ABSTRACT
OBJECTIVE: We aimed to determine whether LR11 (low-density lipoprotein receptor with 11 binding repeats) is a potential key regulator of smooth muscle cell (SMC) proliferation during the progression of hypoxia-induced medial thickening in mice and whether sLR11 (soluble LR11) can serve as a biomarker in patients with pulmonary arterial hypertension. APPROACH AND RESULTS: The role of LR11 in pulmonary arterial hypertension was investigated using mouse and cell models of induced hypoxia. The expression of LR11 and of hypoxia-inducible factor-1α was significantly increased in lung tissues from C57Bl/6 mice after 3 weeks of exposure to hypoxia compared with normoxia. Serum sLR11 levels were also increased. Physiological and histochemical analyses showed that increased right ventricular systolic pressure, right ventricular hypertrophy, and medial thickening induced under hypoxia in wild-type mice were attenuated in LR11(-/-) mice. The proliferation rates stimulated by hypoxia or platelet-derived growth factor-BB were attenuated in SMC derived from LR11(-/-) mice, compared with those from wild-type mice. Exogenous sLR11 protein increased the proliferation rates of SMC from wild-type mice. The expression of LR11 and hypoxia-inducible factor-1α was increased in cultured SMC under hypoxic conditions, and hypoxia-inducible factor-1α knockdown almost abolished the induction of LR11. Serum sLR11 levels were significantly higher in patients with, rather than without, pulmonary arterial hypertension. sLR11 levels positively correlated with pulmonary vascular resistance and mean pulmonary arterial pressure. CONCLUSIONS: LR11 regulated SMC proliferation during the progression of hypoxia-induced medial thickening in mice. The findings obtained from mice, together with those in humans, indicate that sLR11 could serve as a novel biomarker that reflects the pathophysiology of proliferating medial SMC in pulmonary arterial hypertension.
Subject(s)
Cell Proliferation , Hypertension, Pulmonary/metabolism , Hypoxia/complications , Membrane Transport Proteins/deficiency , Muscle, Smooth, Vascular/metabolism , Neointima , Receptors, LDL/deficiency , Vascular Remodeling , Animals , Arterial Pressure , Cells, Cultured , Genotype , Humans , Hypertension, Pulmonary/genetics , Hypertension, Pulmonary/pathology , Hypertension, Pulmonary/prevention & control , Hypertrophy, Right Ventricular/metabolism , Hypertrophy, Right Ventricular/prevention & control , Hypoxia/genetics , Hypoxia/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , LDL-Receptor Related Proteins/metabolism , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Mice, Inbred C57BL , Mice, Knockout , Muscle, Smooth, Vascular/pathology , Muscle, Smooth, Vascular/physiopathology , Myocytes, Smooth Muscle/metabolism , Phenotype , Pulmonary Artery/metabolism , Pulmonary Artery/pathology , Pulmonary Artery/physiopathology , Receptors, LDL/genetics , Signal Transduction , Transfection , Vascular Resistance , Ventricular Dysfunction, Right/metabolism , Ventricular Dysfunction, Right/prevention & control , Ventricular Function, Right , Ventricular PressureABSTRACT
BACKGROUND: The utility of molecules derived from cancer cells as biomarkers of the pathological status in biliary tract and pancreatic cancers is still limited. Soluble LDL receptor relative with 11 ligand-binding repeats (sLR11), a molecule released from immature cells, has been shown to be a circulating biomarker for early stage hematological malignancies. METHODS: We have evaluated the pathological significance of bile sLR11 levels in 147 samples from 72 patients with biliary tract cancer (BTC), pancreatic cancer (PC), or benign diseases. RESULTS: The bile sLR11 levels in the cancer patients were significantly increased compared with those in patients without cancer, independent of cytological detection of cancer cells in bile. The average bile sLR11 levels in cancer patients were significantly higher than in those with benign diseases, while levels of bile carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) were not different. LR11 protein was found to be highly expressed in the BTC and PC cells. The LR11 transcript levels in cholangiocarcinoma and pancreatic cancer cell lines were sharply induced during proliferation and significantly increased under hypoxic conditions. CONCLUSIONS: Therefore, sLR11 levels in bile may be indicative of cancer cell conditions and may serve as potential novel biomarker in patients with BTC and PC.
