Sorcin-STAT3-Serpin E1/CCL5 axis can be the trigger of pancreatic cancer-associated new-onset diabetes

Abstract

AbstractA rise in blood glucose is the early warning signs of underlying pancreatic cancer (PC), which could be the externalization of genetic events in PC progression. But there is still a vacancy in the field of mechanism research on pancreatic cancer-associated new-onset diabetes (PCAND). Using siRNA-mediated gene knockdown in vitro, we made MIN6 cells incubated with conditioned media from transfected PC cells, and detected its response. Immunological techniques were used to explore the interaction between sorcin and STAT3. Human cytokine array was performed to explore the inflammatory cytokines downstream of sorcin. In the present study, we have identified a PCAND driver gene SRI. In PC cells, sorcin and STAT3 form a positive feedback loop to enhance the transcription of serpin E1 and CCL5, which can impair nearby islet β-cells, likely by activating the p38 pathway. In 88 biopsies, expression of sorcin was elevated in PC tissues, especially so in PCAND patient samples. Furthermore, clinical-SRI gene combination model can better distinguish PCAND from T2DM, and serpin E1 level is higher in the peripheral blood samples from PCAND than T2DM. Thus, Sorcin could be the key driver in PCAND, and figuring out sorcin-STAT3-serpin E1/CCL5 signaling axis can help us better understand the pathogenesis of PCAND and identify potential biomarkers.Statement of significanceThis study mapped out a novel sorcin-STAT3-Serpin E1/CCL5 signaling axis in pancreatic cancer cells, which explains how early pre-symptomatic pancreatic cancer may coincide with new-onset diabetes in some patients.