Non‐coding TERRA inhibits the progression of hepatocellular carcinoma via regulating telomerase‐mediated telomere length

: Telomeric repeat-containing RNA (TERRA) is closely involved in the regulation of telomere length, which plays critical role in tumorigenesis. However, the biological significance of TERRA in hepatocellular carcinoma (HCC) remained largely unknown. In this study, we found that HCC cells exhibited a frequent downregulation of TERRA and its positive regulator TTAGGG repeat binding factor-1 (TRF1), whereas the negative regulator TTAGGG repeat binding factor-1 (TRF2) was upregulated. TERRA, TRF1 and TRF2 contributed to poor prognosis of HCC patients. Importantly, we found that the downregulation of TERRA significantly promoted HCC cell growth and metastasis in vitro and in vivo. While, the upregulation of TERRA exhibited an opposite effect. Mechanistically, downregulation of TERRA significantly increased the telomerase activity and promoted the telomere elongation. Moreover, the inhibitory effects of TERRA overexpression on the growth and metastasis of HCC cells were reversed by treatment with TA-65 that activates telomerase activity. In contrast, the pro-tumor effect of TERRA downregulation was reversed by treatment with TMPyP4 that inhibits telomerase activity. Our findings demonstrate that TERRA plays a critical role in HCC cell growth and metastasis, indicating that TERRA is a potential therapeutic target for HCC.