|
1
|
Zhao S, Chen F, Hu L, Li X, Gao Z, Chen M, Wang X, Song Z. Long non-coding rnas as key modulators of the immune microenvironment in hepatocellular carcinoma: implications for Immunotherapy. Front Immunol 2025; 16:1523190. [PMID: 40352941 PMCID: PMC12061944 DOI: 10.3389/fimmu.2025.1523190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 04/02/2025] [Indexed: 05/14/2025] Open
Abstract
Hepatocellular carcinoma (HCC) represents a major global health challenge, characterized by its complex immune microenvironment that plays a pivotal role in tumor progression and therapeutic response. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of various biological processes, including gene expression and immune cell function. This review explores the multifaceted roles of lncRNAs in modulating the immune microenvironment of HCC. We discuss how lncRNAs influence the infiltration and activation of immune cells, shape cytokine profiles, and regulate immune checkpoint molecules, thereby affecting the tumor's immunogenicity and response to immunotherapy. Furthermore, we highlight specific lncRNAs implicated in immune evasion mechanisms and their potential as biomarkers and therapeutic targets. By elucidating the intricate interplay between lncRNAs and the immune landscape in HCC, this review aims to provide insights into novel strategies for enhancing immunotherapeutic efficacy and improving patient outcomes.
Collapse
Affiliation(s)
| | | | | | | | | | - Minjie Chen
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Xiaoguang Wang
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Zhengwei Song
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| |
Collapse
|
|
2
|
Liao Z, Dai T, Yuan F, Li K, Wang G. To Predict the Prognosis and Immunological Characteristics of Pancreatic Cancer Based on Disulfide-Death Gene Death-Related lncRNA. Biomedicines 2025; 13:924. [PMID: 40299524 PMCID: PMC12024541 DOI: 10.3390/biomedicines13040924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 01/19/2025] [Accepted: 04/03/2025] [Indexed: 04/30/2025] Open
Abstract
Background: Disulfide-dependent cell death, known as disulfide death, plays a pivotal regulatory role in the onset and progression of various cancers including pancreatic cancer. Despite its significance, little attention has been given to the study of disulfide death-related long non-coding RNAs (lncRNAs) in pancreatic cancer development and progression. Methods: This study utilized data from the Cancer Genome Atlas Project (TCGA) to analyze the transcriptome of pancreatic cancer. Co-expression analysis of genes associated with disulfide death was performed and six lncRNAs closely linked to disulfide death were identified through univariate and multivariate analysis. These lncRNAs were used to develop clinical prognostic models. The prognostic value of this model was then analyzed and further investigations included pathway enrichment analysis, tumor mutation load analysis, immune cell infiltration analysis, analysis of the tumor microenvironment (TME), and drug sensitivity analysis. Results: The developed prognostic model based on disulfide-associated lncRNAs exhibited significant prognostic value, allowing for reliable predictions of patient outcomes in pancreatic adenocarcinoma (PAAD). The analysis revealed that the six identified lncRNAs serve as independent prognostic factors, significantly correlating with patient survival and recurrence rates. Additionally, findings indicated notable differences in immune cell infiltration and drug sensitivity between high-risk and low-risk patient groups, suggesting potential therapeutic targets for enhancing treatment efficacy. Conclusions: Our findings revealed six disulfide death-associated lncRNAs with independent prognostic value, offering a crucial indicator for predicting the prognosis of pancreatic adenocarcinoma (PAAD) patients. Additionally, the analysis of tumor immune invasion and drug sensitivity provides a novel avenue for controlling tumor invasion and metastasis as well as reducing drug tolerance.
Collapse
Affiliation(s)
| | | | | | | | - Guoying Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510000, China; (Z.L.); (T.D.); (F.Y.); (K.L.)
