PAI-1-dependent inactivation of SMAD4-modulated junction and adhesion complex in obese endometrial cancer
While plasminogen activator inhibitor-1 (PAI-1) is known to potentiate cellular migration via proteolytic regulation, this adipokine is implicated as an oncogenic ligand in the tumor microenvironment. To understand the underlying paracrine mechanism, here we conduct transcriptomic analysis of 1,898 endometrial epithelial cells (EECs) exposed and unexposed to PAI-1-secreting adipose stromal cells. The PAI-1-dependent action deregulates crosstalk among tumor-promoting and -repressing pathways, including TGFβ. When PAI-1 is tethered to LRP1, the internalized signaling causes downregulation of SMAD4 at the transcriptional and post-translational levels that attenuate TGFβ-related transcription programs. Repression of genes encoding junction and adhesion complex preferentially occurs in SMAD4-underexpressed EECs of obese patients. The findings highlight a previously uncharacterized role of PAI-1 signaling that renders ineffective intercellular communication for the development of adiposity-associated endometrial cancer.
Li-Ling Lin, Edward R. Kost, Chun-Lin Lin, Philip Valente, Chiou-Miin Wang, Mikhail G. Kolonin, Alexes C. Daquinag, Xi Tan, Nicholas Lucio, Chia-Nung Hung, Chen-Pin Wang, Nameer B. Kirma* and Tim H.-M. Huang*. Cell Reports. 2020. In Press.