Ferroptosis-Related Long Non-Coding RNA signature predicts the prognosis of Head and neck squamous cell carcinoma.
Tang Yun,Li Cheng,Zhang You-Jing,Wu Zeng-Hong
International journal of biological sciences
: Head and neck squamous cell carcinoma (HNSCC) are head and neck cancers. On the other hand, ferroptosis is a novel iron-dependent and ROS reliant type of cell death observed various disease conditions. : We constructed a prognostic multilncRNA signature based on ferroptosis-related differentially expressed lncRNAs in HNSCC. : We identified 25 differently expressed lncRNAs associated with prognosis of HNSCC. Kaplan-Meier analyses revealed the high-risk lncRNAs signature associated with poor prognosis of HNSCC. Moreover, the AUC of the lncRNAs signature was 0.782, underscoring their utility in prediction HNSCC prognosis. Indeed, our risk assessment model was superior to traditional clinicopathological features in predicting HNSCC prognosis. GSEA revealed the immune and tumor-related pathways in the low risk group individuals. Moreover, TCGA revealed T cell functions including cytolytic activity, HLA, regulation of inflammationp, co-stimulation, co-inhibition and coordination of type II INF response were significantly different between the low-risk and high-risk groups. Immune checkpoints such as PDCD-1 (PD-1), CTLA4 and LAG3, were also expressed differently between the two risk groups. A novel ferroptosis-related lncRNAs signature impacts on the prognosis of HNSCC.
10.7150/ijbs.55552
Crosstalk of lncRNA and Cellular Metabolism and Their Regulatory Mechanism in Cancer.
Lin Yang-Hsiang
International journal of molecular sciences
The imbalanced regulation of metabolic homeostasis and energy production is highly associated with inflammation, tumor growth, metastasis and cancer progression. Both glycolysis and oxidative phosphorylation maintain metabolic homeostasis and energy production in cells. Long noncoding RNAs (lncRNAs) are a class of non-protein-coding transcripts longer than 200 nucleotides. Furthermore, lncRNAs can function as either tumor suppressors or oncogenes in cancer. Dysregulated lncRNAs reportedly regulate cancer hallmarks such as tumor growth, metabolism and metastasis. Accordingly, uncovering the interaction between lncRNAs and cellular metabolism has become a necessity when attempting to identify effective therapeutic and preventive strategies in cancer progression. This review summarizes important knowledge of the actions of known lncRNAs-mediated cancer metabolism.
10.3390/ijms21082947
Role of LncRNAs in regulating cancer amino acid metabolism.
Guo Yuhong,Lv Bin,Liu Renfeng,Dai Zhengzai,Zhang Feifei,Liang Yiping,Yu Bo,Zeng Duo,Lv Xiao-Bin,Zhang Zhiping
Cancer cell international
The metabolic change of tumor cells is an extremely complicated process that involves the intersection and integration of various signal pathways. Compared with normal tissues, cancer cells show distinguished metabolic characteristics called metabolic reprogramming, which has been considered as a sign of cancer occurrence. With the deepening of tumor research in recent years, people gradually found that amino acid metabolism played crucial roles in cancer progression. Long non-coding RNAs (lncRNAs), which are implicated in many important biological processes, were firstly discovered dysregulating in cancer tissues and participating in extensive regulation of tumorigenesis. This review focuses on the reprogramming of amino acid metabolism in cancers and how lncRNAs participate in the regulatory network by interacting with other macromolecular substances. Understanding the functions of lncRNA in amino acid reprogramming in tumors might provide a new vision on the mechanisms of tumorigenesis and the development of new approaches for cancer therapy.
10.1186/s12935-021-01926-8
Long Non-coding RNAs Involved in Metabolic Alterations in Breast and Prostate Cancers.
