Major Action of Endogenous Lysyl Oxidase in Clear Cell Renal Cell Carcinoma Progression and Collagen Stiffness Revealed by Primary Cell Cultures

Abstract

Human clear cell renal cell carcinoma (ccRCC) is therapy resistant; therefore, it is worthwhile studying in depth the molecular aspects of its progression. In ccRCC the biallelic inactivation of the VHL gene leads to stabilization of hypoxia-inducible factors (HIFs). Among the targets of HIF-1α transcriptional activity is the LOX gene, which codes for the inactive proenzyme (Pro-Lox) from which, after extracellular secretion and proteolysis, derives the active enzyme (Lox) and the propeptide (Lox-PP). By increasing stiffness of extracellular matrix by collagen crosslinking, Lox promotes tumor progression and metastasis. Lox and Lox-PP can reenter the cells where Lox promotes cell proliferation and invasion, whereas Lox-PP acts as tumor suppressor because of its Ras recision and apoptotic activity. Few data are available concerning LOX in ccRCC. Using an in vitro model of ccRCC primary cell cultures, we performed, for the first time in ccRCC, a detailed study of endogenous LOX and also investigated their transcriptomic profile. We found that endogenous LOX is overexpressed in ccRCC, is involved in a positive-regulative loop with HIF-1α, and has a major action on ccRCC progression through cellular adhesion, migration, and collagen matrix stiffness increment; however, the oncosuppressive action of Lox-PP was not found to prevail. These findings may suggest translational approaches for new therapeutic strategies in ccRCC.

The glucose and lipid metabolism reprogramming is grade-dependent in clear cell renal cell carcinoma primary cultures and is targetable to modulate cell viability and proliferation

“…To highlight the metabolic signature of ccRCC primary cultures we revised our previously published gene expression microarray data, generated on a collection of ccRCC and normal cortex primary cultures, and corresponding Gene Ontology (GO) enrichment analysis [ 17 ] to focus on metabolic processes. In ccRCC primary cultures, we found a significant enrichment for 35 GO-biological process (BP) terms related to several classes of metabolic processes (Figure 2 ).…”

Urinary collagen degradation products as early markers of progressive renal fibrosis

“…In our study, we only measured levels of collagen degradation markers between 6 and 12 weeks after ADR-injection, the period when lysyl oxidase levels are increasing, but collagen crosslinking has just begon and is not at his final stage. Lysyl oxidase has also been shown to be involved in fibrosis in humans [48, 49]. In patients with CKD the disease is present for longer then 6–12 weeks and collagen crosslinking is already occurring in abundance, making it hard for MMPs to degradate the collagens.…”

The role of collagen in cancer: from bench to bedside

“…Hypoxiainducible factor (HIF)-1, LOX, and MMP participate in the process. COLI fibers are reduced in the hypoxic microenvironment via increased expression of LOX in renal cell carcinoma, decreased expression of MMP-3 in breast cancer, or decreased expression of MMP-1 and MMP-16 in prostate cancer [105,106]. Collagen can be remodeled by HIF-1 regulating LOXL1, LOXL2, and LOXL4 [107].…”