Background Low-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). Methods LRP1 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. Results Low 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. Conclusions LRP1 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.
References
[1]
Jemal A, Bray F, Center MM, Ferlay J, Ward E, et al. (2011) Global cancer statistics. CA Cancer J Clin 61: 69–90.
[2]
Moestrup SK, Gliemann J, Pallesen G (1992) Distribution of the alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein in human tissues. Cell Tissue Res 269: 375–382.
[3]
Takayama Y, May P, Anderson RG, Herz J (2005) Low density lipoprotein receptor-related protein 1 (LRP1) controls endocytosis and c-CBL-mediated ubiquitination of the platelet-derived growth factor receptor beta (PDGFR beta). J Biol Chem 280: 18504–18510.
[4]
Strickland DK, Ashcom JD, Williams S, Burgess WH, Migliorini M, et al. (1990) Sequence identity between the alpha 2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor. J Biol Chem 265: 17401–17404.
[5]
Herz J, Strickland DK (2001) LRP: a multifunctional scavenger and signaling receptor. J Clin Invest 108: 779–784.
[6]
Herz J, Bock HH (2002) Lipoprotein receptors in the nervous system. Annu Rev Biochem 71: 405–434.
[7]
Greenaway J, Lawler J, Moorehead R, Bornstein P, Lamarre J, et al. (2007) Thrombospondin-1 inhibits VEGF levels in the ovary directly by binding and internalization via the low density lipoprotein receptor-related protein-1 (LRP-1). J Cell Physiol 210: 807–818.
[8]
Barnes H, Larsen B, Tyers M, van Der Geer P (2001) Tyrosine-phosphorylated low density lipoprotein receptor-related protein 1 (Lrp1) associates with the adaptor protein SHC in SRC-transformed cells. J Biol Chem 276: 19119–19125.
[9]
Foca C, Moses EK, Quinn MA, Rice GE (2000) Differential expression of the alpha(2)-macroglobulin receptor and the receptor associated protein in normal human endometrium and endometrial carcinoma. Mol Hum Reprod 6: 921–927.
[10]
Sid B, Dedieu S, Delorme N, Sartelet H, Rath GM, et al. (2006) Human thyroid carcinoma cell invasion is controlled by the low density lipoprotein receptor-related protein-mediated clearance of urokinase plasminogen activator. Int J Biochem Cell Biol 38: 1729–1740.
[11]
Desrosiers RR, Rivard ME, Grundy PE, Annabi B (2006) Decrease in LDL receptor-related protein expression and function correlates with advanced stages of Wilms tumors. Pediatr Blood Cancer 46: 40–49.
[12]
Meng H, Chen G, Zhang X, Wang Z, Thomas DG, et al. (2011) Stromal LRP1 in lung adenocarcinoma predicts clinical outcome. Clin Cancer Res 17: 2426–2433.
[13]
Kancha RK, Stearns ME, Hussain MM (1994) Decreased expression of the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor in invasive cell clones derived from human prostate and breast tumor cells. Oncol Res 6: 365–372.
[14]
Song H, Li Y, Lee J, Schwartz AL, Bu G (2009) Low-density lipoprotein receptor-related protein 1 promotes cancer cell migration and invasion by inducing the expression of matrix metalloproteinases 2 and 9. Cancer Res 69: 879–886.
[15]
Song PM, Zhang Y, He YF, Bao HM, Luo JH, et al. (2008) Bioinformatics analysis of metastasis-related proteins in hepatocellular carcinoma. World J Gastroenterol 14: 5816–5822.
[16]
Ke AW, Shi GM, Zhou J, Huang XY, Shi YH, et al. (2011) CD151 amplifies signaling by integrin alpha6beta1 to PI3K and induces the epithelial-mesenchymal transition in HCC cells. Gastroenterology 140: 1629–1641 e1615.