Kamada Shuhei,Takeiwa Toshihiko,Ikeda Kazuhiro,Horie-Inoue Kuniko,Inoue Satoshi
Frontiers in oncology
Breast and prostate cancers are the most prevalent cancers in females and males, respectively. These cancers exhibit sex hormone dependence and thus, hormonal therapies are used to treat these cancers. However, acquired resistance to hormone therapies is a major clinical problem. In addition, certain portions of these cancers initially exhibit hormone-independence due to the absence of sex hormone receptors. Therefore, precise and profound understanding of the cancer pathophysiology is required to develop novel clinical strategies against breast and prostate cancers. Metabolic reprogramming is currently recognized as one of the hallmarks of cancer, as exemplified by the alteration of glucose metabolism, oxidative phosphorylation, and lipid metabolism. Dysregulation of metabolic enzymes and their regulators such as kinases, transcription factors, and other signaling molecules contributes to metabolic alteration in cancer. Moreover, accumulating lines of evidence reveal that long non-coding RNAs (lncRNAs) regulate cancer development and progression by modulating metabolism. Understanding the mechanism and function of lncRNAs associated with cancer-specific metabolic alteration will therefore provide new knowledge for cancer diagnosis and treatment. This review provides an overview of recent studies regarding the role of lncRNAs in metabolism in breast and prostate cancers, with a focus on both sex hormone-dependent and -independent pathways.
10.3389/fonc.2020.593200
Development and validation of a ferroptosis-related lncRNAs prognosis signature in colon cancer.
Bosnian journal of basic medical sciences
Ferroptosis is a form of iron-dependent programmed cell death. Regulation of ferroptosis in tumor cells is a novel treatment modality. The present study aimed to investigate ferroptosis-related long non-coding RNAs (lncRNAs) and construct a prognostic model for colon adenocarcinoma (COAD). RNA- sequencing data and ferroptosis-related genes were obtained from The Cancer Genome Atlas database and FerrDb database. COAD patients were randomly assigned to training- and validation groups. The Least Absolute Shrinkage and Selection Operator regression and Cox regression model were used to determine and develop a predictive model. The model was corroborated using the validation group and the entire group. In total, 259 ferroptosis-related genes and 905 ferroptosis-related LncRNAs were obtained. Cox model revealed and constructed seven ferroptosis-related LncRNAs signature (LINC01503, AC004687.1, AC010973.2, AP001189.3, ARRDC1-AS1, OIP5-AS1, and NCK1-DT). Patients were assigned into two groups according to the median risk score. Kaplan-Meier survival curves showed that overall survival between high- and low-risk groups was statistically significant (P<0.01). Cox multivariate analysis seven ferroptosis-related LncRNAs signature was an independent risk factor for COAD outcomes (P<0.05). The relationship between seven ferroptosis-related LncRNAs and clinicopathological features was also examined. The principal component analysis showed a difference between high- and low-risk groups intuitively. With the aid of gene set enrichment analysis, the underlying mechanisms of seven ferroptosis-related LncRNAs were uncovered, including the MAPK signaling pathway, mTOR signaling pathway, and glutathione metabolism pathway. Finally, we established and validated seven ferroptosis-related lncRNAs signature for COAD patients to predict survival. These results may provide meaningful targets for future study.
10.17305/bjbms.2020.5617
Emerging roles of non-coding RNAs in the metabolic reprogramming of tumor-associated macrophages.
Li Jiali,Lu Zhenyi,Zhang Ying,Xia Lin,Su Zhaoliang
Immunology letters
Macrophages are the most common immune cells in the tumor microenvironment, and tumor-associated macrophages play an important role in cancer development. Metabolic reprogramming is important for the functional plasticity of macrophages. Studies investigating the relevance of non-coding RNAs (ncRNAs) in human cancer found that ncRNAs can regulate the metabolism of cancer cells and tumor-associated macrophages. NcRNAs include short ncRNAs, long ncRNAs (lncRNAs), and circular RNAs (circRNAs). The most common short ncRNAs are microRNAs, which regulate glucose, lipid, and amino acid metabolism in macrophages by acting on metabolism-related pathways and targeting metabolism-related enzymes and proteins, and are therefore involved in cancer progression. The role of lncRNAs and circRNAs in the metabolism of tumor-associated macrophages remains unclear. LncRNAs affect the glucose metabolism of macrophages, whereas their role in lipid and amino acid metabolism is not clear. CircRNAs regulate amino acid metabolism in macrophages. The roles of ncRNAs in energy metabolism and the underlying mechanisms need to be investigated further. Here, we summarize recent findings on the involvement of ncRNAs in metabolic reprogramming in tumor-associated macrophages, which affect the tumor microenvironment and play important roles in the development of cancer. Improving our understanding of the effects of ncRNAs on metabolic reprogramming of tumor-associated macrophages may facilitate the development of effective clinical therapies.
10.1016/j.imlet.2021.02.003
[lncRNA in hepatic glucose and lipid metabolism: a review].
