里，我们报道了 Linc00673 的一个异构体 Linc00673-V3 促进了非小细胞肺癌的化疗耐药性，并且 Linc00673-V3 表达水平的增加与增强的自噬有关。在机制上，我们发现 Linc00673-V3 内 1-100-nt 和 2200-2275-nt 片段之间存在茎环结构。这种结构固有地与 Smad3 相互作用，从而阻碍了 E3 连接酶 STUB1 介导的 Smad3 的泛素化和随后的降解。Smad3 的积累通过上调转录促进自噬，最终赋予 NSCLC 化疗耐药性。我们的结果揭示了 Linc00673-V3、Smad3 和 之间的新型转录调控网络，为自噬调控与 Smad3 的非经典功能之间的相互作用提供了重要的见解。此外，体内实验结果表明，Linc00673-V3 靶向反义寡核苷酸是克服 NSCLC 化疗耐药性的一种很有前途的治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/c9a37abf97ae/LSA-2023-02408_FigS8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/2cf15ed2e0ac/LSA-2023-02408_GA.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/4fedb514ad63/LSA-2023-02408_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/8d8bc445b9c9/LSA-2023-02408_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/18742c91a11e/LSA-2023-02408_Fig2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/20274ac613ee/LSA-2023-02408_FigS7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/12a8b0cba082/LSA-2023-02408_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/c9a37abf97ae/LSA-2023-02408_FigS8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/2cf15ed2e0ac/LSA-2023-02408_GA.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/4fedb514ad63/LSA-2023-02408_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/8d8bc445b9c9/LSA-2023-02408_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/18742c91a11e/LSA-2023-02408_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/043f8aacb00d/LSA-2023-02408_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/9aa1d526a470/LSA-2023-02408_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/17e709d5efc9/LSA-2023-02408_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/dfa26f0fcdb4/LSA-2023-02408_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/57c334a5d1df/LSA-2023-02408_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/223e6c3ddbe7/LSA-2023-02408_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/3580d16976e6/LSA-2023-02408_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/ebaaee490dae/LSA-2023-02408_FigS6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/9a6f29e05a2d/LSA-2023-02408_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/1fe93cba99df/LSA-2023-02408_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/20274ac613ee/LSA-2023-02408_FigS7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/12a8b0cba082/LSA-2023-02408_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9368/10963591/c9a37abf97ae/LSA-2023-02408_FigS8.jpg

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