Recognition of lipoproteins by scavenger receptor class A members.

Scavenger receptor class A (SR-A) proteins are type II transmembrane glycoproteins that form homotrimers on the cell surface. This family has five known members (SCARA1 to 5, or SR-A1 to A5) that recognize a variety of ligands and are involved in multiple biological pathways. Previous reports have shown that some SR-A family members can bind modified low-density lipoproteins (LDLs); however, the mechanisms of the interactions between the SR-A members and these lipoproteins are not fully understood. Here, we systematically characterize the recognition of SR-A receptors with lipoproteins and report that SCARA1 (SR-A1, CD204), MARCO (SCARA2), and SCARA5 recognize acetylated or oxidized LDL and very-low-density lipoprotein in a Ca2+-dependent manner through their C-terminal scavenger receptor cysteine-rich (SRCR) domains. These interactions occur specifically between the SRCR domains and the modified apolipoprotein B component of the lipoproteins, suggesting that they might share a similar mechanism for lipoprotein recognition. Meanwhile, SCARA4, a SR-A member with a carbohydrate recognition domain instead of the SRCR domain at the C terminus, shows low affinity for modified LDL and very-low-density lipoprotein but binds in a Ca2+-independent manner. SCARA3, which does not have a globular domain at the C terminus, was found to have no detectable binding with these lipoproteins. Taken together, these results provide mechanistic insights into the interactions between SR-A family members and lipoproteins that may help us understand the roles of SR-A receptors in lipid transport and related diseases such as atherosclerosis.

SCARA3 inhibits cell proliferation and EMT through AKT signaling pathway in lung cancer.

BACKGROUND: Scavenger receptor class A member 3 (SCARA3) is decreased in prostate cancer and myeloma. However, functions of SCARA3 in various cancers remain unclear. In this study, we tried to evaluate the functional study of SCARA3 in lung cancer. METHODS: The expression level of SCARA3 in the TCGA-database, lung cancer tissue microarray and lung cancer cells and the prognosis of lung cancer patients were measured. Lung cancer tissue microarray was analyzed pathologically using immunohistochemistry, and quantitative analysis of SCARA3 in normal lung cells and lung cancer cells was analyzed using western blot analysis. Survival curves for lung cancer patients were prepared with the Kaplan-Meier method. Migration and invasion of SCARA3 overexpressed lung cancer cells were determined using a Transwell chamber system. Proliferation of lung cancer cells was determined based on cell viability assay using cell culture in vitro and a tumorigenicity model of BALB/C nude mouse in vivo. RESULTS: The expression of SCARA3 was abnormally reduced in TCGA-database, lung tissue microarray, and various lung cancer cells. However, overexpression of SCARA3 reduced the proliferation of lung cancer. The ability of SCARA3 to inhibit cancer cell proliferation was maintained even in vivo using a mouse xenograft model. In addition, overexpression of SCARA3 reduced migration and invasion ability of lung cancer cells and induced decreases of EMT markers such as ß-catenin, vimentin, and MMP9. We aimed to prove the role of SCARA3 in the treatment of Lung cancer, and shown that the expression level of SCARA3 is important in cancer treatment using cisplatin. The enhancement of the effect of cisplatin according to SCARA3 overexpression is via the AKT and JNK pathways. CONCLUSIONS: This study confirmed an abnormal decrease in SCARA3 in lung cancer. Overexpression of SCARA3 potently inhibited tumors in lung cancer and induced apoptosis by increasing sensitivity of lung cancer to cisplatin. These results suggest that SCARA3 is a major biomarker of lung cancer and that the induction of SCARA3 overexpression can indicate an effective treatment.

Scara3 regulates bone marrow mesenchymal stem cell fate switch between osteoblasts and adipocytes by promoting Foxo1.