| |
Collapse
|
|
3
|
Sufianov A, Agaverdiev M, Mashkin A, Ilyasova T. Targeting microRNA methylation: Innovative approaches to diagnosing and treating hepatocellular carcinoma. Noncoding RNA Res 2025; 11:150-157. [PMID: 39829957 PMCID: PMC11742574 DOI: 10.1016/j.ncrna.2024.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 11/15/2024] [Accepted: 12/04/2024] [Indexed: 01/22/2025] Open
Abstract
Hepatocellular carcinoma (HCC) stands as the most prevalent form of primary liver cancer and is frequently linked to underlying chronic liver conditions such as hepatitis B, hepatitis C, and cirrhosis. Despite the progress achieved in the field of oncology, HCC remains a significant clinical challenge, primarily due to its typically late-stage diagnosis and the complex and multifaceted nature of its tumor biology. These factors contribute to the limited effectiveness of current treatment modalities and result in poor patient prognosis. Emerging research has underscored the vital role of microRNAs (miRNAs)-small, non-coding RNA molecules that play a pivotal part in the post-transcriptional regulation of gene expression. These miRNAs are integral to a wide array of cellular functions, including proliferation, apoptosis, and differentiation, and their dysregulation is closely associated with the pathogenesis of various cancers, notably HCC. A major focus in recent studies has been on the epigenetic regulation of miRNAs through methylation, a key mechanism that modulates gene expression. This process, involving the addition of methyl groups to CpG islands in the promoter regions of miRNA genes, can result in either gene silencing or activation, influencing the expression of oncogenes and tumor suppressor genes. Such alterations have profound implications for tumor growth, metastasis, and resistance to treatment. Evidence suggests that aberrant miRNA methylation can serve as a powerful biomarker for early detection and prognosis in HCC and may present novel opportunities for therapeutic intervention. This review aims to provide a comprehensive overview of the current landscape of miRNA methylation in HCC, elucidating its significance in the molecular mechanisms of liver cancer and examining its potential for clinical application. By exploring the diagnostic and therapeutic potential of miRNA methylation, we seek to highlight its value in enhancing personalized treatment strategies and improving patient outcomes.
Collapse
Affiliation(s)
- Albert Sufianov
- Educational and Scientific Institute of Neurosurgery, Рeoples’ Friendship University of Russia (RUDN University), Moscow, Russia
- Department of Neurosurgery, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Murad Agaverdiev
- Bashkir State Medical University, Ufa, Republic of Bashkortostan, 3 Lenin Street, 450008, Russia
| | - Andrey Mashkin
- Educational and Scientific Institute of Neurosurgery, Рeoples’ Friendship University of Russia (RUDN University), Moscow, Russia
- Department of Neurosurgery, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Tatiana Ilyasova
- Bashkir State Medical University, Ufa, Republic of Bashkortostan, 3 Lenin Street, 450008, Russia
| |
Collapse
|
|
4
|
Zhu J, Jian Z, Liu F, Le L. The emerging landscape of small nucleolar RNA host gene 10 in cancer mechanistic insights and clinical relevance. Cell Signal 2025; 127:111590. [PMID: 39798772 DOI: 10.1016/j.cellsig.2025.111590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 12/14/2024] [Accepted: 01/03/2025] [Indexed: 01/15/2025]
Abstract
Small nucleolar RNA host gene 10 (SNHG10) is a newly recognized long non-coding RNA (lncRNA) with significant implications in cancer biology. Abnormal expression of SNHG10 has been observed in various solid tumors and hematological malignancies. Research conducted in vivo and in vitro has revealed that SNHG10 plays a pivotal role in numerous biological processes, including cell proliferation, apoptosis, invasion and migration, drug resistance, energy metabolism, immune evasion, as well as tumor growth and metastasis. SNHG10 regulates tumor development through several mechanisms, such as competing with microRNA (miRNA) for binding sites, modulating various signaling pathways, influencing transcriptional activity, and affecting epigenetic regulation. The diverse biological functions and intricate mechanisms of SNHG10 highlight its considerable clinical relevance, positioning it as a potential pan-cancer biomarker and therapeutic target. This review aims to summarize the role of SNHG10 in tumorigenesis and cancer progression, clarify the molecular mechanisms at play, and explore its clinical significance in cancer diagnosis and prognosis prediction, along with its therapeutic potential.
Collapse
Affiliation(s)
- Jingyu Zhu
- Second Clinical Medical School, Nanchang University, Nanchang, Jiangxi, China
| | - Zihao Jian
- Second Clinical Medical School, Nanchang University, Nanchang, Jiangxi, China
| | - Fangteng Liu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330008, Jiangxi, China.
| | - Lulu Le
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330008, Jiangxi, China.
