Basement membrane component laminin-5 is a target of the tumor suppressor Smad4

Abstract

The tumor suppressor Smad4 is involved in carcinogenesis mainly of the pancreas and colon. Functional inactivation of Smad4 is a genetically late event that occurs upon transition from premalignant stages to invasive and metastatic growth. Smad4 encodes an intracellular messenger common to all signalling cascades induced by members of the transforming growth factor-b (TGF-b) superfamily of cytokines. Despite extensive knowledge about the mechanisms of TGF-b/Smad signal transduction, little is known about Smad4 targets involved in the transition to malignancy. The hallmark of invasive growth is a breakdown of the basement membrane (BM), a specialized sheet of extracellular matrix produced through cooperation of epithelial and stromal cells. Laminin-5, a heterotrimeric epithelial-derived BM component, is commonly lost in carcinomas but not in premalignant tumors. Herein, we report that in human colon and pancreatic tumor cells, Smad4 functions as a positive transcriptional regulator of all three genes encoding laminin-5. Coordinate re-expression of the three laminin-5 chains induced by reconstitution of Smad4 leads to secretion and deposition of the heterotrimeric molecule in BM-like structures. These data define the expression control of an essential BM component as a novel function for the tumor suppressor Smad4.

MicroRNA-483-3p Inhibits Extracellular Matrix Production by Targeting Smad4 in Human Trabecular Meshwork Cells

“…29,46 Our data also supported that laminin production is dependent on Smad4. The feeble effect of knockdown Smad4 on collagen I may be due to other intracellular signaling pathways that regulate collagen I, requiring further study.…”

“…29 As above, we confirmed the inhibitory function of miR-483-3p on ECM production and identified Smad4, a known cofactor in TGF-b signaling pathway, as a direct target of miR-483-3p. Then we further explored the effect of Smad4 on regulating ECM induced by oxidative stress in HTMCs.…”

Natural history of hepatic metastases from colorectal cancer - pathobiological pathways with clinical significance

“…Moreover, laminin-5 is usually absent from the ECM structure in advanced CRC. Interestingly, new synthesis or accumulation of BM molecules (e.g., laminin-1 or 5) may also be imposed by tumours, and this phenomenon suggests the important role of BM in tumour invasion [53,54] . Similarly, modifications in ECM adhesion molecules also occur, while neoplastic cells express the appropriate adhesive receptors on their cellular membrane.…”

“…Type Ⅳ collagen in particular is of great importance and provides the basic scaffold that supports other BM components, such as laminin networks and perlecan oligomers [52][53][54] . Any alteration in ECM structural profile or degradation of any of its molecules may cause cellular and tissue dysfunction and therefore disease.…”

Proteolytic Processing of Laminin-332 by Hepsin and Matriptase and Its Role in Prostate Cancer Progression

“…A polyclonal antibody raised against the C-terminal sequence of Ln-332 β3 chain (Zapatka, Zboralski et al 2007) reacted in western blotting ( Figure 9A), both with the full-length β3 chain in Ln-332 alone and the 100 kDa hepsin-cleaved fragment This result suggested that hepsin cleaves the β3 chain of Ln-332, located in the ~100 kDa C-terminal region of rat Ln-332 β3 chain ( Figure 9A). This result indicates that hepsin cleaves the Ln-332 β3 chain in the vicinity of the N-terminus.…”