TY - JOUR
T1 - Loss of Smad4 promotes aggressive lung cancer metastasis by de-repression of PAK3 via miRNA regulation
AU - Tan, Xiaohong
AU - Tong, Lu
AU - Li, Lin
AU - Xu, Jinjin
AU - Xie, Shaofang
AU - Ji, Lei
AU - Fu, Junjiang
AU - Liu, Qingwu
AU - Shen, Shihui
AU - Liu, Yun
AU - Xiao, Yanhui
AU - Gao, Feiran
AU - Moses, Robb E.
AU - Bardeesy, Nabeel
AU - Wang, Yanxiao
AU - Zhang, Jishuai
AU - Tang, Longying
AU - Li, Lei
AU - Wong, Kwok kin
AU - Song, Dianwen
AU - Yang, Xiao
AU - Liu, Jian
AU - Li, Xiaotao
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - SMAD4 is mutated in human lung cancer, but the underlying mechanism by which Smad4 loss-of-function (LOF) accelerates lung cancer metastasis is yet to be elucidated. Here, we generate a highly aggressive lung cancer mouse model bearing conditional KrasG12D, p53fl/fl LOF and Smad4fl/fl LOF mutations (SPK), showing a much higher incidence of tumor metastases than the KrasG12D, p53fl/fl (PK) mice. Molecularly, PAK3 is identified as a downstream effector of Smad4, mediating metastatic signal transduction via the PAK3-JNK-Jun pathway. Upregulation of PAK3 by Smad4 LOF in SPK mice is 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 is observed in human lung cancer. Our study highlights the Smad4-PAK3 regulation as a point of potential therapy in metastatic lung cancer.
AB - SMAD4 is mutated in human lung cancer, but the underlying mechanism by which Smad4 loss-of-function (LOF) accelerates lung cancer metastasis is yet to be elucidated. Here, we generate a highly aggressive lung cancer mouse model bearing conditional KrasG12D, p53fl/fl LOF and Smad4fl/fl LOF mutations (SPK), showing a much higher incidence of tumor metastases than the KrasG12D, p53fl/fl (PK) mice. Molecularly, PAK3 is identified as a downstream effector of Smad4, mediating metastatic signal transduction via the PAK3-JNK-Jun pathway. Upregulation of PAK3 by Smad4 LOF in SPK mice is 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 is observed in human lung cancer. Our study highlights the Smad4-PAK3 regulation as a point of potential therapy in metastatic lung cancer.
UR - https://www.scopus.com/pages/publications/85112328623
U2 - 10.1038/s41467-021-24898-9
DO - 10.1038/s41467-021-24898-9
M3 - 文章
C2 - 34381046
AN - SCOPUS:85112328623
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4853
ER -
可持续发展目标 3 良好健康与福祉