| |
Collapse
|
|
5
|
Xiong B, Zhang J, Si Y, Fu J. microRNA-875-5p-conjugated gold nanoparticles suppress breast cancer progression through the MTDH/PTEN/AKT signaling pathway. Discov Oncol 2024; 15:804. [PMID: 39692921 DOI: 10.1007/s12672-024-01626-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 11/25/2024] [Indexed: 12/19/2024] Open
Abstract
OBJECTIVE A lack of effective delivery methods has hampered the study of therapeutics targeting miR-875-5p for breast cancer (BC). METHODS The miR-875-5p mimic was conjugated to AuNPs to produce AuNP-miR-875-5p. Then, the effect of AuNP-miR-875-5p on the proliferative, migratory, invasive activities, and apoptosis of BC cells was detected, as well as on tumor growth in animals. The involvement of the MTDH/PTEN/AKT pathway in miR-875-5p-mediated BC progression was identified. RESULTS AuNP-miR-875-5p was delivered to BC cells and hampered cell malignancy. MTDH was targeted by miR-875-5p. MTDH expression was negatively correlated with miR-875-5p expression in BC tissues. The anti-tumor effect of AuNP-miR-875-5p in BC cells was counteracted by MTDH overexpression. AuNP-miR-875-5p enhanced PTEN protein expression, thereby inhibiting AKT activation by targeting MTDH. AuNP-miR-875-5p blocked MCF-7 tumor growth in vivo. CONCLUSION AuNPs can deliver miR-875-5p to BC cells, and AuNP-miR-875-5p has clinical potential for treating unresectable BC.
Collapse
Affiliation(s)
- Bin Xiong
- School of Clinical Medicine, Jining Medical University, Jining City, 272067, Shandong Province, China
| | - Junfeng Zhang
- School of Basic Medicine, Jining Medical University, No. 133 Hehua Road, Taibai Lake District, Jining City, 272067, Shandong Province, China
| | - Yanmei Si
- School of Forensic Medicine and Laboratory Medicine, Jining Medical University, Jining City, 272067, Shandong Province, China.
| | - Jia Fu
- School of Basic Medicine, Jining Medical University, No. 133 Hehua Road, Taibai Lake District, Jining City, 272067, Shandong Province, China.
| |
Collapse
|
|
6
|
Wu J, Zhou Z, Huang Y, Deng X, Zheng S, He S, Huang G, Hu B, Shi M, Liao W, Huang N. Radiofrequency ablation: mechanisms and clinical applications. MedComm (Beijing) 2024; 5:e746. [PMID: 39359691 PMCID: PMC11445673 DOI: 10.1002/mco2.746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 08/31/2024] [Accepted: 09/02/2024] [Indexed: 10/04/2024] Open
Abstract
Radiofrequency ablation (RFA), a form of thermal ablation, employs localized heat to induce protein denaturation in tissue cells, resulting in cell death. It has emerged as a viable treatment option for patients who are ineligible for surgery in various diseases, particularly liver cancer and other tumor-related conditions. In addition to directly eliminating tumor cells, RFA also induces alterations in the infiltrating cells within the tumor microenvironment (TME), which can significantly impact treatment outcomes. Moreover, incomplete RFA (iRFA) may lead to tumor recurrence and metastasis. The current challenge is to enhance the efficacy of RFA by elucidating its underlying mechanisms. This review discusses the clinical applications of RFA in treating various diseases and the mechanisms that contribute to the survival and invasion of tumor cells following iRFA, including the roles of heat shock proteins, hypoxia, and autophagy. Additionally, we analyze the changes occurring in infiltrating cells within the TME after iRFA. Finally, we provide a comprehensive summary of clinical trials involving RFA in conjunction with other treatment modalities in the field of cancer therapy, aiming to offer novel insights and references for improving the effectiveness of RFA.