Chen Xiaoxiao,Sun Chen,Liu Chang,Wu Jie
Sheng wu gong cheng xue bao = Chinese journal of biotechnology
In recent years, long non-coding RNA (lncRNA) has been proved to be involved in the regulation of biological processes at various levels, attracting research interests in life science. LncRNA possesses the unique capability and exert discrete effects on transcription, translation and post-translational modification of the target genes through interacting with DNA, RNA and protein. Current studies have revealed that lncRNA plays an important role in hepatic metabolism via diverse pathways. This review focuses on the function of lncRNA and its relationship with hepatic energy metabolism and the correlated diseases, to elucidate the underlying mechanisms and prospects of lncRNA researches.
10.13345/j.cjb.200211
Metabolon: a novel cellular structure that regulates specific metabolic pathways.
Tian Tian,Fan Jun,Elf Shannon Elisabeth
Cancer communications (London, England)
This manuscript of research highlight focused on one paper recently published in Nature Metabolism entitled "Mitochondrial Long Non-coding RNA GAS5 Tunes TCA Metabolism in Response to Nutrient Stress" from Lin Aifu's group in Zhejiang University. In this manuscript, we discussed the novel findings in Lin's paper and concluded that the metabolon is emerging as a novel cellular structure that regulates specific metabolic pathways.
10.1002/cac2.12154
The Role of Non-Coding RNAs in the Neuroprotective Effects of Glutathione.
Kinoshita Chisato,Aoyama Koji
International journal of molecular sciences
The establishment of antioxidative defense systems might have been mandatory for most living beings with aerobic metabolisms, because oxygen consumption produces adverse byproducts known as reactive oxygen species (ROS). The brain is especially vulnerable to the effect of ROS, since the brain has large amounts of unsaturated fatty acids, which are a target of lipid oxidation, as well as comparably high-energy consumption compared to other organs that results in ROS release from mitochondria. Thus, dysregulation of the synthesis and/or metabolism of antioxidants-particularly glutathione (GSH), which is one of the most important antioxidants in the human body-caused oxidative stress states that resulted in critical diseases, including neurodegenerative diseases in the brain. GSH plays crucial roles not only as an antioxidant but also as an enzyme cofactor, cysteine storage form, the major redox buffer, and a neuromodulator in the central nervous system. The levels of GSH are precisely regulated by uptake systems for GSH precursors as well as GSH biosynthesis and metabolism. The rapid advance of RNA sequencing technologies has contributed to the discovery of numerous non-coding RNAs with a wide range of functions. Recent lines of evidence show that several types of non-coding RNAs, including microRNA, long non-coding RNA and circular RNA, are abundantly expressed in the brain, and their activation or inhibition could contribute to neuroprotection through the regulation of GSH synthesis and/or metabolism. Interestingly, these non-coding RNAs play key roles in gene regulation and growing evidence indicates that non-coding RNAs interact with each other and are co-regulated. In this review, we focus on how the non-coding RNAs modulate the level of GSH and modify the oxidative stress states in the brain.
10.3390/ijms22084245
The lncRNA lincNMR regulates nucleotide metabolism via a YBX1 - RRM2 axis in cancer.
Gandhi Minakshi,Groß Matthias,Holler Jessica M,Coggins Si'Ana A,Patil Nitin,Leupold Joerg H,Munschauer Mathias,Schenone Monica,Hartigan Christina R,Allgayer Heike,Kim Baek,Diederichs Sven
Nature communications
Long intergenic non-coding RNA-Nucleotide Metabolism Regulator (lincNMR) is a long non-coding RNA (lncRNA) which is induced in hepatocellular carcinoma. Its depletion invokes a proliferation defect, triggers senescence and inhibits colony formation in liver, but also breast and lung cancer cells. Triple-label SILAC proteomics profiles reveal a deregulation of key cell cycle regulators in lincNMR-depleted cells like the key dNTP synthesizing enzymes RRM2, TYMS and TK1, implicating lincNMR in regulating nucleotide metabolism. LincNMR silencing decreases dNTP levels, while exogenous dNTPs rescues the proliferation defect induced by lincNMR depletion. In vivo RNA Antisense Purification (RAP-MS) identifies YBX1 as a direct interaction partner of lincNMR which regulates RRM2, TYMS and TK1 expression and binds to their promoter regions. In a Chick Chorioallantoic Membrane (CAM) in vivo model, lincNMR-depleted tumors are significantly smaller. In summary, we discover a lincRNA, lincNMR, which regulates tumor cell proliferation through a YBX1-RRM2-TYMS-TK1 axis governing nucleotide metabolism.
