SPOCK1 Promotes the Development of Hepatocellular Carcinoma

Abstract

The extracellular matrix proteoglycan SPOCK1 is increasingly recognized as a contributor to the development and progression of cancers. Here, we study how SPOCK1, which is present in non-tumorous hepatocytes at low concentrations, promotes the development and progression of malignant hepatocellular tumors. Although SPOCK1 is an extracellular matrix proteoglycan, its concentration increases in the cytoplasm of hepatocytes starting with very low expression in the normal cells and then appearing in much higher quantities in cells of cirrhotic human liver and hepatocellular carcinoma. This observation is similar to that observed after diethylnitrosamine induction of mouse hepatocarcinogenesis. Furthermore, syndecan-1, the major proteoglycan of the liver, and SPOCK1 are in inverse correlation in the course of these events. In hepatoma cell lines, the cytoplasmic SPOCK1 colocalized with mitochondrial markers, such as MitoTracker and TOMM20, a characteristic protein of the outer membrane of the mitochondrion and could be detected in the cell nucleus. SPOCK1 downregulation of hepatoma cell lines by siRNA inhibited cell proliferation, upregulated p21 and p27, and interfered with pAkt and CDK4 expression. A tyrosine kinase array revealed that inhibition of SPOCK1 in the liver cancer cells altered MAPK signaling and downregulated several members of the Sarc family, all related to the aggressivity of the hepatoma cell lines. These studies support the idea that SPOCK1 enhancement in the liver is an active contributor to human and rodent hepatocarcinogenesis and cancer progression. However, its mitochondrial localization raises the possibility that it has a currently unidentified physiological function in normal hepatocytes.

SPOCK1 Overexpression Suggests Poor Prognosis of Ovarian Cancer

“…The construction of plasmid for wild-type and SPOCK1 overexpressing vectors has been described previously [ 15 ]. The transfection was carried out with the Neon Transfection System (MPK5000, Life Technologies, Carlsbad, CA, USA), using a 100 µL pipette tip.…”

“…It inhibits tumor cell apoptosis and, with the cooperation of TGF-β, facilitates EMT [ 14 ]. Recent studies have demonstrated its localization in the nuclei and mitochondria of tumor cells, but its physiological functions have not yet been determined [ 15 ]. Its physiological functions in epithelial cells have yet to be discovered, with the exception of a single publication about its implication in heat regulation of fat cells.…”

“…SPOCK1 has been detected in the blood circulation of patients with sepsis [ 16 ]. Our recent studies on mouse, rat and human livers revealed that experimental hepatocarcinogenesis upregulates testican-1 in the transformed hepatocytes, and that abundant amounts of the proteoglycan can be detected in liver cirrhosis and hepatocellular cancer, but not in the ECM [ 15 ]. Additionally, in vitro experiments revealed that the proteoglycan has a signal for secretion, allowing it to leave the cells and enter the culture medium, thereby maintaining the equilibrium inside the cells.…”

SPOCK2 Promotes the Malignant Behavior of Ovarian Cancer via Regulation of the Wnt/β-Catenin Signaling Pathway

“…SPOCK family proteins are proteoglycans of the vertebrate extracellular matrix (ECM) [ 8 ]. SPOCK-encoded proteins are capable of participating in a variety of physiological and pathological cellular processes, including tumor progression [ 9 ], epithelial-mesenchymal transition [ 10 ], and Alzheimer's disease [ 11 ], which are hallmarks of both pathological processes such as cancer cell invasion and normal physiological processes such as morphogenesis and differentiation. SPOCK2, also known as Testin-2, is a member of the SPOCK family.…”

Proteoglycans: Systems-Level Insight into Their Expression in Healthy and Diseased Placentas

“…Indeed, among the properties shared by placental trophoblast cells and cancer cells are the capabilities to invade healthy tissues, form new vessels, and promote an environment that is protected from the immune system [ 28 ]. Since proteoglycans are strongly involved in various processes during tumorigenesis, which was reviewed by several workgroups [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ], they may have similar key roles in these processes during placentation.…”