Collapse
Affiliation(s)
- Jianhua Wu
- Department of Oncology, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Zhiyuan Zhou
- Department of Oncology, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Yuanwen Huang
- Department of Oncology, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Xinyue Deng
- Department of Oncology, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Siting Zheng
- Department of Oncology, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Shangwen He
- Department of Respiratory and Critical Care MedicineChronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical UniversityGuangzhouGuangdongChina
| | - Genjie Huang
- Department of Oncology, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Binghui Hu
- Department of Oncology, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Min Shi
- Department of Oncology, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Wangjun Liao
- Department of Oncology, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Na Huang
- Department of Oncology, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| |
Collapse
|
|
7
|
Xiao F, Zhang Z, Li L, He X, Chen Y. LINC01370 suppresses hepatocellular carcinoma proliferation and metastasis by regulating the PI3K/AKT pathway. Discov Oncol 2024; 15:326. [PMID: 39090419 PMCID: PMC11294307 DOI: 10.1007/s12672-024-01193-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 07/25/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) poses a serious threat to human health worldwide. lncRNA dysregulation is frequently observed in various cancers, including HCC. However, the function of LINC01370 in HCC progression and its underlying mechanisms remain unclear. METHODS LINC01370 expression in HCC tissues with cells was analyzed by applying the GEO and GEPIA databases and qRT-PCR. CCK-8 and Transwell assays were used to assess HCC cell proliferation, migration, and invasion. The PI3K, AKT, with p-AKT protein expression were analyzed by western blotting. RESULTS Gene Expression Omnibus (GEO) and Gene Expression Profiling Interactive Analysis (GEPIA) showed that LINC01370 expression was significantly lower in HCC tissues than in normal tissues. LINC01370 overexpression markedly repressed HepG2 SMMC-7721 cells proliferation, migration, and invasion. To understand the downstream mechanism of LINC01370 regulation, we further analyzed the genes co-expressed with LINC01370 in GSE136247 and GSE132037 and then performed KEGG analysis. The PA pathway was found to be a downstream pathway regulated by LINC01370 in GSE136247 and GSE132037 via gene co-expression and KEGG analysis. Furthermore, PI3K and p-AKT protein levels decreased after LINC01370 overexpression. Importantly, rescue experiments showed that activation of the PI3K/AKT pathway disrupted the repressive effect of LINC01370 overexpression on the proliferation, migration, and invasion of HepG2 of SMMC-7721 cells. CONCLUSIONS This study verified that LINC01370 suppresses HCC proliferation with metastasis by regulating the PI3K/AKT pathway.
Collapse
Affiliation(s)
- Fei Xiao
- Laboratory Department, Maoming People's Hospital, No. 101 Weimin Road, Maoming, 525000, Guangdong, China
| | - Zhuoyun Zhang
- Cancer Department, Maoming People's Hospital, Maoming, 525000, China
| | - Luqian Li
- Laboratory Department, Maoming People's Hospital, No. 101 Weimin Road, Maoming, 525000, Guangdong, China
| | - Xiaojie He
- Department of Endocrinology, Maoming People's Hospital, Maoming, 525000, China
| | - Yufeng Chen
- Laboratory Department, Maoming People's Hospital, No. 101 Weimin Road, Maoming, 525000, Guangdong, China.
| |
Collapse
|
|
8
|
Adugna A, Muche Y, Melkamu A, Jemal M, Belew H, Amare GA. Current updates on the molecular and genetic signals as diagnostic and therapeutic targets for hepatitis B virus-associated hepatic malignancy. Heliyon 2024; 10:e34288. [PMID: 39100497 PMCID: PMC11295980 DOI: 10.1016/j.heliyon.2024.e34288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 05/28/2024] [Accepted: 07/07/2024] [Indexed: 08/06/2024] Open
Abstract
Liver cancer caused by the hepatitis B virus (HBV) is the third most common cancer-related cause of death worldwide. Early detection of HBV-caused hepatic tumors increases the likelihood of a successful cure. Molecular and genetic signals are becoming more and more recognized as possible indicators of HBV-associated hepatic malignancy and of how well a treatment is working. As a result, we have discussed the current literature on molecular and genetic sensors, including extracellular vesicle microRNAs (EV-miRNAs), long non-coding circulating RNAs (lncRNAs), extracellular vesicles (EVs), and cell free circulating DNA (cfDNA), for the diagnosis and forecasting of HBV-related hepatic cancer. Extracellular vesicle microRNAs such as miR-335-5p, miR-172-5p, miR-1285-5p, miR-497-5p, miR-636, miR-187-5p, miR-223-3p, miR-21, miR-324-3p, miR-210-3p, miR-718, miR-122, miR-522, miR-0308-3p, and miR-375 are essential for the posttranscriptional regulation of oncogenes in hepatic cells as well as the epigenetic modulation of many internal and external signaling pathways in HBV-induced hepatic carcinogenesis. LncRNAs like lnc01977, HULC (highly up-regulated in liver cancer), MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), and HOTAIR (hox transcript antisense intergenic RNA) have been demonstrated to control hepatic-tumors cell growth, relocation, encroachment, and cell death resiliency. They are also becoming more and more involved in immune tracking, hepatic shifting, vasculature oversight, and genomic destabilization. EVs are critical mediators involved in multiple aspects of liver-tumors like angiogenesis, immunology, tumor formation, and the dissemination of malignant hepatocytes. Furthermore, cfDNA contributes to signals associated with tumors, including mutations and abnormal epigenetic changes during HBV-related hepatic tumorigenesis.
