The multifunctional growth factor midkine promotes proliferation and migration in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) has still a devastating prognosis among solid tumors and despite increased knowledge of molecular mechanisms contributing to progression and metastasis, no real progress has been done in establishing new targeted therapy options for this deadly disease.

The expression of the multifunctional growth/differentiation factor Midkine in various cancer cells promotes a variety of cellular functions leading to increased angiogenesis, proliferation, migration and survival. Moreover, Midkine is currently and intensively discussed as a potential new therapy-target and a biomarker for cancer progression and chemotherapeutical-resistance in different cancers. Therefore, the present study investigated the molecular role of Midkine in pancreatic cancer.

We found that Midkine is highly expressed in PDAC and differentially expressed in other histological subtypes of pancreatic cancer, whereas normal pancreatic cells do not express Midkine, and therefore making it an attractive candidate for targeted therapies. As a secreted growth/differentiation factor, we investigated whether Midkine may serve as a biomarker in patient derived serum samples using ELISA. Moreover, we found that siRNA- and shRNA-targeted knockdown of Midkine in pancreatic cancer cells, is linked to decreased proliferation and migration in vitro. Finally, we analyzed the upstream signaling and found that TNFalpha and EGF are main inductors of Midkine expression in PDAC.

Together, our results present novel Midkine functions and identified new upstream signaling molecules that may induce Midkine expression to promote proliferation and migration of PDAC cells and therefore implicates an attractive new therapeutical target molecule in pancreatic cancer.