ABSTRACT
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.
Subject(s)
Lung Neoplasms/pathology , MicroRNAs/genetics , Smad4 Protein/metabolism , p21-Activated Kinases/metabolism , 3' Untranslated Regions , Animals , Cell Movement , Gene Expression Regulation, Neoplastic , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Loss of Function Mutation , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Mice , MicroRNAs/metabolism , Neoplasm Metastasis , Proto-Oncogene Proteins c-jun/metabolism , Signal Transduction , Smad4 Protein/genetics , Transcriptional Activation , p21-Activated Kinases/geneticsABSTRACT
Biomolecules specifically aggregate in the cytoplasm and nucleus, driving liquid-liquid phase separation (LLPS) formation and diverse biological processes. Extensive studies have focused on revealing multiple functional membraneless organelles in both the nucleus and cytoplasm. Condensation compositions of LLPS, such as proteins and RNAs affecting the formation of phase separation, have been gradually unveiled. LncRNAs possessing abundant second structures usually promote phase separation formation by providing architectural scaffolds for diverse RNAs and proteins interaction in both the nucleus and cytoplasm. Beyond scaffolds, lncRNAs may possess more diverse functions, such as functioning as enhancer RNAs or buffers. In this review, we summarized current studies on the function of phase separation and its related lncRNAs, mainly in the nucleus. This review will facilitate our understanding of the formation and function of phase separation and the role of lncRNAs in these processes and related biological activities. A deeper understanding of the formation and maintaining of phase separation will be beneficial for disease diagnosis and treatment.