Collapse
Affiliation(s)
- Adane Adugna
- Medical Laboratory Sciences, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Yalew Muche
- Medical Laboratory Sciences, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Abateneh Melkamu
- Medical Laboratory Sciences, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Mohammed Jemal
- Department of Biomedical Sciences, School of Medicine, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Habtamu Belew
- Medical Laboratory Sciences, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Gashaw Azanaw Amare
- Medical Laboratory Sciences, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| |
Collapse
|
|
9
|
Lu Y, Yang Z, Zhang J, Ma X, Bi X, Xu L, Feng K, Wu Z, Ma X, Zhuang L. RNA-binding protein QKI promotes the progression of HCC by interacting with long non-coding RNA EGOT. Int Immunopharmacol 2024; 136:112297. [PMID: 38810307 DOI: 10.1016/j.intimp.2024.112297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Revised: 05/10/2024] [Accepted: 05/16/2024] [Indexed: 05/31/2024]
Abstract
BACKGROUND RNA-binding proteins are revealed to play important roles during the progression of hepatocellular carcinoma (HCC). However, the regulatory mechanisms of RNA-binding protein Quaking (QKI) in the expression and role of long non-coding RNAs (lncRNAs) in HCC cells remain not well understood. METHODS Cell Counting Kit-8, wound-healing, Transwell and colony-forming assays were performed to evaluate the effects of QKI and lncRNA EGOT on proliferation and migration of HCC cells. Tumor growth of HCC was analyzed using a mouse xenograft model. Immunoprecipitation (RIP) assay was used to investigate the interaction between QKI and EGOT. RESULTS The expression of QKI was significantly upregulated in HCC tissues and the higher QKI level was significantly associated with a poorer prognosis. Overexpression of QKI promoted the proliferation, migration, and colony-forming ability of HCC cells in vitro and tumor growth of HCC in vivo. Mechanistically, QKI protein could bind to EGOT RNA and increase its expression. Inhibition of EGOT attenuated the effects of QKI on the malignant phenotypes of HCC cells. In addition, both QKI and EGOT could activate the SAPK/JNK signaling pathway in HCC cells. CONCLUSIONS Our findings indicated that QKI exerted promotive effects on the malignant phenotypes of HCC through its interaction with EGOT.
Collapse
Affiliation(s)
- Yi Lu
- Central Laboratory, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China
| | - Zhenpeng Yang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Jie Zhang
- Central Laboratory, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China
| | - Xuefeng Ma
- Central Laboratory, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China
| | - Xiaoye Bi
- Central Laboratory, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China
| | - Longhai Xu
- Central Laboratory, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China
| | - Keqing Feng
- Central Laboratory, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China
| | - Zehua Wu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Xiang Ma
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266071, China.
| | - Likun Zhuang
- Central Laboratory, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China.
| |
Collapse
|
|
10
|
Xie X, Sinha S. Quantitative estimates of the regulatory influence of long non-coding RNAs on global gene expression variation using TCGA breast cancer transcriptomic data. PLoS Comput Biol 2024; 20:e1012103. [PMID: 38838009 PMCID: PMC11198904 DOI: 10.1371/journal.pcbi.1012103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 06/25/2024] [Accepted: 04/24/2024] [Indexed: 06/07/2024] Open
Abstract
Long non-coding RNAs (lncRNAs) have received attention in recent years for their regulatory roles in diverse biological contexts including cancer, yet large gaps remain in our understanding of their mechanisms and global maps of their targets. In this work, we investigated a basic unanswered question of lncRNA systems biology: to what extent can gene expression variation across individuals be attributed to lncRNA-driven regulation? To answer this, we analyzed RNA-seq data from a cohort of breast cancer patients, explaining each gene's expression variation using a small set of automatically selected lncRNA regulators. A key aspect of this analysis is that it accounts for confounding effects of transcription factors (TFs) as common regulators of a lncRNA-mRNA pair, to enrich the explained gene expression for lncRNA-mediated regulation. We found that for 16% of analyzed genes, lncRNAs can explain more than 20% of expression variation. We observed 25-50% of the putative regulator lncRNAs to be in 'cis' to, i.e., overlapping or located proximally to the target gene. This led us to quantify the global regulatory impact of such cis-located lncRNAs, which was found to be substantially greater than that of trans-located lncRNAs. Additionally, by including statistical interaction terms involving lncRNA-protein pairs as predictors in our regression models, we identified cases where a lncRNA's regulatory effect depends on the presence of a TF or RNA-binding protein. Finally, we created a high-confidence lncRNA-gene regulatory network whose edges are supported by co-expression as well as a plausible mechanism such as cis-action, protein scaffolding or competing endogenous RNAs. Our work is a first attempt to quantify the extent of gene expression control exerted globally by lncRNAs, especially those located proximally to their regulatory targets, in a specific biological (breast cancer) context. It also marks a first step towards systematic reconstruction of lncRNA regulatory networks, going beyond the current paradigm of co-expression networks, and motivates future analyses assessing the generalizability of our findings to additional biological contexts.
