Functional long non-coding RNAs in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a prevalent human malignancy with high morbidity worldwide. Hepatocarcinogenesis is a complex multistep process, and its underlying molecular mechanisms remain largely unknown. Recently, long non-coding RNAs (lncRNAs), a class of newly discovered molecules, have been revealed as essential regulators in the development of HCC. HCC-associated lncRNAs affect multiple malignant phenotypes by modulating gene expression or protein activity. Moreover, the dysregulation of lncRNAs in the liver is also associated with diseases predisposing to HCC, such as chronic viral infection, nonalcoholic steatohepatitis, and liver fibrosis/cirrhosis. A deeper understanding of the lncRNA regulatory network in the multistep processes of HCC development will provide new insights into the diagnosis and treatment of HCC. In this review, we introduce the biogenesis and function of lncRNAs and summarize recent knowledge on how lncRNAs regulate the malignant hallmarks of HCC, such as uncontrolled cell proliferation, resistance to cell death, metabolic reprogramming, immune escape, angiogenesis, and metastasis. We also review emerging insights into the role of lncRNAs in HCC-associated liver diseases. Finally, we discuss the potential applications of lncRNAs as early diagnostic biomarkers and therapeutic targets.

Introduction

Long non-coding RNAs (lncRNAs) are newly discovered non-protein-coding transcripts of more than 200 nt in length. To date, more than fifty thousand lncRNAs have been identified, accounting for more than 60% of the human transcriptome [1]. Furthermore, extensive experimental evidence has supported the function of lncRNAs in physiological and pathological processes. In particular, lncRNAs with tumour-suppressive and oncogenic roles have been characterized in diverse cancer types.

Hepatocellular carcinoma (HCC) is one of the most prevalent human malignancies and the second most lethal tumour worldwide [2,3]. The risk factors for HCC include hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, alcohol abuse, metabolic liver disease and exposure to dietary toxins [4]. These stimuli trigger inflammatory responses and chronic liver damage that, in the long run, promote liver fibrosis accompanied by genetic or epigenetic changes in hepatocytes, thus creating a pro-tumourigenic microenvironment [4,5]. Due to the lack of symptoms in the early disease stages, most patients were diagnosed at the advanced disease stages with metastasis, thus losing the opportunity of curative resection. Besides, insufficient anti-tumoural activity, potential liver toxicity in the context of cirrhosis, and inadequate patient selection have rendered few survival benefits to HCC patients for most of the systemic therapeutic agents. Recent studies revealed that the dysregulation of lncRNAs contributes to hepatocarcinogenesis, and much progress has been made in disclosing the functions and mechanisms of HCC-related lncRNAs, which constitute a rich resource for clinical applications in HCC diagnosis and treatment. In this review, we primarily introduce the biogenesis and functions of lncRNAs and then summarize the lncRNAs that regulate the malignant phenotypes of HCC and the liver diseases predisposing to HCC and the challenges in this field. In addition, we briefly discuss the potential of lncRNAs as diagnostic biomarkers and therapeutic targets.