EIF5A2 Is Highly Expressed in Anaplastic Thyroid Carcinoma and Is Associated With Tumor Growth by Modulating TGF- Signals

Abstract

Anaplastic thyroid carcinoma (ATC) are resistant to standard therapies and has no effective treatment. Eukaryotic translation initiation factor 5A2 (EIF5A2) has shown to be upregulated inmany malignant tumors and proposed to be a critical gene involved in tumor metastasis. In thisstudy, we aim to investigate the expression status of EIF5A2 in human ATC tissues, and to study therole and mechanisms of EIF5A2 in ATC tumorigenesis in vitro and in vivo. Expression of EIF5A2protein were analyzed in paraffin-embedded human ATC tissues and adjacent nontumorous tissues(ANCT) (n=24) by immunochemistry. Expression of EIF5A2 mRNA and protein were analyzed infresh-matched ATC and ANCT (n=23) and ATC cell lines by real-time PCR and western blotting. Theeffect of targeting EIF5A2 with short hairpin RNA (shRNA) or EIF5A2 overexpression on the ATCtumorigenesis and TGF-β/Smad2/3 signals in vitro and in vivo was investigated. Expression ofEIF5A2 was significantly upregulated in ATC tissues and cell lines compared with ANCT and normalfollicular epithelial cell line. Functional studies found that targeting EIF5A2 induced SW1736 celldeath in vitro and in vivo, followed by significantly downregulated phosphorylation of Smad2/3(p-Smad2/3) in SW1736 cells at the protein level. Ectopic expression of EIF5A2 could promoted8505C cell growth in vitro and in vivo, followed by significantly upregulated p-Smad3 at the proteinlevel. Recombinant human TGF-β1 (hTGF-β1) treatment decreased the anti-proliferative activity ofthe EIF5A2 downexpressing 8505C cells through reversing p-Smad2/3. Using the specific inhibitorSB431542 to block TGF-β pathway or Smad3 siRNA to knockdown of Smad3 increased theanti-proliferative activity of the EIF5A2 overexpressing 8505C cells through inhibiting p-Smad2/3.Our findings indicated that EIF5A2 controled cell growth in ATC cells, and EIF5A/TGF-β/Smad2/3signal may be as a potential therapeutic target for ATC treatment.

HERC3 regulates epithelial-mesenchymal transition by directly ubiquitination degradation EIF5A2 and inhibits metastasis of colorectal cancer

“…Through western blotting and IF, first, we found that EIF5A2 downregulation could independently increase the expression of E-cadherin and decrease the expression of N-cadherin and Vimentin in HCT116 cells and EIF5A2 overexpression could decrease the expression of E-cadherin and increase the expression of N-cadherin and Vimentin in SW620 cells. Moreover, EIF5A2 could modulate TGF-/Smad2/3 signal in thyroid carcinoma [26]. And this regulatory still worked in CRC cell lines, EIF5A2 could activate the TGF-β signaling.…”

Eukaryotic translation initiation factor 5A in the pathogenesis of cancers (Review)

“…Accumulating studies have demonstrated that eIF5A2 regulated numerous signals related to cell apoptosis, angiogenesis, invasion and metastasis, such as Akt/MMP-2 ( 160 ), MTA1 ( 70 ), ROS-related pathways ( 50 ), HIF1α-mediated signaling pathway ( 20 ), (PEAK1) ( 15 ) and TGF-β ( 161 ). eIF5A2 was able to induce EMT in CRC cells, a key event in tumor invasion and metastasis, characterized by downregulation of epithelial markers such as E-cadherin and β-catenin and upregulation of mesenchymal markers such as fibronectin, N-cadherin, α-smooth muscle actin and vimentin ( 162 ).…”

Targeting eIF5A2 inhibits prostate carcinogenesis, migration, invasion and metastasis in vitro and in vivo

“…Recently, it has demonstrated that eIF5A is widely involved in the pathogenesis of many diseases, including upper urinary tract urothelial carcinoma and prostate cancer (PCa) [16][17][18]. In particular, eIF5A2 plays an important role in regulating tumor growth, invasion and metastasis [4,13,21,22]. It was also shown to serve as a potential biomarker and target for the diagnosis and treatment of cancers [5,6,8].…”

“…The eukaryotic initiation factor −5A2 (eIF5-A2) gene, located on chromosome 3q26, was first discovered in the primary ovarian cancer cell line in 2001 and has been classified as an oncogene [3]. Accumulative clinical and experimental, evidence show that EIF5A2 is overexpressed in many malignant tumor tissues, and upregulation of eIF5A2 is associated with poor survival, advanced disease stage, poor response for chemotherapeutic drugs as well as metastasis for patients with cancer [4][5][6][7][8][9][10], suggesting that eIF5A2 might be a potential prognostic biomarker for malignancies.…”

“…Numerous evidence demonstrated that enforced eIF5A2 enhances cancer cell growth, increases cancer cell metastasis, and promotes chemotherapy resistance through multiple means [4,[11][12][13]. Furthermore, targeting eIF5A2 attenuats tumor growth and metastasis as well as overcomes chemotherapeutic resistance [12][13][14][15], suggesting that targeting eIF5A2 may provide an effective approach for the treatment of malignancies.…”