Collapse
Affiliation(s)
- Xiaoman Xie
- Center for Biophysics and Quantitative Biology, University of Illinois Urbana-Champaign, Urbana, Illinois, United States of America
| | - Saurabh Sinha
- Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, Georgia Institute of Technology, Atlanta, Georgia, United States of America
- H. Milton Stewart School of Industrial and Systems Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America
| |
Collapse
|
|
11
|
Tian Y, Zhang M, Liu LX, Wang ZC, Liu B, Huang Y, Wang X, Ling YZ, Wang F, Feng X, Tu Y. Exploring non-coding RNA mechanisms in hepatocellular carcinoma: implications for therapy and prognosis. Front Immunol 2024; 15:1400744. [PMID: 38799446 PMCID: PMC11116607 DOI: 10.3389/fimmu.2024.1400744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 04/03/2024] [Indexed: 05/29/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a significant contributor to cancer-related deaths in the world. The development and progression of HCC are closely correlated with the abnormal regulation of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Important biological pathways in cancer biology, such as cell proliferation, death, and metastasis, are impacted by these ncRNAs, which modulate gene expression. The abnormal expression of non-coding RNAs in HCC raises the possibility that they could be applied as new biomarkers for diagnosis, prognosis, and treatment targets. Furthermore, by controlling the expression of cancer-related genes, miRNAs can function as either tumor suppressors or oncogenes. On the other hand, lncRNAs play a role in the advancement of cancer by interacting with other molecules within the cell, which, in turn, affects processes such as chromatin remodeling, transcription, and post-transcriptional processes. The importance of ncRNA-driven regulatory systems in HCC is being highlighted by current research, which sheds light on tumor behavior and therapy response. This research highlights the great potential of ncRNAs to improve patient outcomes in this difficult disease landscape by augmenting the present methods of HCC care through the use of precision medicine approaches.
Collapse
Affiliation(s)
- Yu Tian
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
- School of Public Health, Benedictine University, Lisle, IL, United States
| | - Meng Zhang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Hebei University, Baoding, China
| | - Li-xia Liu
- Department of Ultrasound, Hebei Key Laboratory of Precise Imaging of Inflammation Related Tumors, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Zi-chao Wang
- Department of Ultrasound, Hebei Key Laboratory of Precise Imaging of Inflammation Related Tumors, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Bin Liu
- Central Laboratory, Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Youcai Huang
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Xiaoling Wang
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Yun-zhi Ling
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Furong Wang
- Department of Pathology, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Xiaoqiang Feng
- Center of Stem Cell and Regenerative Medicine, Gaozhou People’s Hospital, Gaozhou, Guangdong, China
| | - Yanyang Tu
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| |
Collapse
|
|
12
|
Wang X, Wang X. The regulation of hypoxia-related lncRNAs in hepatocellular carcinoma. Discov Oncol 2024; 15:144. [PMID: 38713276 PMCID: PMC11076439 DOI: 10.1007/s12672-024-01002-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 04/30/2024] [Indexed: 05/08/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is still a public health disease with its high prevalence and morbidity. Short of early diagnosis biomarkers and effective therapy, the treatment of HCC patients hasn't achieved ideal effect. Hypoxia is a hallmark of HCC, which is mainly induced by imbalance of tumor cell proliferation and insufficient supply of oxygen. Recently, amounting evidence suggested lncRNAs, especially hypoxia-related lncRNAs play a pivotal role in regulating HCC. Hypoxia-related lncRNAs are involved in altering glucose metabolism, maintaining of cancer stem cell-like properties (CSCs), cell apotosis, proliferation and immune escape, which all contribute to the poor prognosis of HCC patients. The novel identified hypoxia-related lncRNAs could be the potential target or biomarkers of HCC, which are beneficial to the clinical treatment. Herein, we summarized currently reported hypoxia-related lncRNAs and their related mechanisms, providing potential application and future perspective of hypoxia-related lncRNAs as a potential therapeutic target.
