期刊
EMBO REPORTS
卷 22, 期 6, 页码 -出版社
WILEY
DOI: 10.15252/embr.202052079
关键词
KLF6; metastasis; QKI‐ 5; TGF‐ β ‐ induced EMT; TGFβ R1
资金
- National Natural Science Foundation of China [81872343, 81672277]
- Suzhou Key Laboratory for Molecular Cancer Genetics [SZS201209]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
QKI-5 is significantly decreased in metastatic lung adenocarcinoma, and its overexpression inhibits TGF-beta-induced EMT and invasion. KLF6 positively regulates QKI-5 at the transcriptional level, which is associated with TGF beta R1. Targeting the KLF6/QKI-5/TGF beta R1 axis may be a promising strategy for treating LUAD.
Quaking (QKI) proteins belong to the signal transduction and activation of RNA (STAR) family of RNA-binding proteins that have multiple functions in RNA biology. Here, we show that QKI-5 is dramatically decreased in metastatic lung adenocarcinoma (LUAD). QKI-5 overexpression inhibits TGF-beta-induced epithelial-mesenchymal transition (EMT) and invasion, whereas QKI-5 knockdown has the opposite effect. QKI-5 overexpression and silencing suppresses and promotes TGF-beta-stimulated metastasis in vivo, respectively. QKI-5 inhibits TGF-beta-induced EMT and invasion in a TGF beta R1-dependent manner. KLF6 knockdown increases TGF beta R1 expression and promotes TGF-beta-induced EMT, which is partly abrogated by QKI-5 overexpression. Mechanistically, QKI-5 directly interacts with the TGF beta R1 3 ' UTR and causes post-transcriptional degradation of TGF beta R1 mRNA, thereby inhibiting TGF-beta-induced SMAD3 phosphorylation and TGF-beta/SMAD signaling. QKI-5 is positively regulated by KLF6 at the transcriptional level. In LUAD tissues, KLF6 is lowly expressed and positively correlated with QKI-5 expression, while TGF beta R1 expression is up-regulated and inversely correlated with QKI-5 expression. We reveal a novel mechanism by which KLF6 transcriptionally regulates QKI-5 and suggest that targeting the KLF6/QKI-5/TGF beta R1 axis is a promising targeting strategy for metastatic LUAD.
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