10.1038/s41467-020-17007-9
Long non‑coding RNAs: Key regulators involved in metabolic reprogramming in cancer (Review).
Liu Chunxia,Li Hao,Chu Fenglan,Zhou Xi,Xie Rui,Wei Qiongqiong,Yang Shiming,Li Tao,Liang Sicheng,Lü Muhan
Oncology reports
Metabolism is defined as the biochemical processes that produce or consume energy in living organisms. Otto Warburg suggested that cancer is a metabolic disease, thus metabolic reprogramming is widely considered as an emerging hallmark of cancer cells. Long non‑coding RNAs (lncRNAs), which are defined as transcripts >200 nucleotides with limited protein coding potential, are involved in cancer metabolism. lncRNAs can control pathophysiological processes of cancer by regulating gene expression at epigenetic, transcriptional and post‑transcriptional levels. The process of tumorigenesis is usually accompanied by alterations in metabolic patterns, involving glycolysis, the tricarboxylic acid cycle, mitochondrial oxidative phosphorylation, the pentose phosphate signaling pathway, glutamine metabolism and lipid metabolism, which is also known as metabolic reprogramming. The present review summarized the functions of lncRNAs in cancer metabolism and discussed how the dysregulation of lncRNAs contributed to metabolic reprogramming and tumorigenesis, which may provide novel therapeutic targets for cancer.
10.3892/or.2021.8005
Prognostic Signatures of Metabolic Genes and Metabolism-Related Long Non-coding RNAs Accurately Predict Overall Survival for Osteosarcoma Patients.
Frontiers in cell and developmental biology
In this study, we identified eight survival-related metabolic genes in differentially expressed metabolic genes by univariate Cox regression analysis based on the therapeutically applicable research to generate effective treatments ( = 84) data set and genotype tissue expression data set ( = 396). We also constructed a six metabolic gene signature to predict the overall survival of osteosarcoma (OS) patients using least absolute shrinkage and selection operator (Lasso) Cox regression analysis. Our results show that the six metabolic gene signature showed good performance in predicting survival of OS patients and was also an independent prognostic factor. Stratified correlation analysis showed that the metabolic gene signature accurately predicted survival outcomes in high-risk and low-risk OS patients. The six metabolic gene signature was also verified to perform well in predicting survival of OS patients in an independent cohort (GSE21257). Then, using univariate Cox regression and Lasso Cox regression analyses, we identified an eight metabolism-related long noncoding RNA (lncRNA) signature that accurately predicts overall survival of OS patients. Gene set variation analysis showed that the apical surface and bile acid metabolism, epithelial mesenchymal transition, and P53 pathway were activated in the high-risk group based on the eight metabolism-related lncRNA signature. Furthermore, we constructed a competing endogenous RNA (ceRNA) network and conducted immunization score analysis based on the eight metabolism-related lncRNA signature. These results showed that the six metabolic gene signature and eight metabolism-related lncRNA signature have good performance in predicting the survival outcomes of OS patients.
10.3389/fcell.2021.644220
Emerging roles of long non-coding RNAs in tumor metabolism.
Sun Hui,Huang Zhaohui,Sheng Weiqi,Xu Mi-Die
Journal of hematology & oncology
Compared with normal cells, tumor cells display distinct metabolic characteristics. Long non-coding RNAs (lncRNAs), a large class of regulatory RNA molecules with limited or no protein-coding capacity, play key roles in tumorigenesis and progression. Recent advances have revealed that lncRNAs play a vital role in cell metabolism by regulating the reprogramming of the metabolic pathways in cancer cells. LncRNAs could regulate various metabolic enzymes that integrate cell malignant transformation and metabolic reprogramming. In addition to the known functions of lncRNAs in regulating glycolysis and glucose homeostasis, recent studies also implicate lncRNAs in amino acid and lipid metabolism. These observations reveal the high complexity of the malignant metabolism. Elucidating the metabolic-related functions of lncRNAs will provide a better understanding of the regulatory mechanisms of metabolism and thus may provide insights for the clinical development of cancer diagnostics, prognostics and therapeutics.
10.1186/s13045-018-0648-7
Regulation of Glucose and Lipid Metabolism by Long Non-coding RNAs: Facts and Research Progress.
