α2 Integrin-Dependent Suppression of Pancreatic Adenocarcinoma Cell Invasion Involves Ectodomain Regulation of Kallikrein-Related Peptidase-5

[摘要] Previous reports demonstrate that theα2-integrin (α2) mediates pancreatic ductal adenocarcinoma (PDAC) cell interactions with collagens. We found that while well-differentiated cells useα2 exclusively to adhere and migrate on collagenI, poorly differentiated PDAC cells demonstrate reduced reliance on, or complete loss of,α2. Since well-differentiated PDAC lines exhibit reducedin vitroinvasion andα2-blockade suppressed invasion of well-differentiated lines exclusively, we hypothesized thatα2 may suppress the malignant phenotype in PDAC. Accordingly, ectopic expression ofα2 retardedin vitroinvasion and maintenance on collagenI exacerbated this effect. Affymetrix profiling revealed that kallikrein-related peptidase-5 (KLK5) was specifically upregulated byα2, and reducedα2 and KLK5 expression was observed in poorly differentiated PDAC cellsin situ. Accordingly, well-differentiated PDAC lines express KLK5, and KLK5 blockade increased the invasion of KLK5-positive lines. Theα2-cytoplasmic domain was dispensable for these effects, demonstrating that theα2-ectodomain and KLK5 coordinately regulate a less invasive phenotype in PDAC.

[学科分类] 肿瘤学