Tazarotene-Induced Gene 1 (TIG1) Interacts with Serine Protease Inhibitor Kazal-Type 2 (SPINK2) to Inhibit Cellular Invasion of Testicular Carcinoma Cells.

Rong-Yaun Shyu,Fu-Ming Tsai,Chang-Chieh Wu,Mao-Liang Chen,Ming-Cheng Lee,Yi-Ying Lin,Chun-Hua Wang,Lu-Kai Wang,Chan-Yen Kuo

doi:10.1155/2019/6171065

Abstract

Tazarotene-induced gene 1 (TIG1) encodes a protein that is a retinoid-regulated tumor suppressor. TIG1 is expressed in most normal tissues, and downregulation of TIG1 expression in multiple cancers is caused by promoter hypermethylation. Kazal-type serine protease inhibitor-2 (SPINK2) is a serine protease inhibitor, and the SPINK protein family has been shown to inhibit the expression of urokinase-type plasminogen activator (uPA). In addition, increased levels of uPA and the uPA receptor were observed in testicular cancer tissues. This study demonstrated that TIG1 interacts with SPINK2 in NT2/D1 testicular carcinoma cells. TIG1 and SPINK2 were highly expressed in normal testis tissues, while low expression levels of TIG1 and SPINK2 were found in testicular cancer tissues. TIG1 inhibited cell invasion, migration, and epithelial–mesenchymal transition (EMT) of NT2/D1 cells. SPINK2 enhanced TIG1-regulated uPA activity and EMT suppression, while silencing SPINK2 alleviated TIG1-mediated EMT regulation, cell migration, and invasion. Therefore, the results suggest that the interaction between TIG1 and SPINK2 plays an important role in the inhibition of testicular cancer cell EMT, and suppression is mediated through downregulation of the uPA/uPAR signaling pathway.

Highlights

Tazarotene-induced gene 1 (TIG1), known as retinoic acid receptor responder 1 (RARRES1), is a retinoic acid regulated tumor suppressor gene [1]
Because the SPINK protein family has been shown to inhibit urokinase-type plasminogen activator (uPA) activity, which may contribute to epithelial-to-mesenchymal transition (EMT) and tumor metastasis, we hypothesized that SPINK2 might participate in TIG1-mediated inhibition of cancer cell invasion. erefore, the current study investigated whether TIG1 affects the activity of uPA, which is negatively regulated by SPINK2, potentially preventing epithelial–mesenchymal transition (EMT) and suppressing cell migration and invasion
Since TIG1 and SPINK2 are highly expressed in testis tissue, we detected their mRNA expression in normal testicular cells, testicular embryonal carcinomas, and testicular seminomas (Figure 1(b))

Summary

Introduction

Tazarotene-induced gene 1 (TIG1), known as retinoic acid receptor responder 1 (RARRES1), is a retinoic acid regulated tumor suppressor gene [1]. TIG1 belongs to the latexin family of putative cytoplasmic carboxypeptidase inhibitors, and it has been shown to regulate the α-tubulin tyrosination cycle via the ATP/GTP binding protein-like 2 (AGBL2) protein [8]. In addition to regulation of α-tubulin, which is related to mitochondrial function, ectopic TIG1 exhibits cell growth suppression and induction of autophagy in cervical, colon, and nasopharyngeal cancer cells [9,10,11,12,13]. Microarray analysis of mifepristone-inducible TIG1 expression in colon cells revealed G protein-coupled receptor kinase 5 (GRK5)-mediated TIG1-induced cell growth suppression through the Wnt and cAMP signaling pathways [9, 10]. The heat shock protein DNAJC8 and the transmembrane protein 192 have been shown to participate in TIG1-mediated glycolysis metabolism and autophagy regulation [11, 12]. Knockdown of TIG1 leads to enhanced invasion capacity of HK1-EBV nasopharyngeal cells [13]; the underlying mechanism of cell invasion mediated by TIG1 is still unclear

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