Lumican in Carcinogenesis-Revisited

Abstract

Carcinogenesis is a multifactorial process with the input and interactions of environmental, genetic, and metabolic factors. During cancer development, a significant remodeling of the extracellular matrix (ECM) is evident. Proteoglycans (PGs), such as lumican, are glycosylated proteins that participate in the formation of the ECM and are established biological mediators. Notably, lumican is involved in cellular processes associated with tumorigeneses, such as EMT (epithelial-to-mesenchymal transition), cellular proliferation, migration, invasion, and adhesion. Furthermore, lumican is expressed in various cancer tissues and is reported to have a positive or negative correlation with tumor progression. This review focuses on significant advances achieved regardingthe role of lumican in the tumor biology. Here, the effects of lumican on cancer cell growth, invasion, motility, and metastasis are discussed, as well as the repercussions on autophagy and apoptosis. Finally, in light of the available data, novel roles for lumican as a cancer prognosis marker, chemoresistance regulator, and cancer therapy target are proposed.

Keywords: biomarker; cancer; cancer cell growth; extracellular matrix; lumican; metastasis; motility; proteoglycans.

Figure 1

Schematic representation of lumican’s signaling in carcinogenesis. (a) Inhibiting the binding of FOXO3 to the lumican promoter by the small molecular weight leads to decreased FOXO3-dependent lumican expression and neuroblastoma cell migration. (b) Upon lumican downregulation, its colocalization with p120 catenin (p120ctn) decreases, leading to actin cytoskeleton remodeling and accelerated lung cancer cell invasion. (c) Lumican-deficient hepatic cancer cells show decreased invasion and migration mediated by reducing IGF-IR, ERK-1, and JNK activation status. (d) Lumican is an upstream regulator of the TGF-β2/Smad 2 signaling pathway in an osteosarcoma cell model, regulating cell adhesion. (e) Lumican interacts with the integrin β1/FAK signaling axis, affecting tumor progression positively or negatively. (f) Lumican induces the dimerization of the EGFR receptors and their subsequent uptake and degradation, leading to attenuated PDAC cell growth. (g) Hypoxia significantly reduces lumican secretion from pancreatic stellate cells and results in attenuated PDAC cell growth. (h) Lumican affects the signaling of Snail, an EMT trigger molecule that facilitates cancer metastasis, attenuating melanoma metastasis to the lungs.

Figure 2

Lumican affects cancer cell behavior.Lumican alters cancer cell proliferation, migration, adhesion, invasion, metastasis, and apoptosis, and affects autophagy and inflammation signaling pathways with different mechanisms.