Long noncoding RNA HULC accelerates liver cancer by inhibiting PTEN via autophagy cooperation to miR15a

Abstract

BackgroundLong noncoding RNA HULC is highly up-regulation in human hepatocellular carcinoma (HCC). However, the functions of HULC in hepatocarcinogenesis remains unclear.MethodsRT-PCR, Western blotting, Chromatin immunoprecipitation (CHIP) assay, RNA Immunoprecipitation (RIP) and tumorignesis test in vitro and in vivo were performed.ResultsHULC is negatively associated with expression of PTEN or miR15a in patients of human liver cancer. Moreover, HULC accelerates malignant progression of liver cancer cells in vitro and in vivo. Mechanistically, HULC increasesthe expression of P62 via decreasing mature miR15a. On the other hand, excessive HULC increases the expression of LC3 on the level of transcription and then activates LC3 through Sirt1 (a deacetylase). Notably, HULC enhanced the interplay between LC3 and ATG3. Furthermore, HULC also increases the expression of becline-1(autophagy related gene). Therefore, HULC increases the cellular autophagy by increasing LC3II dependent on Sirt1.Noteworthy, excessive HULC reduces the expression of PTEN, β-catenin and enhances the expression of SAPK/JUNK, PKM2, CDK2, NOTCH1, C-Jun in liver cancer cells. Of significance, our observations also revealed that HULC inhibited PTEN through ubiquitin–proteasome system mediated by autophagy-P62.Ultimately,HULC activates AKT-PI3K-mTOR pathway through inhibiting PTEN in human liver cancer cells.ConclusionsThis study elucidates a novel mechanism that lncRNA HULC produces a vital function during hepatocarcinogenesis.

Long noncoding RNA HULC accelerates the growth of human liver cancer stem cells by upregulating CyclinD1 through miR675-PKM2 pathway via autophagy

“…(b) HULC accelerates growth in vivo of liver cancer stem cells. Several studies indicate that HULC promotes proliferation and migration [34][35][36][37][38]. Our present results are consistent with these reports and provide novel evidence for an active role of HULC in promoting malignant formation and growth of LCSCs.…”

LncRNAs Act as a Link between Chronic Liver Disease and Hepatocellular Carcinoma

“…HULC promotes the proliferation of HCC cells via the regulation of regulating cell cycle-related genes in HCC cells [59]. HULC is negatively associated with PTEN or miR-15a expression in HCC patients, which promotes malignant progression [83]. HULC contributes to malignant development by acting as a sponge of miRNAs such as miR-9, miR-107, and miR-372, which induce PPARα, E2F1, and cAMP response element-binding protein (CREB) respectively [47][48][49].…”

β-Elemene suppresses tumor growth of diffuse large B-cell lymphoma through regulating lncRNA HULC-mediated apoptotic pathway

“…HULC promotes tumor growth and progression in several cancers by mediating multiple signaling pathways and interacting with miRNAs. It has been indicated that HULC accelerated liver cancer by inhibiting PTEN via autophagy cooperation to miR15a and increasing HMGA2 expression via sequestration of the miR186 [19,30]. HULC modulated the phosphorylation of YB-1 through serving as a scaffold of extracellular signal-regulated kinase and YB-1 to enhance hepatocarcinogenesis [31].…”

“…Highly up-regulated in liver cancer (HULC), located on chromosome 6p24.3, is a 500 nt-nucleotide-long lncRNA which is first found overexpressed in liver cancer and is closely related to the tumor progression. HULC is also aberrantly up-regulated in a wide spectrum of malignancies, including liver cancer, prostate cancer, ovarian cancer, bladder cancer, osteosarcoma, gastric cancer, and myeloid leukemia [19][20][21][22][23][24][25]. A meta-analysis indicated that HULC overexpression is a predictor of poor prognosis in various cancer types and the higher incidence of tumor metastasis [26].…”