Abstract
BackgroundLow-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor involved in receptor-mediated endocytosis and cell signaling. The aim of this study was to elucidate the expression and mechanism of LRP1 in hepatocellular carcinoma (HCC).MethodsLRP1 expression in 4 HCC cell lines and 40 HCC samples was detected. After interruption of LRP1 expression in a HCC cell line either with specific lentiviral-mediated shRNA LRP1 or in the presence of the LRP1-specific chaperone, receptor-associated protein (RAP), the role of LRP1 in the migration and invasion of HCC cells was assessed in vivo and in vitro, and the expression of matrix metalloproteinase (MMP) 9 in cells and the bioactivity of MMP9 in the supernatant were assayed. The expression and prognostic value of LRP1 were investigated in 327 HCC specimens.ResultsLow LRP1 expression was associated with poor HCC prognosis, with low expression independently related to shortened overall survival and increased tumor recurrence rate. Expression of LRP1 in non-recurrent HCC samples was significantly higher than that in early recurrent samples. LRP1 expression in HCC cell lines was inversely correlated with their metastatic potential. After inhibition of LRP1, low-metastatic SMCC-7721 cells showed enhanced migration and invasion and increased expression and bioactivity of MMP9. Correlation analysis showed a negative correlation between LRP1 and MMP9 expression in HCC patients. The prognostic value of LRP1 expression was validated in the independent data set.ConclusionsLRP1 modulated the level of MMP9 and low level of LRP1 expression was associated with aggressiveness and invasiveness in HCCs. LRP1 offered a possible strategy for tumor molecular therapy.
Highlights
Hepatocellular carcinoma (HCC) is one of most frequent neoplasm worldwide [1], and has become a major cause of cancerrelated death globally, owing to its high potential of invasion and metastasis
Low Expression of lipoprotein receptor-related protein 1 (LRP1) was Correlated with High Metastatic Potential in hepatocellular carcinoma (HCC)
LRP1 expression was detected in 4 HCC cell lines with different metastatic potential at the mRNA (Fig. 1A) and protein (Fig. 1B) levels. Quantitative Real-time Polymerase Chain Reaction (qRT-PCR) showed that LRP1 expression level in the highest metastatic cell HCCLM3 was the lowest among 4 HCC cell lines (Fig. 1A, P,0.05), in line with the results from immunoblotting (Fig. 1B)
Summary
Hepatocellular carcinoma (HCC) is one of most frequent neoplasm worldwide [1], and has become a major cause of cancerrelated death globally, owing to its high potential of invasion and metastasis. The molecular mechanism linked to invasion and metastasis of HCC is not fully understood. The low-density lipoprotein receptor (LDLR)-related protein-1 (LRP1) is a member of LDLR family, which is ubiquitously expressed in a variety of organs including adipose tissue, liver and brain [2]. It consists of a 515 kDa heavy chain that contains four clusters of ligand binding domains and a non-covalently associated 85 kDa light chain that contains a trans-membrane and cytoplasmic domain [3]. The aim of this study was to elucidate the expression and mechanism of LRP1 in hepatocellular carcinoma (HCC)
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