Gp130-Mediated STAT3 Activation Contributes to the Aggressiveness of Pancreatic Cancer through H19 Long Non-Coding RNA Expression

SIMPLE SUMMARY: The signal transducer and activator of transcription 3 (STAT3) activation correlate with the aggressiveness of pancreatic ductal adenocarcinoma (PDAC). We demonstrated that the autocrine/paracrine interleukin-6 (IL-6) or leukemia inhibitory factor (LIF)/glycoprotein 130 (gp130)/STAT3 pathway contributes to the maintenance of stemness features and membrane-type 1 matrix metalloproteinase (MT1-MMP) expression, and modulates transforming growth factor (TGF)-β1/Smad signaling-mediated epithelial-mesenchymal transition (EMT) and invasion through regulation of TGFβ-RII expression in PDAC cancer stem cell (CSC)-like cells. Furthermore, we demonstrated that p-STAT3 acts through the IL-6 or LIF/gp130/STAT3 pathway to access the active promoter region of metastasis-related long non-coding RNA H19 and contribute to its transcription in CSC-like cells. Therefore, the autocrine/paracrine IL-6 or LIF/gp130/STAT3 pathway in PDAC CSC-like cells exhibiting H19 expression is considered to be involved in the aggressiveness of PDAC, and inhibition of the gp130/STAT3 pathway is a promising strategy to target CSCs for the elimination of PDAC (146/150). ABSTRACT: Signaling pathways involving signal transducer and activator of transcription 3 (STAT3) play key roles in the aggressiveness of pancreatic ductal adenocarcinoma (PDAC), including their tumorigenesis, invasion, and metastasis. Cancer stem cells (CSCs) have been correlated with PDAC aggressiveness, and activation of STAT3 is involved in the regulation of CSC properties. Here, we investigated the involvement of interleukin-6 (IL-6) or the leukemia inhibitory factor (LIF)/glycoprotein 130 (gp130)/STAT3 pathway and their role in pancreatic CSCs. In PDAC CSC-like cells formed by culturing on a low attachment plate, autocrine/paracrine IL-6 or LIF contributes to gp130/STAT3 pathway activation. Using a gp130 inhibitor, we determined that the gp130/STAT3 pathway contributes to the maintenance of stemness features, the expression of membrane-type 1 matrix metalloproteinase (MT1-MMP), and the invasion of PDAC CSC-like cells. The gp130/STAT3 pathway also modulates the transforming growth factor (TGF)-β1/Smad pathway required for epithelial-mesenchymal transition induction through regulation of TGFβ-RII expression in PDAC CSC-like cells. Furthermore, chromatin immunoprecipitation assays revealed that p-STAT3 can access the active promoter region of H19 to influence this metastasis-related long non-coding RNA and contribute to its transcription in PDAC CSC-like cells. Therefore, the autocrine/paracrine IL-6 or LIF/gp130/STAT3 pathway in PDAC CSC-like cells may eventually facilitate invasion and metastasis, two hallmarks of malignancy. We propose that inhibition of the gp130/STAT3 pathway provides a promising strategy for targeting CSCs for the treatment of PDAC.