[17]
Ke AW, Shi GM, Zhou J, Wu FZ, Ding ZB, et al. (2009) Role of overexpression of CD151 and/or c-Met in predicting prognosis of hepatocellular carcinoma. Hepatology 49: 491–503.
[18]
Devbhandari RP, Shi GM, Ke AW, Wu FZ, Huang XY, et al. (2011) Profiling of the Tetraspanin CD151 Web and Conspiracy of CD151/Integrin beta1 Complex in the Progression of Hepatocellular Carcinoma. PLoS One 6: e24901.
[19]
Xu Z, Shen MX, Ma DZ, Wang LY, Zha XL (2003) TGF-beta1-promoted epithelial-to-mesenchymal transformation and cell adhesion contribute to TGF-beta1-enhanced cell migration in SMMC-7721 cells. Cell Res 13: 343–350.
[20]
Shi GM, Xu Y, Fan J, Zhou J, Yang XR, et al. (2008) Identification of side population cells in human hepatocellular carcinoma cell lines with stepwise metastatic potentials. J Cancer Res Clin Oncol 134: 1155–1163.
[21]
Shi GM, Ke AW, Zhou J, Wang XY, Xu Y, et al. (2010) CD151 modulates expression of matrix metalloproteinase 9 and promotes neoangiogenesis and progression of hepatocellular carcinoma. Hepatology 52: 183–196.
[22]
Wittekind C (2006) [Pitfalls in the classification of liver tumors]. Pathologe 27: 289–293.
[23]
Ding ZB, Shi YH, Zhou J, Shi GM, Ke AW, et al. (2009) Liver-intestine cadherin predicts microvascular invasion and poor prognosis of hepatitis B virus-positive hepatocellular carcinoma. Cancer 115: 4753–4765.
[24]
Huang XY, Ke AW, Shi GM, Ding ZB, Devbhandari RP, et al. (2010) Overexpression of CD151 as an adverse marker for intrahepatic cholangiocarcinoma patients. Cancer 116: 5440–5451.
[25]
Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, et al. (2008) Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 100: 698–711.
[26]
Sohda T, Iwata K, Kitamura Y, Suzuki N, Takeyama Y, et al. (2008) Reduced expression of low-density lipoprotein receptor in hepatocellular carcinoma with paraneoplastic hypercholesterolemia. J Gastroenterol Hepatol 23: e153–156.
[27]
de Vries TJ, Verheijen JH, de Bart AC, Weidle UH, Ruiter DJ, et al. (1996) Decreased expression of both the low-density lipoprotein receptor-related protein/alpha(2)-macroglobulin receptor and its receptor-associated protein in late stages of cutaneous melanocytic tumor progression. Cancer Res 56: 1432–1439.
[28]
Song H, Bu G (2009) MicroRNA-205 inhibits tumor cell migration through down-regulating the expression of the LDL receptor-related protein 1. Biochem Biophys Res Commun 388: 400–405.
Wu L, Arandjelovic S, Gonias SL (2004) Effects of low density lipoprotein receptor-related protein-1 on the expression of platelet-derived growth factor beta-receptor in vitro. J Cell Biochem 93: 1169–1177.
[31]
Arii S, Mise M, Harada T, Furutani M, Ishigami S, et al. (1996) Overexpression of matrix metalloproteinase 9 gene in hepatocellular carcinoma with invasive potential. Hepatology 24: 316–322.
[32]
Langlois B, Perrot G, Schneider C, Henriet P, Emonard H, et al. (2010) LRP-1 promotes cancer cell invasion by supporting ERK and inhibiting JNK signaling pathways. PLoS One 5: e11584.
[33]
Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2: 161–174.
[34]
Hahn-Dantona E, Ruiz JF, Bornstein P, Strickland DK (2001) The low density lipoprotein receptor-related protein modulates levels of matrix metalloproteinase 9 (MMP-9) by mediating its cellular catabolism. J Biol Chem 276: 15498–15503.
