Abstract
Recently, increasing numbers of long noncoding RNAs (lncRNAs), with both oncogenic and tumor-suppressive potential, have been found to be aberrantly expressed in various human cancers. However, the function of lncRNAs in hepatocellular carcinoma (HCC) progression remains largely unknown. In this study, we performed a comprehensive microarray analysis of lncRNA expression using human HCC specimens. After validation in 119 human HCC tissues, we identified a novel tumor suppressor lncRNA, CPS1 intronic transcript 1 (CPS1-IT1). To elucidate the clinical significance of CPS1-IT1 in HCC, correlations between CPS1-IT1 levels, clinical parameters, and survival outcomes were analyzed. In vitro and in vivo functional assays were also performed to dissect the potential underlying mechanisms. Expression of CPS1-IT1 was significantly decreased in 73% of HCC tissues, and patients with low CPS1-IT1 expression had poor survival outcomes. Furthermore, in vitro functional assays indicated that CPS1-IT1 significantly reduced cell proliferation, migration and invasion capacities through reduced Hsp90 binding to and activation of HIF-1α, thereby suppressing the epithelial-mesenchymal transition (EMT). An in vivo animal model also demonstrated the tumor suppressor role of CPS1- IT1 via decreased tumor growth and metastasis. In conclusion, lncRNA CPS1-IT1 acts as a tumor suppressor in HCC by reducing HIF-1α activation and suppressing EMT. The findings of this study establish a function for CPS1-IT1 in HCC progression and suggest its potential as a new prognostic biomarker and target for HCC therapy.
Highlights
Human hepatocellular carcinoma (HCC) is the most common cancer of the liver and ranks third in cancerrelated death worldwide [1]
Identification of long noncoding RNAs (lncRNAs) deregulated in HCC tissues by microarray analysis To screen lncRNAs involved in HCC progression, tumor and non-cancerous normal tissues obtained from three HCC patients were selected for microarray analysis (Affymetrix GeneChip® Human Gene 2.0)
Among these lncRNAs, we further examined the role of CPS1-IT1 in hepatomagenesis
Summary
Human hepatocellular carcinoma (HCC) is the most common cancer of the liver and ranks third in cancerrelated death worldwide [1]. According to the annual report of the Department of Health in Taiwan, HCC is the second-most life-threatening malignancy for both sexes in Taiwan [2,3,4]. Surgical resection, percutaneous ethanol injection and liver transplantation are the major therapeutic approaches for HCC. For patients www.impactjournals.com/oncotarget who are not eligible for resection or those with metastasis, chemotherapy is the primary treatment. Due to tumor recurrence, metastasis, and poor response to chemotherapy and radiotherapy, the therapeutic response is not satisfactory [5,6,7]; the recurrence rate during long-term follow-up is still more than 75% for patients with resectable HCC [8, 9]. It is important to explore new diagnostic and therapeutic molecular targets for HCC
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