Decorin deficiency promotes hepatic carcinogenesis

Abstract

Hepatocellular carcinoma represents one of the most-rapidly spreading cancers in the world. In the majority of cases, an inflammation-driven fibrosis or cirrhosis precedes the development of the tumor. During malignant transformation, the tumor microenvironment undergoes qualitative and quantitative changes that modulate the behavior of the malignant cells. A key constituent for the hepatic microenvironment is the small leucine-rich proteoglycan decorin, known to interfere with cellular events of tumorigenesis mainly by blocking various receptor tyrosine kinases (RTK) such as EGFR, Met, IGF-IR, PDGFR and VEGFR2. In this study, we characterized cell signaling events evoked by decorin deficiency in two experimental models of hepatocarcinogenesis using thioacetamide or diethyl nitrosamine as carcinogens. Genetic ablation of decorin led to enhanced tumor occurrence as compared to wild-type animals. These findings correlated with decreased levels of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 and a concurrent elevation in retinoblastoma protein phosphorylation via cyclin dependent kinase 4. Decreased steady state p21Waf1/Cip1 levels correlated with enhanced expression of transcription factor AP4, a known transcriptional repressor of p21Waf1/Cip1, and enhanced c-Myc protein levels. In addition, translocation of β-catenin was a typical event in diethyl nitrosamine-evoked tumors. In parallel, decreased phosphorylation of both c-Myc and β-catenin was observed in Dcn−/− livers likely due to the hindered GSK3β-mediated targeting of these proteins to proteasomal degradation. We discovered that in a genetic background lacking decorin, four RTKs were constitutively activated (phosphorylated), including three known targets of decorin such as PDGFRα, EGFR, IGF-IR, and a novel RTK MSPR/RON. Our findings provide powerful genetic evidence for a crucial in vivo role of decorin during hepatocarcinogenesis as lack of decorin in the liver and hepatic stroma facilitates experimental carcinogenesis by providing an environment devoid of this potent pan-RTK inhibitor. Thus, our results support future utilization of decorin as an antitumor agent in liver cancer.

Decorin as a multivalent therapeutic agent against cancer

“…From this screen, PDGFR-α/β emerged (Fig. 1B) as a viable candidate to which decorin engages with high affinity and suppresses the formation of HCC [68]. Importantly, these results are congruent with the finding that decorin is suppressed, at the transcriptomic level, in HCC [69].…”

“…Screening the RTKome of two different chemically induced models of hepatocellular carcinoma (HCC), it was found that, in a Dcn null background, many RTKs are constitutively activated [68]. Indeed, the global loss of decorin permits inappropriate, basal activation of several RTKs as measured by an increase in the phospho-Tyr signal.…”

“…desmoplastic-type reaction) as well as acting in a paracrine manner to downregulate the adjacent RTKs present on the tumor cell surface. As it pertains to the tumor proper, several studies have clearly demonstrated a complete loss of decorin expression in several tumor types, such as urothelial, prostate, myeloma, and hepatic carcinoma [63-68]. Utilizing an unbiased deep RNA sequencing method of hepatocellular carcinomas, several prominent matrix constituents were decreased, including decorin [69].…”

Insights into the key roles of proteoglycans in breast cancer biology and translational medicine

“…Foremost, decorin is a pan-receptor tyrosine kinase (RTK) inhibitor [58, 59] that affects receptor function at multiple levels, including modulation and bioavailability of receptor ligands [60], for tumorigenic and metastatic suppression [61–65]. Perhaps the most striking evidence for decorin as “a guardian from the matrix” derives from the observation that decorin deficiency is permissive for tumorigenesis [66–68] and increases the basal activity of multiple receptor tyrosine kinases and is further permissive for progression of HCC [69]. Further, as decorin can integrate signaling over multiple receptors including EGFR and IGF-IR, it remains possible that decorin can affect the ERs as well in estrogen responsive breast carcinomas [27].…”

Extracellular matrix as target for antitumor therapy

“…Upregulation of decorin A549 tumor cells resulted in decreased TGF-β1, cyclin D1 expression, and phosphorylation of EGFR, but higher levels of p53 and of p21 (Waf1/Cip1). The changes of these signaling molecules could be correlated with the decreased invasive growth and cell cycle blockage at G1 76,77…”