Laminin-5 gamma2 Chain in Breast Cancer Metastasis

摘要

To metastasize, cancer cells have to break through the basement membrane. Ln-5 is one of the basement membrane proteins, consisting of three chains a3,B3 and y2. Ln-5 y2 chain continas DIII domain, a functional EGFR ligand, which can be released by MMP processing. It has been suggested by our lab that DIII domain may facilitate cancer progression by preventing anoikis. However, both the increased and decreased expression levels of Ln-5 subchains are reported in the literature. The fact that y2 chain exists in two different forms (as a secreted monomer, or as a part of the Ln-5 heterotrimer) leads us to hypothesize that those two forms may play different roles in cancer progression. What we report here is that removing Ln-5 heterotrimer (knocking down y2 chain by shRNA) promotes tumor progression by inducing Warburg effect in cancer cells. The Warburg effect describes that cancer cells consume more glucose than normal cells by converting it to lactate. It has been shown in almost all type of cancer. Reduced secretion of Ln-5, by knock-down of its y2 subunit (LAMC2-kd), caused increased glucose uptake, lactate production, and cytoplasmic NAD(P)H levels. This metabolic shift was dependent upon increased plasma membrane GLUTI. A blocking antibody to the Ln-332 receptor, integrin a3B1, caused GLUTI translocation in control cells (LAMC2-ctrl), pointing to a signaling pathway that regulates this anti-Warburg effect. LAMC2-kd cells produced tumors approximately 50 times larger than LAMC2-ctrl. Thus, we conclude that loss of contact with BMassociated ECM can unleash the Warburg effect, promoting tumor progression. The anti-Warburg effect by Ln-332 links ECM to metabolism and adds an unforeseen dimension to physiological functions of ECM and ECM receptors.