ABSTRACT
BACKGROUND/AIM: R-spondins control WNT signaling and RSPO1 and LGR6, two of its receptors, are uniquely expressed at high levels in high-grade serous ovarian cancer (HGSOC). The aim of this study was to assess the interrelations between the expression of the RSPOs and LGRs in HGSOC and in the ovarian surface (OSE) and fallopian tube surface epithelium (FTSE) from which HGSOC arises. MATERIALS AND METHODS: Analysis of TCGA (HGSOC), CCLE (ovary), and other publicly accessed RNA-Seq data using UC San Diego Computational Cancer Analysis Library (CCAL) to perform differential expression analysis, association studies, and gene set inspection using the single-sample GSEA method. Additionally, we employed multiple publicly available databases including StringDB, Human Protein Atlas, and cBioPortal to aid the investigation. RESULTS: Among normal tissues, expression of RSPO1, LGR5 and LGR6 was highest in the fallopian tube. The relative levels of expression of the RSPOs and LGRs in the OSE and FTSE matched those in HGSOC. RSPO1 and LGR6 were highly co-expressed in all three tissues. Gene set enrichment analysis (GSEA) showed that expression of RSPO1 was strongly linked to the enrichment of three separate WNT-driven GO pathways. Analysis of genes that impacted overall survival identified two other immediately adjacent genes that control WNT signaling, KREMEN1 and ZNRF3 whose expression and copy number were coordinately linked. CONCLUSION: RSPO1 and LGR6 are coordinately expressed in HGSOC and the two normal tissues from which this tumor arises, and their expression is linked to WNT signaling pathways known the control cell fate and proliferation.
Subject(s)
Cystadenocarcinoma, Serous/metabolism , Cystadenocarcinoma, Serous/pathology , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Receptors, G-Protein-Coupled/metabolism , Thrombospondins/metabolism , Wnt Signaling Pathway , Cystadenocarcinoma, Serous/genetics , Fallopian Tubes/pathology , Female , Gene Expression Regulation, Neoplastic , Humans , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/metabolism , Neoplasm Grading , Ovarian Neoplasms/genetics , Ovary/pathology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, G-Protein-Coupled/genetics , Thrombospondins/genetics , Wnt Signaling Pathway/geneticsABSTRACT
This patient presented with a neck mass diagnosed as a papillary thyroid carcinoma by fine-needle aspiration. Preoperative computed tomography revealed a papillary carcinoma within a juxtathyroidal thyroglossal duct cyst. After surgery, the initial diagnosis was papillary thyroid carcinoma. After correlation with the computed tomography, the diagnosis was revised to a papillary thyroid carcinoma plus a follicular adenoma in a juxtathyroidal thyroglossal duct cyst. This case demonstrates the need for close clinical and radiographic correlation in such a complex case.
Subject(s)
Adenoma/diagnosis , Carcinoma, Papillary/diagnosis , Thyroglossal Cyst/diagnosis , Thyroid Neoplasms/diagnosis , Adenoma/surgery , Adult , Carcinoma, Papillary/surgery , Humans , Male , Thyroglossal Cyst/surgery , Thyroid Neoplasms/surgery , Tomography, X-Ray ComputedABSTRACT
OBJECTIVE: CCL11 (Eotaxin) is a potent eosinophil chemoattractant that is abundant in atheromatous plaques. The major receptor for CCL11 is CCR3, which is found on leukocytes and on some nonleukocytic cells. We sought to determine whether vascular smooth muscle cells (SMCs) possessed functional CCR3. METHODS AND RESULTS: CCR3 mRNA (by RT-PCR) and protein (by Western blot analysis and flow cytometry) were present in mouse aortic SMCs. CCL11 induced concentration-dependent SMC chemotaxis in a modified Boyden chamber, with maximum effect seen at 100 ng/mL. SMC migration was markedly inhibited by antibody to CCR3, but not to CCR2. CCL11 also induced CCR3-dependent SMC migration in a scrape-wound assay. CCL11 had no effect on SMC proliferation. CCR3 and CCL11 staining were minimal in the normal arterial wall, but were abundant in medial SMC and intimal SMC 5 days and 28 days after mouse femoral arterial injury, respectively, times at which SMCs possess a more migratory phenotype. CONCLUSIONS: These data demonstrate that SMCs possess CCR3 under conditions associated with migration and that CCL11 is a potent chemotactic factor for SMCs. Because CCL11 is expressed abundantly in SMC-rich areas of the atherosclerotic plaque and in injured arteries, it may play an important role in regulating SMC migration.
