Sorting nexin 5 of a new diagnostic marker of papillary thyroid carcinoma regulates Caspase‐2

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. (Cancer Sci 2012; 103: 1356-1362 T he thyroid gland, controlling energy production and many metabolic pathways, is the most common site for the development of malignant tumors among a variety of endocrine organs.(1) The proportion of malignant thyroid tumors has steadily increased over the last three decades.(2-4) Most thyroid tumors originate from thyroid follicular epithelial cells known as thyrocytes and exhibit various histopathological subtypes, of which papillary thyroid carcinoma (PTC) comprises the predominant subtype, with a female:male ratio of about 3:1. While PTC generally has a favorable prognosis, the tumor can potentially metastasize to regional lymph nodes, the lung and other organs.(5-8) Pre-existing benign thyroid lesions and ionizing radiation are known risk factors, and gene alterations such as BRAF and RAS point mutations, and RET/PTC and TRK gene rearrangements have been reported in PTC. (9)(10)(11)(12)(13) Gene regulatory factors making critical contributions during the development of thyrocytes are of diagnostic value for PTC in the pathologic laboratory, including thyroid transcription factors including TTF-1 and TTF-2, a hematopoietically expressed homeobox (HHEX), and paired box gene-8 (PAX8). (14)(15)(16)(17) However, the etiology of the tumor development has not been fully clarified.Thyrocytes synthesize the thyroid hormones through a multiple intracellular process coordinated by thyroid-stimulating hormone. During the process, a transcytotic pathwa...

Loss of sorting nexin 5 stabilizes internalized growth factor receptors to promote thyroid cancer progression

“…These findings suggest that cell growth signals are primarily induced in Snx5 −/− thyrocytes. No significant changes were observed in the levels of an apoptosis‐related protein, caspase 2, which was upregulated in Snx5‐overexpressing epithelial cells in our in vitro study (Figure G) .…”

“…Band intensities were measured using ImageJ software. Immunohistochemistry and immunofluorescence laser confocal microscopy were conducted under ELYRAS.1 LSM780 (Carl Zeiss, Oberkochen, Germany) as described previously . For analyzing endosomes, primary thyrocytes were seeded onto a glass‐base confocal dish with DMEM containing 10% FBS at 37 °C.…”

“…Band intensities were measured using ImageJ software. Immunohistochemistry and immunofluorescence laser confocal microscopy were conducted under ELYRAS.1 LSM780 (Carl Zeiss, Oberkochen, Germany) as described previously [4,23]. For analyzing endosomes, primary thyrocytes were seeded onto a glass-base confocal dish with DMEM containing 10% FBS at 37 ∘ C. Then a GFP-conjugated marker protein for early or late endosomes, Rab5 or Rab7 (Cell Light BacMan; Thermo Fisher Scientific, Waltham, MA, USA), respectively, was transiently transfected by adding to the media and incubating at 37 ∘ C for 16 h. GFP fluorescence was detected by laser confocal microscopy.…”

“…We previously reported a characteristic expression profile of sorting nexin 5 (Snx5) in thyroid carcinoma; WDTC like PTC preferentially expressed Snx5, whereas Snx5 was undetectable in PDTC . The relationship between Snx5 and prognosis of thyroid carcinoma suggests the involvement of Snx5 in its development.…”

Identification of potential predictive markers of dexamethasone resistance in childhood acute lymphoblastic leukemia

“…Sorting nexins as PI3P-binding proteins actively determine cell fate through diverse functions in cell signalling, protein-protein/lipid interaction, organelle movement, receptor downregulation and membrane trafficking (Chen et al 2013;Nguyen et al 2006;Danson et al 2013;Pons et al 2012). It is well demonstrated that abnormalities of intracellular vesicles in endosome network occur in many tumor cells (Ara et al 2012). Also, dysfunctions of sorting proteins can alter cell surface receptors and signalling cascades in cells and can eventually cause of induction of tumorogenesis.…”