Collapse
Affiliation(s)
- Xuejing Wang
- Department of Integrated Traditional Chinese and Western Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
| | - Xiaojun Wang
- Department of Integrated Traditional Chinese and Western Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China.
| |
Collapse
|
|
13
|
Wei M, Lu L, Luo Z, Ma J, Wang J. Prognostic analysis of hepatocellular carcinoma based on cuproptosis -associated lncRNAs. BMC Gastroenterol 2024; 24:142. [PMID: 38654165 DOI: 10.1186/s12876-024-03219-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 04/01/2024] [Indexed: 04/25/2024] Open
Abstract
OBJECTIVES Cuproptosis represents an innovative type of cell death, distinct from apoptosis, driven by copper dependency, yet the involvement of copper apoptosis-associated long non-coding RNAs (CRLncRNAs) in hepatocellular carcinoma (HCC) remains unclear. This study is dedicated to unveiling the role and significance of these copper apoptosis-related lncRNAs within the context of HCC, focusing on their impact on both the development of the disease and its prognosis. METHODS We conducted an analysis of gene transcriptomic and clinical data for HCC cases by sourcing information from The Cancer Genome Atlas database. By incorporating cuproptosis-related genes, we established prognostic features associated with cuproptosis-related lncRNAs. Furthermore, we elucidated the mechanism of cuproptosis-related lncRNAs in the prognosis and treatment of HCC through comprehensive approaches, including Lasso and Cox regression analyses, survival analyses of samples, as well as examinations of tumor mutation burden and immune function. RESULTS We developed a prognostic model featuring six cuproptosis-related lncRNAs: AC026412.3, AC125437.1, AL353572.4, MKLN1-AS, TMCC1-AS1, and SLC6A1-AS1. This model demonstrated exceptional prognostic accuracy in both training and validation cohorts for patients with tumors, showing significantly longer survival times for those categorized in the low-risk group compared to the high-risk group. Additionally, our analyses, including tumor mutation burden, immune function, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway enrichment, and drug sensitivity, further elucidated the potential mechanisms through which cuproptosis-associated lncRNAs may influence disease outcome. CONCLUSIONS The model developed using cuproptosis-related long non-coding RNAs (lncRNAs) demonstrates promising predictive capabilities for both the prognosis and immunotherapy outcomes of tumor patients. This could play a crucial role in patient management and the optimization of immunotherapeutic strategies, offering valuable insights for future research.
Collapse
Affiliation(s)
- Mingwei Wei
- Guangxi Clinical Medical Research Center for Hepatobiliary Diseases, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
- Department of Hepatobiliary and Pancreatic Surgery, Baidong Hospital, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Libai Lu
- Department of Hepatobiliary and Pancreatic Surgery, Baidong Hospital, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Zongjiang Luo
- Department of Hepatobiliary and Pancreatic Surgery, Baidong Hospital, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Jiasheng Ma
- Department of Hepatobiliary and Pancreatic Surgery, Baidong Hospital, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Jianchu Wang
- Guangxi Clinical Medical Research Center for Hepatobiliary Diseases, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.
- Department of Hepatobiliary and Pancreatic Surgery, Baidong Hospital, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.
| |
Collapse
|
|
14
|
Davodabadi F, Farasati Far B, Sargazi S, Fatemeh Sajjadi S, Fathi-Karkan S, Mirinejad S, Ghotekar S, Sargazi S, Rahman MM. Nanomaterials-Based Targeting of Long Non-Coding RNAs in Cancer: A Cutting-Edge Review of Current Trends. ChemMedChem 2024; 19:e202300528. [PMID: 38267373 DOI: 10.1002/cmdc.202300528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 01/21/2024] [Accepted: 01/22/2024] [Indexed: 01/26/2024]
Abstract
This review article spotlights the burgeoning potential of using nanotherapeutic strategies to target long non-coding RNAs (lncRNAs) in cancer cells. This updated discourse underlines the prominent role of lncRNAs in instigating cancer, facilitating its progression, and metastasis, validating lncRNAs' potential for being effective diagnostic biomarkers and therapeutic targets. The manuscript offers an in-depth examination of different strategies presently employed to modulate lncRNA expression and function for therapeutic purposes. Among these strategies, Antisense Oligonucleotides (ASOs), RNA interference (RNAi) technologies, and the innovative clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing tools garner noteworthy mention. A significant section of the review is dedicated to nanocarriers and their crucial role in drug delivery. These nanocarriers' efficiency in targeting lncRNAs in varied types of cancers is elaborated upon, validating the importance of targeted therapy. The manuscript culminates by reaffirming the promising prospects of targeting lncRNAs to enhance the accuracy of cancer diagnosis and improve treatment efficacy. Consequently, new paths are opened to more research and innovation in employing nanotherapeutic approaches against lncRNAs in cancer cells. Thus, this comprehensive manuscript serves as a valuable resource that underscores the vital role of lncRNAs and the various nano-strategies for targeting them in cancer treatment. Future research should also focus on unraveling the complex regulatory networks involving lncRNAs and identifying fundamental functional interactions to refine therapeutic strategies targeting lncRNAs in cancer.
