1. The Medical College of Qingdao University, Qingdao, 266071, China.
2. The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, China.
3. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
4. Graduate Department, Bengbu Medical College, Bengbu 233030, China.
5. The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China.
6. Department of Obstetrics and Gynaecology, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou 310013, China.
#These authors contributed equally to this work.
Long non-coding RNAs (lncRNAs) are critical drivers and suppressors of human hepatocellular carcinoma (HCC). The downregulation of transmembrane protein 220 antisense RNA 1 (TMEM220-AS1) is correlated with poor prognosis in HCC. Nevertheless, the role of TMEM220-AS1 in HCC and the underlying mechanism remains unclear. In this study, TMEM220-AS1 levels were markedly reduced in HCC tissues compared with noncancerous tissues. TMEM220-AS1 downregulation was confirmed in HCC cell lines. TMEM220-AS1 expression was associated with tumor stage, venous infiltration, tumor size, and survival of HCC patients. TMEM220-AS1 overexpression suppressed the migration, invasion, and proliferation of HCC cells. Interestingly, ectopic expression of TMEM220-AS1 increased TMEM220 levels in HCC cells. Decreased TMEM220 levels were observed in HCC tissues and cell lines. TMEM220 expression was positively correlated with TMEM220-AS1 levels in HCC tissue samples and TMEM220 downregulation was significantly correlated with reduced patient survival. TMEM220 overexpression suppressed HCC cell proliferation and mobility. TMEM220 knockdown eliminated the suppressive effect of TMEM220-AS1 in HCCLM3 cells. Mechanistically, TMEM220 overexpression reduced the nuclear accumulation of β-catenin and decreased MYC, Cyclin D1, and Snail1 mRNA levels in HCCLM3 cells. BIO, a GSK3β inhibitor, eliminated TMEM220-induced Wnt/β-catenin pathway inactivation and inhibited HCC cell proliferation and mobility. In conclusion, TMEM220-AS1 and TMEM220 were expressed at low levels in HCC patients. TMEM220-AS1 inhibited the malignant behavior of HCC cells by enhancing TMEM220 expression and subsequently inactivating the Wnt/β-catenin pathway.
Keywords: Hepatocellular carcinoma, TMEM220-AS1, TMEM220, β-catenin, Tumor progression