Subject(s)
Bile/metabolism , Biliary Tract Neoplasms/metabolism , LDL-Receptor Related Proteins/metabolism , Membrane Transport Proteins/metabolism , Pancreatic Neoplasms/metabolism , Biliary Tract Neoplasms/pathology , CA-19-9 Antigen/metabolism , Carcinoembryonic Antigen/metabolism , Cell Line, Tumor , Cell Proliferation , Humans , Pancreatic Neoplasms/pathologyABSTRACT
BACKGROUND: LR11 (also called SorLA or SORL1) is a type I membrane protein, originally identified as a biomarker for atherosclerosis and Alzheimer's disease. We recently found that LR11 was specifically expressed in Diffuse Large B-cell lymphoma (DLBCL) cells, and high serum sLR11 concentrations in retrospective cohort indicated inferior survival. In this study, we prospectively validated the clinical impact of serum sLR11 in 97 patients with newly-diagnosed, untreated DLBCL. RESULTS: Serum sLR11 concentrations were increased in DLBCL patients compared to normal controls (mean±SD: 21.2±27.6 vs. 8.8±1.8ng/ml, P<0.0001), and significantly reduced at remission (mean±SD: 17.4±16.4 vs. 10.9±4.5ng/ml, P=0.02). Increased serum sLR11 concentrations were affected by tumor burden and bone marrow invasion. The 2-y OS and PFS were significantly lower in patients with high sLR11 concentrations (≤18.1ng/ml vs. >18.1ng/ml; 2-y OS: 89.0% vs. 56.4%, P<0.0001; 2-y PFS: 85.8% vs. 56.9%, P<0.0001). CONCLUSIONS: Serum sLR11 is a tumor-derived biomarker for predicting the survival of newly diagnosed patients with DLBCL.
Subject(s)
LDL-Receptor Related Proteins/blood , LDL-Receptor Related Proteins/chemistry , Lymphoma, Large B-Cell, Diffuse/blood , Lymphoma, Large B-Cell, Diffuse/diagnosis , Membrane Transport Proteins/blood , Membrane Transport Proteins/chemistry , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/blood , Biomarkers, Tumor/chemistry , Bone Marrow/pathology , Female , Humans , Male , Middle Aged , Reproducibility of Results , Solubility , Survival Analysis , Tumor Burden , Young AdultABSTRACT
BACKGROUND: We reported that the soluble LDL receptor relative with 11 ligand-binding repeats (sLR11) is a promising biomarker for follicular lymphoma (FL). In this study, we evaluated the fluctuations in serum sLR11 levels compared with those of serum soluble urokinase-type plasminogen activator receptor (suPAR) and soluble interleukin-2 receptor (sIL-2R) in patients with non-Hodgkin's lymphoma (NHL). METHODS: Serum sLR11, suPAR, and sIL-2R levels were measured using ELISA in 175 NHL patients and 57 healthy controls. The levels at diagnosis and at remission were evaluated in 64 paired samples. RESULTS: Serum sLR11 levels were significantly increased in FL, diffuse large B-cell lymphoma (DLBCL), and peripheral T-cell lymphoma patients compared with healthy controls. Serum sLR11 levels revealed significant positive correlations with serum suPAR and sIL-2R levels. Serum sLR11 levels at remission were decreased compared with those at diagnosis, and the declines at remission expressed a slope of approximately -1 with an intercept near that of controls. The receiver operating characteristic-area under the curve of serum sLR11 concentrations was equivalent to that of serum suPAR and sIL-2R concentrations in an early-stage DLBCL and FL. CONCLUSIONS: sLR11 may be a novel soluble receptor indicative of early-stage NHL, with potential use for evaluating therapeutic efficacy.