Zhang Tie-Ning,Wang Wei,Yang Ni,Huang Xin-Mei,Liu Chun-Feng
Frontiers in endocrinology
Long non-coding RNAs (lncRNAs) are a type of non-coding RNA with a length that exceeds 200 nucleotides. Previous studies have shown that lncRNAs play an important role in the pathogenesis of various diseases. Research in both animal models and humans has begun to unravel the profound complexity of lncRNAs and demonstrated that lncRNAs exert direct effects on glucose and lipid metabolism both and . Such research has elucidated the regulatory role of lncRNAs in glucose and lipid metabolism in human disease. lncRNAs mediate glucose and lipid metabolism under physiological and pathological conditions and contribute to various metabolism disorders. This review provides an update on our understanding of the regulatory role of lncRNAs in glucose and lipid metabolism in various diseases. As our understanding of the function of lncRNAs improves, the future is promising for the development of new diagnostic biomarkers that utilize lncRNAs and treatments that target lncRNAs to improve clinical outcomes.
10.3389/fendo.2020.00457
The Role of Long Non-coding RNAs in Cancer Metabolism: A Concise Review.
Frontiers in oncology
Dysregulation of metabolic pathways in cancer cells is regarded as a hallmark of cancer. Identification of these abnormalities in cancer cells dates back to more than six decades, far before discovery of oncogenes and tumor suppressor genes. Based on the importance of these pathways, several researchers have aimed at modulation of these functions to intervene with the pathogenic course of cancer. Numerous genes have been shown to participate in the regulation of metabolic pathways, thus aberrant expression of these genes can be involved in the pathogenesis of cancer. The recent decade has experienced a significant attention toward the role of long non-coding RNAs (lncRNAs) in the biological functions. These transcripts regulate expression of genes at several levels, therefore influencing the activity of cancer-related pathways. Among the most affected pathways are those modulating glucose homeostasis, as well as amino acid and lipid metabolism. Moreover, critical roles of lncRNAs in regulation of mitochondrial function potentiate these transcripts as novel targets for cancer treatment. In the current review, we summarize the most recent literature regarding the role of lncRNAs in the cancer metabolism and their significance in the design of therapeutic modalities.
10.3389/fonc.2020.555825
The emerging regulatory roles of long non-coding RNAs implicated in cancer metabolism.
Molecular therapy : the journal of the American Society of Gene Therapy
Compared to normal cells, cancer cells exhibit specific metabolic characteristics that facilitate the growth and metastasis of cancer. It is now widely appreciated that long non-coding RNAs (lncRNAs) exert extensive regulatory effects on a spectrum of biological processes through diverse mechanisms. In this review, we focus on the rapidly advancing field of lncRNAs and summarize the relationship between the dysregulation of lncRNAs and cancer metabolism, with a particular emphasis on the specific roles of lncRNAs in glycolysis, mitochondrial function, glutamine, and lipid metabolism. These investigations reveal that lncRNAs are a key factor in the complexity of malignant cancer metabolism. Only through understanding the relevance between lncRNAs and cancer metabolic reprogramming can we open a new chapter in the history of carcinogenesis, one that promises to alter the methods of cancer diagnosis and treatment.
10.1016/j.ymthe.2021.03.017
Involvement of Long Non-Coding RNAs in Glucose Metabolism in Cancer.
Cancers
The rapid and uncontrolled proliferation of cancer cells is supported by metabolic reprogramming. Altered glucose metabolism supports cancer growth and progression. Compared with normal cells, cancer cells show increased glucose uptake, aerobic glycolysis and lactate production. Byproducts of adjusted glucose metabolism provide additional benefits supporting hallmark capabilities of cancer cells. Long non-coding RNAs (lncRNAs) are a heterogeneous group of transcripts of more than 200 nucleotides in length. They regulate numerous cellular processes, primarily through physical interaction with other molecules. Dysregulated lncRNAs are involved in all hallmarks of cancer including metabolic alterations. They may upregulate metabolic enzymes, modulate the expression of oncogenic or tumor-suppressive genes and disturb metabolic signaling pathways favoring cancer progression. Thus, lncRNAs are not only potential clinical biomarkers for cancer diagnostics and prediction but also possible therapeutic targets. This review summarizes the lncRNAs involved in cancer glucose metabolism and highlights their underlying molecular mechanisms.
10.3390/cancers13050977
Autophagy in the liver: functions in health and disease.