Subject(s)
Chemokines, CC/pharmacology , Chemotactic Factors/pharmacology , Chemotaxis/drug effects , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle/drug effects , Receptors, Chemokine/drug effects , Animals , Aorta/cytology , Becaplermin , Cell Movement/drug effects , Cells, Cultured/drug effects , Cells, Cultured/physiology , Chemokine CCL11 , Chemokines, CC/physiology , Eosinophils/chemistry , Femoral Artery/injuries , Femoral Artery/pathology , Humans , Mice , Mice, Inbred C57BL , Myocytes, Smooth Muscle/physiology , Platelet-Derived Growth Factor/pharmacology , Proto-Oncogene Proteins c-sis , RNA, Messenger/biosynthesis , Receptors, CCR3 , Receptors, Chemokine/biosynthesis , Receptors, Chemokine/genetics , Receptors, Chemokine/physiology , Recombinant Proteins/pharmacology , Tunica Intima/pathology , Tunica Media/pathologyABSTRACT
SM-20 encodes an intracellular prolyl hydroxylase that acts on hypoxia inducible factor (HIF)-1alpha, targeting it for proteasomal degradation. By decreasing HIF-alpha, SM-20 is thought to modulate the expression of hypoxia-regulated genes. SM-20 expression in the arterial wall is restricted to smooth muscle cells, which play a critical role in atherosclerosis and arterial injury. To further elucidate the regulation of SM-20 in smooth muscle, we cloned and analyzed the rat SM-20 promoter. In transient transfections, the SM-20 promoter displayed approximately 6-fold greater activity in smooth muscle cells vs. fibroblasts. Deletion analysis and electrophoretic mobility shift assays demonstrated that SM-20 transcription was regulated by two Sp1/Sp3 sites. A shift in binding to the Sp1/Sp3 sites, a decrease in Sp1 and Sp3 protein levels, and the emergence of a lower molecular weight form of Sp1 were seen in serum-deprived or post-confluent SMC, suggesting that SM-20 is regulated during smooth muscle cell differentiation.
Subject(s)
Muscle, Smooth, Vascular/metabolism , Procollagen-Proline Dioxygenase/genetics , Animals , Base Sequence , DNA , Electrophoretic Mobility Shift Assay , Molecular Sequence Data , Muscle, Smooth, Vascular/cytology , Mutation , Promoter Regions, Genetic , Rats , Rats, Sprague-DawleyABSTRACT
Monocyte chemoattractant protein (MCP)-1 is abundant in smooth muscle cells (SMC) and macrophages of atherosclerotic plaques and in the injured arterial wall. MCP-1 and its receptor, CCR2, are important mediators of macrophage accumulation and atherosclerotic plaque progression. We have recently reported that CCR2(-/-) mice have a approximately 60% decrease in intimal hyperplasia and medial DNA synthesis in response to femoral arterial injury. We have now examined the response to femoral arterial injury in MCP-1(-/-) mice. MCP-1 deficiency was associated with a approximately 30% reduction in intimal hyperplasia at 4 weeks and was not associated with diminished medial DNA synthesis. Despite inducing tissue factor in SMC culture, MCP-1 deficiency was not associated with a decrease in neointimal tissue factor after injury. These data suggest that MCP-1 and CCR2 deficiencies have distinct effects on arterial injury. The effects of MCP-1 on intimal hyperplasia may be mediated largely through SMC migration.
Subject(s)
Arteries/injuries , Chemokine CCL2/deficiency , Chemokine CCL2/physiology , Tunica Intima/pathology , Animals , Bromodeoxyuridine/pharmacology , Cell Division , Cell Movement , Chemokine CCL2/genetics , Chemokines/metabolism , DNA/biosynthesis , DNA/metabolism , Femoral Artery/pathology , Hyperplasia , Immunohistochemistry , Macrophages/metabolism , Mice , Mice, Transgenic , Muscle, Smooth/pathology , Receptors, CCR2 , Receptors, Chemokine/metabolismABSTRACT
Monocyte chemoattractant protein (MCP)-1 is upregulated in atherosclerotic plaques and in the media and intima of injured arteries. CC chemokine receptor 2 (CCR2) is the only known functional receptor for MCP-1. Mice deficient in MCP-1 or CCR2 have marked reductions in atherosclerosis. This study examines the effect of CCR2 deficiency in a murine model of femoral arterial injury. Four weeks after injury, arteries from CCR2(-/-) mice showed a 61.4% reduction (P<0.01) in intimal area and a 62% reduction (P<0.05) in intima/media ratio when compared with CCR2(+/+) littermates. The response of CCR2(+/-) mice was not significantly different from that of CCR2(+/+) mice. Five days after injury, the medial proliferation index, determined by bromodeoxyuridine incorporation, was decreased by 59.8% in CCR2(-/-) mice when compared with CCR2(+/+) littermates (P<0.05). Although leukocytes rapidly adhered to the injured arterial surface, there was no significant macrophage infiltration in the arterial wall of either CCR2(-/-) or CCR2(+/+) mice 5 and 28 days after injury. These results demonstrate that CCR2 plays an important role in mediating smooth muscle cell proliferation and intimal hyperplasia in a non-hyperlipidemic model of acute arterial injury. CCR2 may thus be an important target for inhibiting the response to acute arterial injury.
