Abstract
LincRNA-p21 is a downstream long non-coding RNA (lncRNA) transcript of p53. LincRNA-p21 serves as a repressor in p53-dependent transcriptional responses and participates in diverse biological processes, including apoptosis, cell cycle, metabolism and pluripotency. However, the role of lincRNA-p21 in human hepatocellular carcinoma remains to be defined. Here in this work, we demonstrated that lincRNA-p21 acted as a tumor suppressive lncRNA in human hepatocellular carcinoma. We firstly found the downregulation of lincRNA-p21 level in human hepatocellular carcinoma tissues, and showed that low expression of lincRNA-p21 was associated with high disease stage and predicted poor survival. Further we showed that lincRNA-p21 knockdown promoted proliferation and colony formation of HepG2, Huh7 and Bel-7042 cells in vitro, while lincRNA-p21 overexpression obtained oppose results. Using tumor xenograft experiments, we also demonstrated that lincRNA-p21 inhibited HepG2 cell growth in vivo and lincRNA-p21 contributed to sorafenib-induced growth regression of HepG2 cell in vivo. Further mechanism analysis revealed that lincRNA-p21 promoted ER stress both in vitro and in vivo, which facilitated apoptosis of hepatocellular carcinoma cells. Finally, we demonstrated that ER stress accounted for lincRNA-p21 effects on apoptosis, proliferation and in vivo growth of hepatocellular carcinoma. These findings implicate that lincRNA-p21 is a potential prognostic factor and therapeutic target for human hepatocellular carcinoma.
Highlights
Hepatocellular carcinoma (HCC) causes more than 500,000 deaths each year worldwide [1]
All of these long non-coding RNA (lncRNA) were up-regulated in HCC (Supplementary Figure S1), which was different from lincRNA-p21
We tested the activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK), which is responsible for phosphorylation of initiation factor eIF2α, We found that lincRNA-p21 could up-regulate the phosphorylation level of PERK (Supplementary Figure S6)
Summary
Hepatocellular carcinoma (HCC) causes more than 500,000 deaths each year worldwide [1]. Current therapies for HCC often obtain poor long-term outcome due to drug resistance with elusive mechanisms [3]. These facts prompt us to identify novel molecular mechanisms for hepatocellular carcinoma development and drug resistance. Several drugs that activate ER stress have been approved for preclinical and clinical use. These drugs include sorafenib, eeyarestatin, 17-AAG, radicicol, and MAL3–101 [5]. The mechanism by which sorafenib induces ER stress and HCC cell apoptosis is still elusive
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