LAMC2 modulates the acidity of microenvironments to promote invasion and migration of pancreatic cancer cells via regulating AKT-dependent NHE1 activity

Abstract

LAMC2, as a unique chain in the Laminin 5 molecule, has been found to be associated with malignant metastases in some cancers. However, the roles and mechanisms by which LAMC2 affects the migration and invasion of pancreatic cancer cells remain unclear. First, we found that laminin 5/LAMC2 and its receptors were highly expressed in pancreatic cancer tissues and cells. Then, we investigated the effects of LAMC2 on pancreatic cancer cell migration/invasion and extracellular (pHe). We also demonstrated that LAMC2 phosphorylated Akt-Ser473 to promote the expression, activity and cell membrane accumulation of NHE1 within pancreatic cancer cells. So we speculated that LAMC2 modulated the pHe to promote migration and invasion of pancreatic cancer cells. Additionally, our data also showed that LAMC2/NHE1 resulted in altered cell morphology and aberrant expression of mesenchymal markers. The function of actin-binding proteins (ABPs) were affected by LAMC2/NHE1 signaling. LAMC2/NHE1 signaling generated extracellular acidification to induce dynamic actin-dependent pseudopodial formation and EMT programs that promote tumor cell invasion in pancreatic cancer cells. Therefore, we found that LAMC2 was responsible for generating the extracellular acidic conditions that mediated invasion of pancreatic cancer cells by activating Akt/NHE1 signaling. LAMC2 is a characteristic prognostic and therapeutic agent of PDCA.