Abstract
Highly upregulated in liver cancer (HULC) is a long noncoding RNA (lncRNA), which has recently been identified as a key regulator in the progression of hepatocellular carcinoma, gliomas and gastric cancer. However, its role in epithelial ovarian carcinoma (EOC) remains unknown. In this study, HULC expression was examined in EOC, borderline and benign ovarian tumors, and normal ovarian tissues by RT-PCR. Ovarian cancer cell phenotypes, as well as autophagy-associated proteins were examined after HULC overexpression or downregulation by plasmid or small interfering RNA (siRNA) transfection, respectively. LncRNA–protein interactions were examined by ribonucleoprotein immunoprecipitation (RIP) assays. We found that HULC expression levels were higher in EOC tissues than normal samples. HULC overexpression induced cell proliferation, migration, invasion, whereas reduced cell apoptosis in vitro and induced tumor growth in vivo. In contrast, downregulation of HULC by siRNA transfection reduced cell proliferation, migration and invasion, and induced cell apoptosis and autophagy. Our results showed that HULC overexpression reduced ATG7, LC3-II and LAMP1 expression, while inducing SQSTM1 (P62) and ITGB1 expression. HULC downregulation had the opposite effects. Furthermore, RIP indicated that ATG7 interacted with HULC; ATG7 downregulation also induced cell proliferation, reduced apoptosis and inhibited autophagy in vitro by reducing LC3-II and LAMP1 expression, while inducing SQSTM1 expression. Furthermore, ATG7 co-transfection with HULC reversed the oncogenic effects of HULC both in vitro and in vivo; however, downregulating ATG7 did not affect cell migration and invasive ability. We found that ITGB1 siRNA co-transfection with HULC reversed the function of HULC in inducing ovarian cancer cell migration and invasive ability. Taken together, our results show that HULC may promote ovarian carcinoma tumorigenesis by inhibiting ATG7 and inducing progression by regulating ITGB1.
Highlights
Epithelial ovarian cancer (EOC) is the second most common gynecologic malignancy in women worldwide.[1]
Studies have demonstrated that the Long noncoding RNAs (lncRNAs) highly upregulated in liver cancer (HULC) is associated with the proliferation, invasion, metastasis and survival of tumor cells in certain cancers.[17,18,19,20,21,22]
Our results are consistent with Peng et al.[23], who showed that the lncRNA HULC is a novel biomarker in patients with pancreatic cancer and diffuse large B-cell lymphoma.[24]
Summary
Epithelial ovarian cancer (EOC) is the second most common gynecologic malignancy in women worldwide.[1]. Recent studies have shown that, during caspase-mediated non-apoptotic cell death, the expression of autophagy-related genes, such as ATG5, ATG7 and Beclin-1, is upregulated.[11,12] This type of cell death is defined as type II programmed cell death, or autophagic cell death, and deregulation of this process can lead to changes in cell homeostasis, resulting in tumorigenesis.[13] it is essential to determine the underlying molecular mechanisms of autophagy in ovarian cancer, which may be helpful for early detection, diagnosis and treatment. Long noncoding RNAs (lncRNAs) are novel regulators of gene expression involved in the regulation of many cellular processes including tumor growth and development, apoptosis, proliferation, differentiation and cell autophagy, and, are implicated in cancers and other diseases.[14,15,16] The highly upregulated in liver cancer (HULC) human lncRNA is multifunctional and has been implicated in various cellular processes. We demonstrate that HULC may promote ovarian carcinoma tumorigenesis and progression, and inhibit autophagy
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