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Roles and Regulation of Long Noncoding Rnas in Hepatocellular Carcinoma Lee Jin Lim1, Samuel Y.S.Wong2, Feiyang Huang3, Sheng Lim1,2,4, Samuel S

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Roles and Regulation of Long Noncoding Rnas in Hepatocellular Carcinoma Lee Jin Lim1, Samuel Y.S.Wong2, Feiyang Huang3, Sheng Lim1,2,4, Samuel S Published OnlineFirst July 23, 2019; DOI: 10.1158/0008-5472.CAN-19-0255 Cancer Review Research Roles and Regulation of Long Noncoding RNAs in Hepatocellular Carcinoma Lee Jin Lim1, Samuel Y.S.Wong2, Feiyang Huang3, Sheng Lim1,2,4, Samuel S. Chong5, London Lucien Ooi6,7,OiLianKon2, and Caroline G. Lee1,2,6,8 Abstract Next-generation sequencing has uncovered thousands of ulated gene/protein expression. Notably, 63 deregulated long noncoding RNAs (lncRNA).Manyarereportedtobe lncRNAs are significantly associated with clinicopathologic aberrantly expressed in various cancers, including hepato- features of HCC. Twenty-three deregulated lncRNAs associ- cellular carcinoma (HCC), and play key roles in tumori- ated with both tumor and metastatic clinical features were genesis. This review provides an in-depth discussion of the also tumorigenic and prometastatic in experimental models oncogenic mechanisms reported to be associated with of HCC, and eight of these mapped to known cancer path- deregulated HCC-associated lncRNAs. Transcriptional ways. Fifty-two upregulated lncRNAs exhibit oncogenic expression of lncRNAs in HCC is modulated through tran- properties and are associated with prominent hallmarks of scription factors, or epigenetically by aberrant histone acet- cancer, whereas 22 downregulated lncRNAs have tumor- ylation or DNA methylation, and posttranscriptionally by suppressive properties. Aberrantly expressed lncRNAs in lncRNA transcript stability modulated by miRNAs and RNA- HCC exert pleiotropic effects on miRNAs, mRNAs, and binding proteins. Seventy-four deregulated lncRNAs have proteins. They affect multiple cancer phenotypes by altering been identified in HCC, of which, 52 are upregulated. This miRNA and mRNA expression and stability, as well as review maps the oncogenic roles of these deregulated through effects on protein expression, degradation, struc- lncRNAs by integrating diverse datasets including clinico- ture, or interactions with transcriptional regulators. Hence, pathologic features, affected cancer phenotypes, associated these insights reveal novel lncRNAs as potential biomarkers miRNA and/or protein-interacting partners as well as mod- and may enable the design of precision therapy for HCC. Introduction stage HCC (2). Potentially curative options like surgical resection and liver transplantation are only indicated for early stage disease As the sixth most common and fourth most fatal cancer in the and are possible in only 10% to 20% of patients who present with world (1), hepatocellular carcinoma (HCC) is a major global HCC, with expected 5-year overall survival rates of 40% to health problem. The high mortality is due to the late stage of 70% (3). However, the risk of recurrences within 5 years is high, presentation in the majority of cases and the limited treatment both for patients who undergo resection (70%) and also liver options in that situation where curative surgery is no longer transplantation (10%–60%) due to the underlying disease caus- possible. This late presentation is due in a large part to the absence ing HCC formation in the first instance (3–5). The majority of symptoms in the early stages of disease, and the lack of (80%) of patients present with advanced HCC, which are not diagnostic biomarkers and other methods for detecting early amenable to surgery, and for which other treatment options are essentially palliative. These treatment options can be locoregional or systemic methods. Locoregional therapies include ablation 1 Department of Biochemistry, Yong Loo Lin School of Medicine, National (radiofrequency, microwave, cryotherapy) or catheter-based University of Singapore, Singapore, Singapore. 2Division of Cellular and Molec- ular Research, Humphrey Oei Institute of Cancer Research, National Cancer transhepatic arterial embolization with chemotherapeutic agents Centre Singapore, Singapore, Singapore. 3NUS High School of Math and Science, (transarterial chemoembolization) or radionuclear agents like Singapore, Singapore. 4Raffles Institution, Singapore, Singapore. 5Department Yttrium 90 (selective internal radiation therapy; ref. 3). For of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, systemic treatment, there are chemotherapy and targeted therapy 6 Singapore, Singapore. Duke-NUS Graduate Medical School, Singapore, options, although only sorafenib (6–9) and regorafenib (10, 11), 7 Singapore. Department of Hepato-Pancreato-Biliary and Transplant Surgery, both multityrosine kinase inhibitors, are clinically approved for Singapore General Hospital, Singapore, Singapore. 8NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singa- treating locally advanced or metastatic HCC, which extend sur- pore, Singapore. vival by only a few months (3). Given the dismal landscape of therapeutic options if diagnosis is made late, there is, therefore, an Note: Supplementary data for this article are available at Cancer Research fi Online (http://cancerres.aacrjournals.org/). urgent need for a ne-grained molecular landscape of HCC from which to discover clinically relevant early diagnostic and prog- Corresponding Author: Caroline G. Lee, National University of Singapore, 8 nostic biomarkers, and to develop curative precision therapies. Medical Drive, Singapore 117596, Singapore. Phone: 011-65-6516-3251; Fax: 011-65-6436-8353; E-mail: [email protected] Risk factors for HCC include viral infections with hepatitis B (HBV) or C virus (HCV), alcoholism, immune-related liver dis- Cancer Res 2019;XX:XX–XX eases, nonalcoholic fatty liver disease, obesity, and aflatoxin doi: 10.1158/0008-5472.CAN-19-0255 exposure, and these factors vary with gender, geographic region, Ó2019 American Association for Cancer Research. and ethnicity (12). HBV and HCV infections are the most strongly www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst July 23, 2019; DOI: 10.1158/0008-5472.CAN-19-0255 Lim et al. associated risk factors; epidemiologic studies have shown that mRNAs, the functions of lncRNAs are less understood as they 50% to 55% of HCC cases globally are associated with HBV (2, 13) cannot be inferred due to low sequence conservation (34). None- and 25% to 30% with HCV infections (13). In highly endemic theless, increasing evidence implicates lncRNAs in every aspect in regions like Southeast Asia, HBV infection can account for approx- the life cycle of a gene, including transcription, splicing, RNA imately 80% of HCC (13, 14). The link between HBV infection decay, and translation (35). and HCC is one of the closest relationships identified between an Expression of lncRNAs is deregulated in various pathologic environmental agent and a cancer, as exemplified by the 20-fold conditions including HCC (22) and other cancers (27, 36). to 100-fold higher risk for developing HCC among chronic HBV In recent years, several lncRNAs were reported to be signifi- carriers (14–17). cantly deregulated in HCC (see 22, 37–42). HBV (43–45), The progression from normal liver tissue to HCC (18) is a the etiological agent most commonly associated with HCC, multistep process involving repeated cycles of hepatocyte and its key gene, HBx (37, 46, 47), deregulate the expression damage, followed by regeneration leading to chronic liver disease. of cellular lncRNAs and modulate the hallmarks of can- In chronic liver disease, regenerating hepatocytes are present in cer (48, 49). Significantly, the HBx-LINE1 fusion transcript is cytologically normal hyperplastic nodules, signaling an initial an lncRNA that activates Wnt signaling, promotes HCC devel- first step toward HCC formation. Progression to premalignant opment and progression, and correlates with shorter patient dysplastic nodules is visualized by abnormal liver architecture survival (50). These observations point to the considerable with thickened trabeculae and abnormal cytological features such potential of lncRNAs as a source of novel targetable molecules as clear cell changes and nuclear crowding. Dysplastic nodules for HCC precision therapy and for discovering new diagnostic may then evolve into overt HCC having invasive and metastatic biomarkers. capabilities. Accumulation of numerous aberrations and dysre- Recent reviews of lncRNAs in HCC (37–42) have focused gulations of the genome and epigenome affecting both mRNAs mainly on the functions and regulatory mechanisms of indi- and noncoding RNAs (ncRNA), including long noncoding RNAs vidual deregulated lncRNAs in isolation from other deregu- (lncRNA), are key events in this multistep progression and con- lated lncRNAs, and were necessarily fragmentary snapshots tribute to both tumorigenicity and the invasive behavior of of the field (37–42). The primary focus of this review is on HCC (19). 74 deregulated lncRNAs in HCC and their mechanisms of Advances in molecular and cell biology, detailed characteriza- action in hepatocarcinogenesis. By integrating diverse datasets, tions of genomes, epigenomes, proteomes, and metabolomes in including clinicopathologic associations, cancer phenotypes, HCC have added new insights into hepatic carcinogenesis (see miRNA- and protein-interacting partners, altered transcrip- reviews; refs. 20, 21), but with scant clinical benefits as much more tomes, and protein expression, this review attempts to provide remains unknown. The advent of state-of-the-art next-generation a perspective of 74 lncRNAs known to be deregulated in HCC, sequencing
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