LncRNA TUG1 sponges miR-145 to promote cancer progression and regulate glutamine metabolism via Sirt3/GDH axis
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Bing Zeng1,2,*, Huilin Ye1,*, Jianming Chen3,*, Di Cheng4, Canfeng Cai2, Guoxing Chen2, Xiang Chen2, Haiyang Xin2, Chaoming Tang2 and Jun Zeng2
1Department of Hepatopancreatobiliary Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China
2Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Guangzhou Medical University, Qing Yuan People’s Hospital, Guangdong 511518, China
3Department of Gastroenterology, The 251st Hospital of PLA, Zhangjiakou 075000, China
4Department of Gastroenterology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China
*These authors have contributed equally to this work
Jun Zeng, email: [email protected]
Chaoming Tang, email: [email protected]
Keywords: TUG1; intrahepatic cholangiocarcinoma; miR-145; glutamine metabolism; Sirt3
Received: June 14, 2017 Accepted: September 08, 2017 Published: October 19, 2017
Long noncoding RNAs (lncRNAs) are important regulators in cancer progression. Deregulation of the lncRNA taurine upregulated gene 1 (TUG1) predicts poor prognosis and is implicated in the development of several cancers. In this study, we investigated the role of TUG1 in the pathogenesis of intrahepatic cholangiocarcinoma (ICC). We found that TUG1 is upregulated in ICC samples, which correlates with poor prognosis and adverse clinical pathological characteristics. Knockdown of TUG1 inhibited the proliferation, motility, and invasiveness of cultured ICC cells, and decreased tumor burden in a xenograft mouse model. When we explored the mechanisms underlying these effects, we found that TUG1 acts as an endogenous competing RNA (ceRNA) that ‘sponges’ miR-145, thereby preventing the degradation of Sirt3 mRNA and increasing expression of Sirt3 and GDH proteins. Accordingly, glutamine consumption, α-KG production, and ATP levels were dramatically decreased by TUG1 knockdown in ICC cells, and this effect was reversed by miR-145 inhibition. These findings indicate that the TUG1/miR-145/Sirt3/GDH regulatory network may provide a novel therapeutic strategy for treatment of ICC.
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