OBJECTIVES: Scavenger receptor class A, member 3 (Scara3) was involved in adipogenesis. However, the effect of Scara3 on the switch between osteogenesis and adipogenesis of bone marrow mesenchymal stem cells (BMSCs) remains elusive. MATERIALS AND METHODS: The correlations between SCARA3 with the osteogenic-related were analysed based on the GTEx database. The effects of Scara3 on osteogenic or adipogenic differentiation of BMSCs were evaluated by qPCR, Western blot (WB) and cell staining. The mechanisms of Scara3 regulating Foxo1 and autophagy were validated by co-expression analysis, WB and immunofluorescence. In vivo, Scara3 adeno-associated virus was injected into intra-bone marrow of the aged mice and ovariectomized (OVX) mice whose phenotypes were confirmed by micro-CT, calcein double labelling and immunochemistry (HE and OCN staining). RESULTS: SCARA3 was positively correlated with osteogenic-related genes. Scara3 expression gradually decreased during adipogenesis but increased during osteogenesis. Moreover, the deletion of Scara3 favoured adipogenesis over osteogenesis, whereas overexpression of Scara3 significantly enhanced the osteogenesis at the expense of adipogenesis. Mechanistically, Scara3 controlled the cell fate by promoting Foxo1 expression and autophagy flux. In vivo, Scara3 promoted bone formation and reduced bone marrow fat accumulation in OVX mice. In the aged mice, Scara3 overexpression alleviated bone loss as well. CONCLUSIONS: This study suggested that Scara3 regulated the switch between adipocyte and osteoblast differentiation, which represented a potential therapeutic target for bone loss and osteoporosis.

Identification of SCARA3 with potential roles in metabolic disorders.

Obesity is characterized by the expansion of adipose tissue which is partially modulated by adipogenesis. In the present study, we identified five differentially expressed genes by incorporating two adipogenesis-related datasets from the GEO database and their correlation with adipogenic markers. However, the role of scavenger receptor class A member 3 (SCARA3) in obesity-related disorders has been rarely reported. We found that Scara3 expression in old adipose tissue-derived mesenchymal stem cells (Ad-MSCs) was lower than it in young Ad-MSCs. Obese mice caused by deletion of the leptin receptor gene (db/db) or by a high-fat diet both showed reduced Scara3 expression in inguinal white adipose tissue. Moreover, hypermethylation of SCARA3 was observed in patients with type 2 diabetes and atherosclerosis. Data from the CTD database indicated that SCARA3 is a potential target for metabolic diseases. Mechanistically, JUN was predicted as a transcriptional factor of SCARA3 in different databases which is consistent with our further bioinformatics analysis. Collectively, our study suggested that SCARA3 is potentially associated with age-related metabolic dysfunction, which provided new insights into the pathogenesis and treatment of obesity as well as other obesity-associated metabolic complications.

Corneal Oxidative Damage in Keratoconus Cells due to Decreased Oxidant Elimination from Modified Expression Levels of SOD Enzymes, PRDX6, SCARA3, CPSF3, and FOXM1.

PURPOSE: To compare the levels of gene expression for enzymes involved in production and elimination of reactive oxygen/nitrogen species (ROS/RNS) in normal human corneal cells (NL cells) with those in human corneal cells with keratoconus (KC cells) in vitro. METHODS: Primary NL and KC stromal fibroblast cultures were incubated with apocynin (an inhibitor of NADPH oxidase) or N-nitro-L-arginine (N-LLA; an inhibitor of nitric oxide synthase). ROS/RNS levels were measured using an H2 DCFDA fluorescent assay. The RT2 Profiler™ PCR Array for Oxidative Stress and Antioxidant Defense was used for initial screening of the NL and KC cultures. Transcription levels for genes related to production or elimination of ROS/RNS were analyzed using quantitative PCR. Immunohistochemistry was performed on 10 intact human corneas using antibodies against SCARA3 and CPSF3. RESULTS: Array screening of 84 antioxidant-related genes identified 12 genes that were differentially expressed between NL and KC cultures. Compared with NL cells, quantitative PCR showed that KC cells had decreased expression of antioxidant genes SCARA3 isoform 2 (0.59-fold, P = 0.02) and FOXM1 isoform 1 (0.61-fold, P = 0.03). KC cells also had downregulation of the antioxidant genes SOD1 (0.4-fold, P = 0.0001) and SOD3 (0.37-fold, P = 0.02) but increased expression of SOD2 (3.3-fold, P < 0.0001), PRDX6 (1.47-fold, P = 0.01), and CPSF3 (1.44-fold, P = 0.02). CONCLUSION: The difference in expression of antioxidant enzymes between KC and NL suggests that the oxidative stress imbalances found in KC are caused by defects in ROS/RNS removal rather than increased ROS/RNS production.