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Series GSE164436 Query DataSets for GSE164436
Status Public on May 07, 2021
Title Loss of Smad4 promotes aggressive lung cancer metastasis by de-repression of PAK3 via miRNA regulation
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary 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 3’UTR 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.
 
Overall design In this study, we used adeno-Cre to conditionally activate a KrasG12D allele with concomitant deletion of Smad4 (Smad4 fl/fl) and p53 (p53fl/fl) genes to induce lung cancer. Expression of mutant KrasG12D along with p53 and Smad4 loss-of-function (LOF) engendered a high incidence of metastasis to different tissues, compared to that found in p53fl/fl; KrasG12D mice. We isolated lung tumors from Adeno-Cre - Smad4 fl/fl - p53 fl/fl - KrasG12D (SPK) mice and from Adeno-Cre - p53 fl/fl - KrasG12D (PK) mice, respectively. And then we conducted RNA-Seq analysis between SPK cells and PK cells.
 
Contributor(s) Li L, Song D, Yang X, Liu J, Li X
Citation(s) 34381046
Submission date Jan 08, 2021
Last update date Aug 12, 2021
Contact name Jian Liu
E-mail(s) JianL@intl.zju.edu.cn
Organization name Zhejiang University
Department Zhejiang University - University of Edinburgh Institute
Lab Jian Liu's lab
Street address 718 East Haizhou Rd.
City Haining
State/province Zhejiang
ZIP/Postal code 314400
Country China
 
Platforms (1)
GPL21273 HiSeq X Ten (Mus musculus)
Samples (6)
GSM5009595 SPK-1
GSM5009596 SPK-2
GSM5009597 SPK-3
Relations
BioProject PRJNA690712
SRA SRP300884

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE164436_RNAseq-FPKM.txt.gz 397.0 Kb (ftp)(http) TXT
SRA Run SelectorHelp
Raw data are available in SRA
Processed data are available on Series record

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