Ueno Takashi,Komatsu Masaaki
Nature reviews. Gastroenterology & hepatology
The concept of macroautophagy was established in 1963, soon after the discovery of lysosomes in rat liver. Over the 50 years since, studies of liver autophagy have produced many important findings. The liver is rich in lysosomes and possesses high levels of metabolic-stress-induced autophagy, which is precisely regulated by concentrations of hormones and amino acids. Liver autophagy provides starved cells with amino acids, glucose and free fatty acids for use in energy production and synthesis of new macromolecules, and also controls the quality and quantity of organelles such as mitochondria. Although the efforts of early investigators contributed markedly to our current knowledge of autophagy, the identification of autophagy-related genes represented a revolutionary breakthrough in our understanding of the physiological roles of autophagy in the liver. A growing body of evidence has shown that liver autophagy contributes to basic hepatic functions, including glycogenolysis, gluconeogenesis and β-oxidation, through selective turnover of specific cargos controlled by a series of transcription factors. In this Review, we outline the history of liver autophagy study, and then describe the roles of autophagy in hepatic metabolism under healthy and disease conditions, including the involvement of autophagy in α1-antitrypsin deficiency, NAFLD, hepatocellular carcinoma and viral hepatitis.
10.1038/nrgastro.2016.185
Recurrently deregulated lncRNAs in hepatocellular carcinoma.
Yang Yang,Chen Lei,Gu Jin,Zhang Hanshuo,Yuan Jiapei,Lian Qiuyu,Lv Guishuai,Wang Siqi,Wu Yang,Yang Yu-Cheng T,Wang Dongfang,Liu Yang,Tang Jing,Luo Guijuan,Li Yang,Hu Long,Sun Xinbao,Wang Dong,Guo Mingzhou,Xi Qiaoran,Xi Jianzhong,Wang Hongyang,Zhang Michael Q,Lu Zhi John
Nature communications
Hepatocellular carcinoma (HCC) cells often invade the portal venous system and subsequently develop into portal vein tumour thrombosis (PVTT). Long noncoding RNAs (lncRNAs) have been associated with HCC, but a comprehensive analysis of their specific association with HCC metastasis has not been conducted. Here, by analysing 60 clinical samples' RNA-seq data from 20 HCC patients, we have identified and characterized 8,603 candidate lncRNAs. The expression patterns of 917 recurrently deregulated lncRNAs are correlated with clinical data in a TCGA cohort and published liver cancer data. Matched array data from the 60 samples show that copy number variations (CNVs) and alterations in DNA methylation contribute to the observed recurrent deregulation of 235 lncRNAs. Many recurrently deregulated lncRNAs are enriched in co-expressed clusters of genes related to cell adhesion, immune response and metabolic processes. Candidate lncRNAs related to metastasis, such as HAND2-AS1, were further validated using RNAi-based loss-of-function assays. Thus, we provide a valuable resource of functional lncRNAs and biomarkers associated with HCC tumorigenesis and metastasis.
10.1038/ncomms14421
Non-coding RNAs in hepatocellular carcinoma: molecular functions and pathological implications.
Wong Chun-Ming,Tsang Felice Ho-Ching,Ng Irene Oi-Lin
Nature reviews. Gastroenterology & hepatology
Hepatocellular carcinoma (HCC) is a leading lethal malignancy worldwide. However, the molecular mechanisms underlying liver carcinogenesis remain poorly understood. Over the past two decades, overwhelming evidence has demonstrated the regulatory roles of different classes of non-coding RNAs (ncRNAs) in liver carcinogenesis related to a number of aetiologies, including HBV, HCV and NAFLD. Among the ncRNAs, microRNAs, which belong to a distinct class of small ncRNAs, have been proven to play a crucial role in the post-transcriptional regulation of gene expression. Deregulation of microRNAs has been broadly implicated in the inactivation of tumour-suppressor genes and activation of oncogenes in HCC. Modern high-throughput sequencing analyses have unprecedentedly identified a very large number of non-coding transcripts. Divergent groups of long ncRNAs have been implicated in liver carcinogenesis through interactions with DNA, RNA or proteins. Overall, ncRNAs represent a burgeoning field of cancer research, and we are only beginning to understand the importance and complicity of the ncRNAs in liver carcinogenesis. In this Review, we summarize the common deregulation of small and long ncRNAs in human HCC. We also comprehensively review the pathological roles of ncRNAs in liver carcinogenesis, epithelial-to-mesenchymal transition and HCC metastasis and discuss the potential applications of ncRNAs as diagnostic tools and therapeutic targets in human HCC.
