ABSTRACT
Papillary thyroid carcinoma (PTC) is a well-differentiated endocrine malignant tumor that develops from thyroid follicular epithelium. The tumor represents the most common type of endocrine malignancy; however, its tumorigenesis is not fully elucidated. The aim of this study was to address the functional role of the sorting nexin (SNX) family in PTC because of recent experimental evidence suggesting that the SNX family members actively control endocytotic transportation as well as cell fate. Expression profiles of SNX family members of PTC showed a significant quantity of transcripts of SNX5. Further immunohistochemical analysis with an SNX5-specific monoclonal antibody established in this study consistently demonstrated the preferential expression of SNX5 in PTC (94.2%, 113/120 cases) as indicated by studies on 440 cases of various tumors. In contrast, other major carcinomas originating from the lung (2.6%, 1/38 cases), breast (5.1%, 2/39 cases), and intestine (4.2%, 1/24 cases) scarcely expressed SNX5. When we investigated models of murine thyroid tumors induced by the administration of carcinogens, high expression of Snx5 was also observed in well-differentiated thyroid tumors, further implying that the tumorigenesis of the thyroid gland was tightly associated with the abundance of SNX5/Snx5. Moreover epithelial cells expressing excess SNX5 showed high levels of Caspase-2 of an initiator caspase. Collectively these findings suggest that the evaluation of SNX5 expression would support pathological diagnosis of primary and secondary PTC.
Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Papillary/metabolism , Caspase 2/metabolism , Sorting Nexins/metabolism , Thyroid Neoplasms/metabolism , Animals , Biomarkers, Tumor/genetics , Blotting, Western , Carcinogens/toxicity , Carcinoma, Papillary/diagnosis , Carcinoma, Papillary/genetics , Caspase 2/genetics , Female , Gene Expression Profiling , HEK293 Cells , Humans , Immunohistochemistry , Male , Mice , Mice, Inbred BALB C , Neoplasms, Experimental/chemically induced , Neoplasms, Experimental/genetics , Neoplasms, Experimental/metabolism , Nitrosamines/toxicity , Reverse Transcriptase Polymerase Chain Reaction , Sorting Nexins/genetics , Thyroid Gland/drug effects , Thyroid Gland/metabolism , Thyroid Gland/pathology , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/genetics , Tumor Cells, CulturedABSTRACT
In this study, we report the unique role of arachidonate 5-lipoxygenase (Alox5) in the regulation of specific humoral immune responses. We previously reported an L22 monoclonal antibody with which human primary resting B cells in the mantle zones of lymphoid follicles are well-defined. Proteomics analyses enabled identification of an L22 antigen as Alox5, which was highly expressed by naive and memory B cells surrounding germinal centers. Cellular growth of mantle cell lymphoma cells also seemed to depend on Alox5. Alox5(-/-) mice exhibited weak antibody responses specific to foreign antigens at the initial and recall phases. This was probably attributable to the low number of follicular and memory B cells and the functional loss of interleukin-21-mediated responses of follicular B cells. Moreover, Alox5(-/-) mice could not fully foster the development of follicular B helper T (Tfh) cells even after immunization with foreign antigens. Further experiments indicated that Alox5 affected mortality in experimentally induced enterocolitis in germ-prone circumstances, indicating that Alox5 would endow immunologic milieu. Our results illustrate the novel role of Alox5 in adaptive humoral immunity by managing primary B cells and Tfh cells in vivo.
