SMAD4 overexpression

Inhibition of hedgehog with cyclopamine effectively antagonized TGF-β1-induced EMT, thereby suggesting that the hedgehog signaling may act as a downstream cascade signaling of TGF-β1...Importantly, Gli1 activity was upregulated by Smad4 knockdown in PANC-1 cells and downregulated by Smad4 overexpression in BxPc-3 cells, indicating that Gli1 may be a negative target protein downstream of Smad4. Thus, Smad4 regulates TGF-β1-mediated hedgehog activation to promote EMT in PCCs by suppressing Gli1 activity.

In conclusion, the S100A2/SMAD4 axis modulates EMT to accelerate PDAC development. Our results supplement and enrich the understanding of the pathogenesis underlying PDAC and provide a new theoretical basis and strategy targeting S100A2 for the diagnosis and treatment of PDAC.

In addition, Smad4 expression was inversely correlated with laminin subunit gamma 1 (LAMC1) expression. The upregulation or downregulation of LAMC1 expression partially abolished the effect of Smad4 overexpression or silencing on the IM resistance of CML cells. The downregulation of Smad4 expression might induce drug resistance in CML cells and displayed a possible mechanism through which Smad4 modulates CML cell survival and apoptosis upon IM treatment.