10.1038/nrgastro.2017.169
Immune-Related lncRNA to Construct Novel Signature and Predict the Immune Landscape of Human Hepatocellular Carcinoma.
Hong Weifeng,Liang Li,Gu Yujun,Qi Zhenhua,Qiu Haibo,Yang Xiaosong,Zeng Weian,Ma Liheng,Xie Jingdun
Molecular therapy. Nucleic acids
The signature composed of immune-related long noncoding ribonucleic acids (irlncRNAs) with no requirement of specific expression level seems to be valuable in predicting the survival of patients with hepatocellular carcinoma (HCC). Here, we retrieved raw transcriptome data from The Cancer Genome Atlas (TCGA), identified irlncRNAs by co-expression analysis, and recognized differently expressed irlncRNA (DEirlncRNA) pairs using univariate analysis. In addition, we modified Lasso penalized regression. Then, we compared the areas under curve, counted the Akaike information criterion (AIC) values of 5-year receiver operating characteristic curve, and identified the cut-off point to set up an optimal model for distinguishing the high- or low-disease-risk groups among patients with HCC. We then reevaluated them from the viewpoints of survival, clinic-pathological characteristics, tumor-infiltrating immune cells, chemotherapeutics efficacy, and immunosuppressed biomarkers. 36 DEirlncRNA pairs were identified, 12 of which were included in a Cox regression model. After regrouping the patients by the cut-off point, we could more effectively differentiate between them based on unfavorable survival outcome, aggressive clinic-pathological characteristics, specific tumor immune infiltration status, low chemotherapeutics sensitivity, and highly expressed immunosuppressed biomarkers. The signature established by paring irlncRNA regardless of expression levels showed a promising clinical prediction value.
10.1016/j.omtn.2020.10.002
Development and validation of a 14-gene signature for prognosis prediction in hepatocellular carcinoma.
Zhang Bo-Han,Yang Jian,Jiang Li,Lyu Tao,Kong Ling-Xiang,Tan Yi-Fei,Li Bo,Zhu Yun-Feng,Xi Ao-Yao,Xu Xi,Yan Lyu-Nan,Yang Jia-Yin
Genomics
Worldwide, hepatocellular carcinoma (HCC) remains a crucial medical problem. Precise and concise prognostic models are urgently needed because of the intricate gene variations among liver cancer cells. We conducted this study to identify a prognostic gene signature with biological significance. We applied two algorithms to generate differentially expressed genes (DEGs) between HCC and normal specimens in The Cancer Genome Atlas cohort (training set included) and performed enrichment analyses to expound on their biological significance. A protein-protein interactions network was established based on the STRING online tool. We then used Cytoscape to screen hub genes in crucial modules. A multigene signature was constructed by Cox regression analysis of hub genes to stratify the prognoses of HCC patients in the training set. The prognostic value of the multigene signature was externally validated in two other sets from Gene Expression Omnibus (GSE14520 and GSE76427), and its role in recurrence prediction was also investigated. A total of 2000 DEGs were obtained, including 1542 upregulated genes and 458 downregulated genes. Subsequently, we constructed a 14-gene signature on the basis of 56 hub genes, which was a good predictor of overall survival. The prognostic signature could be replicated in GSE14520 and GSE76427. Moreover, the 14-gene signature could be applied for recurrence prediction in the training set and GSE14520. In summary, the 14-gene signature extracted from hub genes was involved in some of the HCC-related signalling pathways; it not only served as a predictive signature for HCC outcome but could also be used to predict HCC recurrence.
10.1016/j.ygeno.2020.03.013
Cellular senescence and hepatitis B-related hepatocellular carcinoma: An intriguing link.
