Here we revealed, for the first time to our knowledge, an intracellular pathway in which ADAM8, a metalloprotease-disintegrin that is clearly distinct from the classical membrane shedding enzyme, regulates aberrant STAT3 signaling by controlling the expression of the intracellular lncRNA NEAT1 in pancreatic cancer cell lines via ADAM8-dependent miR-181a-5p expression. Here, STAT3 is linked to familial pancreatic carcinoma.