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

Abstract

Thyroid carcinoma is the most common endocrine malignancy and its prevalence has recently been increasing worldwide. We previously reported that the level of sorting nexin 5 (Snx5), an endosomal translocator, is preferentially decreased during the progression of well-differentiated thyroid carcinoma into poorly differentiated carcinoma. To address the functional role of Snx5 in the development and progression of thyroid carcinoma, we established Snx5-deficient (Snx5 ) mice. In comparison to wild-type (Snx5 ) mice, Snx5 mice showed enlarged thyroid glands that consisted of thyrocytes with large irregular-shaped vacuoles. Snx5 thyrocytes exhibited a higher growth potential and higher sensitivity to thyroid-stimulating hormone (TSH). A high content of early endosomes enriched with TSH receptors was found in Snx5 thyrocytes, suggesting that loss of Snx5 caused retention of the TSH receptor (TSHR) in response to TSH. Similar data were found for internalized EGF in primary thyrocytes. The increased TSH sensitivities in Snx5 thyrocytes were also confirmed by results showing that Snx5 mice steadily developed thyroid tumors with high metastatic potential under high TSH. Furthermore, a thyroid cancer model using carcinogen and an anti-thyroidal agent revealed that Snx5 mice developed metastasizing thyroid tumors with activation of MAP kinase and AKT pathways, which are postulated to be major pathways of malignant progression of human thyroid carcinoma. Our results suggest that thyrocytes require Snx5 to lessen tumorigenic signaling driven by TSH, which is a major risk factor for thyroid carcinoma. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Sorting Nexin 5 Controls Head and Neck Squamous Cell Carcinoma Progression by Modulating FBW7

“…Loss of SNX5 enhances the tumorigenic signaling driven by thyroid-stimulating hormone (TSH) to promote thyroid cancer progression. The SNX5 -/- thyroid tumors showed expanded malignant potential and the pulmonary metastasis of SNX5 -/- thyroid tumors was more frequent than that of wild-type tumors 9. These reports support a potential tumor suppressor role of SNX5 in thyroid cancers.…”

“…Levels of SNX1 are significantly down-regulated in 75% of human colon cancers and this SNX1 down-regulation promotes colon tumorigenesis 7. SNX5 is reported to be highly expressed in papillary thyroid carcinomas 8, 9. However, the mechanisms by which SNXs control tumorigenesis have not been clearly demonstrated.…”

lncRNA TMEM51-AS1 and RUSC1-AS1 function as ceRNAs for induction of laryngeal squamous cell carcinoma and prediction of prognosis

“…miR-106b was reported to promote the proliferation and invasion of LSCC cells by targeting RUNX3 (Ying et al, 2013), while induce cell cycle G0/G1 arrest by inhibiting tumor suppressor RB (Cai, Wang & Bao, 2011). Although no study revealed the roles of SNX21 in cancer, its family genes, such as SNX1 (Zhan et al, 2018), SNX5 (Jitsukawa et al, 2017) and SNX9 (Bendris et al, 2016) were suggested to be tumor suppressor related. Therefore, SNX21 may be theoretically downregulated in LSCC by miR-106b.…”

CMTCN: a web tool for investigating cancer-specific microRNA and transcription factor co-regulatory networks

“…The aberrant methylation, and hence silencing, of DAPK2 has been reported to play a critical role in thyroid cancer tumorigenesis and progression ( Hu et al, 2006 ). Finally, reduced expression of SNX5 was shown recently to be related to promotion of thyroid tumorigenesis ( Jitsukawa et al, 2017 ) and SNX5 expression studies can be used to support a pathology diagnosis of thyroid cancer ( Ara et al, 2012 ). Additionally, CMTCN carried out a functional enrichment analysis for genes and TFs in the THCA-specific miRNA-TF co-regulatory network.…”