Expression of laminin gamma2 chain monomer enhances invasive growth of human carcinoma cells in vivo

Abstract

Laminin gamma2 chain is a subunit of the heterotrimeric basement membrane protein laminin-332 (alpha3beta3gamma2). The gamma2 chain is highly expressed by human cancers at the invasion fronts and this expression correlates with poor prognosis of the cancers. Our previous study showed that the gamma2 chain is expressed as a monomer form in invading carcinoma cells. However, the role of the gamma2 protein in tumor invasion remains unknown. Here, we demonstrate that the monomeric gamma2 chain promotes invasive growth of human cancer cells in vivo. First, we analyzed regulatory factors for the gamma2 chain expression using 2 gastric carcinoma cell lines. It was found that tumor necrosis factor-alpha, by itself or in a combination with transforming growth factor-beta1, strongly induced the secretion of the monomeric gamma2 chain. In addition, epidermal growth factor families appeared to function as the gamma2 chain inducers in human cancers. Next, we established T-24 bladder carcinoma cell lines expressing the full-length or the short arm of the laminin gamma2 chain. When these cell lines were i.p. injected into nude mice, they produced larger tumors in the abdominal cavity and showed much stronger invasive growth onto the diaphragms than the control cell line. The gamma2-expressing T-24 cells often produced ascites fluid, but scarcely the control cells. In culture, the gamma2-expressing cells migrated through Matrigel more efficiently than the control cells. These findings imply that the gamma2 monomer is induced in human cancers by inflammatory and stromal cytokines and promotes their invasive growth in vivo.