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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.

SUBMITTER: Ara S

PROVIDER: S-EPMC7659183 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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

Ara Shihoko S Kikuchi Tomoki T Matsumiya Hiroshi H Kojima Takashi T Kubo Terufumi T Ye Rui Carrie RC Sato Akinori A Kon Shin-Ichiro S Honma Tomo T Asakura Kohji K Hasegawa Tadashi T Himi Tetsuo T Sato Noriyuki N Ichimiya Shingo S

Cancer science 20120604 7

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. Exp ...[more]

PMID: 22486813

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Project description:BACKGROUND:We present a functional gene association network of the CLIP2 gene, generated by de-novo reconstruction from transcriptomic microarray data. CLIP2 was previously identified as a potential marker for radiation induced papillary thyroid carcinoma (PTC) of young patients in the aftermath of the Chernobyl reactor accident. Considering the rising thyroid cancer incidence rates in western societies, potentially related to medical radiation exposure, the functional characterization of CLIP2 is of relevance and contributes to the knowledge about radiation-induced thyroid malignancies. METHODS:We generated a transcriptomic mRNA expression data set from a CLIP2-perturbed thyroid cancer cell line (TPC-1) with induced CLIP2 mRNA overexpression and siRNA knockdown, respectively, followed by gene-association network reconstruction using the partial correlation-based approach GeneNet. Furthermore, we investigated different approaches for prioritizing differentially expressed genes for network reconstruction and compared the resulting networks with existing functional interaction networks from the Reactome, Biogrid and STRING databases. The derived CLIP2 interaction partners were validated on transcript and protein level. RESULTS:The best reconstructed network with regard to selection parameters contained a set of 20 genes in the 1st neighborhood of CLIP2 and suggests involvement of CLIP2 in the biological processes DNA repair/maintenance, chromosomal instability, promotion of proliferation and metastasis. Peptidylprolyl Isomerase Like 3 (PPIL3), previously identified as a potential direct interaction partner of CLIP2, was confirmed in this study by co-expression at the transcript and protein level. CONCLUSION:In our study we present an optimized preselection approach for genes subjected to gene-association network reconstruction, which was applied to CLIP2 perturbation transcriptome data of a thyroid cancer cell culture model. Our data support the potential carcinogenic role of CLIP2 overexpression in radiation-induced PTC and further suggest potential interaction partners of the gene.

Project description:Background:The primary goal of papillary thyroid cancer (PTC) management was to stratify patients at pre- and post-surgical level to identify the small proportion of cases with potentially aggressive disease. Purpose:The aim of our study is to evaluate the possible role of programmed cell death 4 (PDCD4) and BRAF status as prognostic markers in PTC. Patients and methods:We investigate programmed cell death 4 (PDCD4) immunohistochemical expression in 125 consecutive PTCs with median follow-up of 75.3 months (range, 15-98 months) to verify the possible correlation between BRAF status and correlate the classical clinicopathological prognostic factors and PTC outcome with PDCD4 expression. To further support the data, miR-21 expression was tested (by quantitative real-time PCR and in situ hybridization) in a different series of 30 cases (15 PTCs BRAFwt and 15 PTCs BRAFV600E). Moreover, we validated our results using TGCA thyroid carcinoma dataset. Results:We found that 59.8% of the patients showed low-grade PDCD4 nuclear expression and low-grade expression correlated with BRAF V600E. Compared with BRAF 15 wild-type tissue samples, a significant miR-21 up-regulation was associated with BRAF V600E mutations. Low-grade PDCD4 resulted, and was associated with aggressive histological variants, higher cancer size, extra-thyroidal extension, multifocality, lymph-node metastasis and lymph nodal ratio at the diagnosis. Concerning the outcome, the low-grade PDCD4 expression correlated at univariate and multivariate analysis, with lower levels of recurrence-free survival rate (RFS) and with poor outcome. Moreover, there was significant association between BRAF V600E patients with PDCD4 nuclear loss and lower RFS, whilet here was significant association between BRAF wild-type patients with PDCD4 nuclear expression and better outcome. Conclusion:These results showed that PDCD4 could predict PTC outcome and that the sum of PDCD4 and BRAF alterations increases the prognostic power of BRAF mutation alone.

Dataset Information

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

Publications

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

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