Loss of Smad4 promotes aggressive lung cancer metastasis by de-repression of PAK3 via miRNA regulation
2021
Over 85% of lung cancer patients harbor overt or subclinical metastases at diagnosis, and therefore
most patients die of progressive metastatic disease despite aggressive local and systemic therapies.
Somatic mutations in the Smad4 gene have been found in non-small-cell lung cancer, but the
underlying mechanism by which Smad4 loss-of-function (LOF) accelerates lung cancer metastasis
is yet to be elucidated. Here, we generated a highly aggressive lung cancer mouse model bearing
conditional KrasG12D, p53fl/fl LOF and/or Smad4 fl/fl LOF mutations. The Smad4fl/fl; p53 fl/fl; KrasG12D
(SPK) mutant mice manifested a much higher incidence of tumor metastases than the p53 fl/fl;
KrasG12D (PK) mice. Molecularly, PAK3 was identified as a novel downstream effector of Smad4,
mediating metastatic signal transduction via the PAK3-JNK-Jun pathway. Upregulation of PAK3
by Smad4 LOF in SPK mice was achieved by attenuating Smad4-dependent transcription of miR-
495 and miR-543. These microRNAs (miRNAs) directly bind to the PAK3 39UTR for blockade of
PAK3 production, ultimately regulating lung cancer metastasis. An inverse correlation between
Smad4 and PAK3 pathway components suggests clinical use of Smad4 LOF as a potential marker
for prognosis in human lung cancer. Our study highlights the Smad4-PAK3 regulation as a point of
potential therapy in metastatic lung cancer.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
60
References
1
Citations
NaN
KQI