Karakousis Nikolaos D,Papatheodoridi Alkistis,Chatzigeorgiou Antonios,Papatheodoridis George
Liver international : official journal of the International Association for the Study of the Liver
Chronic hepatitis B is mainly responsible for the morbidity and mortality from hepatitis B virus (HBV)-related complications, including hepatocellular carcinoma (HCC) and decompensated cirrhosis. Hepatocellular carcinoma remains the main challenge in the management of not only undiagnosed and/or untreated but also diagnosed and treated patients with chronic HBV infection, as its incidence decreases but is not eliminated even after many years of effective anti-HBV therapy. The exact mechanisms used by HBV to cause malignant transformation remain uncertain, although much of the available data are in favour of a pathogenetic role of HBx protein. Senescence is a cellular state, in which cells lose their ability to proliferate. This biological mechanism may function in a dual mode, namely being both cancer-protective as a result of reduced cellular proliferation, but also cancer-enhancing as a result of modulation of the tissular microenvironment by immune cells during persistent accumulation of senescent cells. Protein X of HBV protein exhibits many similarities in terms of the implemented mechanisms of action and pathways related to the biological process of cellular senescence. Concurrently, insufficient clearance of both senescent and precancerous hepatocytes combined with inadequate immune surveillance as a result of immunosenescence caused by chronic HBV infection may lead to hepatocarcinogenesis. Thus, the effect of HBV seems to be critical as a connecting link between cellular senescence and development of HCC. An ongoing research is underway towards identifying and validating markers of hepatocyte senescence, which could improve the landscape for evaluation of chronic liver disease, thereby providing valuable information in terms of HBV-related carcinogenesis.
10.1111/liv.14659
A Novel Ten-Gene Signature Predicting Prognosis in Hepatocellular Carcinoma.
Zhou Taicheng,Cai Zhihua,Ma Ning,Xie Wenzhuan,Gao Chan,Huang Mengli,Bai Yuezong,Ni Yangpeng,Tang Yunqiang
Frontiers in cell and developmental biology
Hepatocellular carcinoma (HCC) has a dismal long-term outcome. We aimed to construct a multi-gene model for prognosis prediction to inform HCC management. The cancer-specific differentially expressed genes (DEGs) were identified using RNA-seq data of paired tumor and normal tissue. A prognostic signature was built by LASSO regression analysis. Gene set enrichment analysis (GSEA) was performed to further understand the underlying molecular mechanisms. A 10-gene signature was constructed to stratify the TCGA and ICGC cohorts into high- and low-risk groups where prognosis was significantly worse in the high-risk group across cohorts ( < 0.001 for all). The 10-gene signature outperformed all previously reported models for both C-index and the AUCs for 1-, 3-, 5-year survival prediction (C-index, 0.84 vs 0.67 to 0.73; AUCs for 1-, 3- and 5-year OS, 0.84 vs 0.68 to 0.79, 0.81 to 0.68 to 0.80, and 0.85 vs 0.67 to 0.78, respectively). Multivariate Cox regression analysis revealed risk group and tumor stage to be independent predictors of survival in HCC. A nomogram incorporating tumor stage and signature-based risk group showed better performance for 1- and 3-year survival than for 5-year survival. GSEA revealed enrichment of pathways related to cell cycle regulation among high-risk samples and metabolic processes in the low-risk group. Our 10-gene model is robust for prognosis prediction and may help inform clinical management of HCC.
10.3389/fcell.2020.00629
An immune-related gene signature for predicting survival and immunotherapy efficacy in hepatocellular carcinoma.
Dai Yifei,Qiang Weijie,Lin Kequan,Gui Yu,Lan Xun,Wang Dong
Cancer immunology, immunotherapy : CII
BACKGROUND:Hepatocellular carcinoma (HCC) ranks the fourth in terms of cancer-related mortality globally. Herein, in this research, we attempted to develop a novel immune-related gene signature that could predict survival and efficacy of immunotherapy for HCC patients. METHODS:The transcriptomic and clinical data of HCC samples were downloaded from The Cancer Genome Atlas (TCGA) and GSE14520 datasets, followed by acquiring immune-related genes from the ImmPort database. Afterwards, an immune-related gene-based prognostic index (IRGPI) was constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) regression model. Kaplan-Meier survival curves as well as time-dependent receiver operating characteristic (ROC) curve were performed to evaluate its predictive capability. Besides, both univariate and multivariate analyses on overall survival for the IRGPI and multiple clinicopathologic factors were carried out, followed by the construction of a nomogram. Finally, we explored the possible correlation of IRGPI with immune cell infiltration or immunotherapy efficacy. RESULTS:Analysis of 365 HCC samples identified 11 differentially expressed immune-related genes, which were selected to establish the IRGPI. Notably, it can predict the survival of HCC patients more accurately than published biomarkers. Furthermore, IRGPI can predict the infiltration of immune cells in the tumor microenvironment of HCC, as well as the response of immunotherapy. CONCLUSION:Collectively, the currently established IRGPI can accurately predict survival, reflect the immune microenvironment, and predict the efficacy of immunotherapy among HCC patients.
10.1007/s00262-020-02743-0