Collapse
Affiliation(s)
- Fatemeh Davodabadi
- Department of Biology, Faculty of Basic Science, Payame Noor University, Tehran, Iran
| | - Bahareh Farasati Far
- Department of Chemistry, Iran University of Science and Technology, Tehran, Iran
| | - Saman Sargazi
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Seyedeh Fatemeh Sajjadi
- School of Biological Science, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran
| | - Sonia Fathi-Karkan
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, 9453155166, Iran
- Department of Advanced Sciences and Technologies in Medicine, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, 9414974877, Iran
| | - Shekoufeh Mirinejad
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Suresh Ghotekar
- Centre for Herbal Pharmacology and Environmental Sustainability, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, 603103, Tamil Nadu, India
| | - Sara Sargazi
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Mohammed M Rahman
- Center of Excellence for Advanced Materials Research (CEAMR) & Department of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| |
Collapse
|
|
15
|
Wang X, Mo X, Yang Z, Zhao C. Qntrolling the LncRNA HULC-Tregs-PD-1 axis inhibits immune escape in the tumor microenvironment. Heliyon 2024; 10:e28386. [PMID: 38560250 PMCID: PMC10979100 DOI: 10.1016/j.heliyon.2024.e28386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 03/15/2024] [Accepted: 03/18/2024] [Indexed: 04/04/2024] Open
Abstract
Background Immune escape remains a major challenge in the treatment of malignant tumors. Here, we studied the mechanisms underlying immune escape in the tumor microenvironment and identified a potential therapeutic target. Methods Pathological specimens from patients with liver cancer, soft tissue sarcoma, and liver metastasis of colon cancer were subjected to immunohistochemistry analysis to detect the expression of programmed death-1 (PD-1) in the tumor microenvironment (TME). Additionally, the expression of regulatory T cells (Tregs) and long non-coding RNAs (lncRNAs), such as highly upregulated in liver cancer (HULC) was evaluated by fluorescence in situ hybridization, and the relationship between HULC, Treg cells, and PD-1 was determined. The animals were divided into H22 hepatic carcinoma and S180 sarcoma groups. Each group was divided into Foxp3-/-C57BL/6J and C57BL/6J mice. Thereafter, mice were inoculated with 0.1 ml S180 sarcoma cells or 0.1 ml H22 hepatoma cells, at a concentration of 1 × 107/ml. The number of splenic CD4+CD25+Foxp3+ T cells was detected by flow cytometry, and serum interleukin-10 (IL-10) and transforming growth factor β1 (TGF-β1) levels were detected using a Luminex liquid suspension chip. Expression of PD-1, fork head box P3 (Foxp3), and HULC in the TME, were analyzed and the therapeutic effect of inhibiting the lncRNA HULC-Treg-PD-1 axis in malignant tumors was determined. Results High expression of lncRNA HULC promotes the proliferation of Treg cells and increases PD-1 expression in the tumor microenvironment. The HULC-Treg-PD-1 axis plays an immunosuppressive role and promotes the proliferation of malignant tumors. Knocking out the Foxp3 gene can affect the HULC-Treg-PD-1 axis and reduce PD-1, IL-10, and TGF-β1 expression to control the growth of malignant tumors. Conclusion The lncRNA HULC-Treg-PD-1 axis promotes the growth of malignant tumors. This axis could be modulated to reduce PD-1, IL-10, and TGF-β1 expression and the subsequent immune escape. The inhibition of immune escape in the tumor microenvironment can be achieved by controlling the LncRNA HULC-Treg-PD-1 axis.
Collapse
Affiliation(s)
- XiaoYu Wang
- School of Health Science, Guangdong Pharmaceutical University, Guangzhou, 51006, China
| | - Xiaoyan Mo
- The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, 51006, China
| | - Zhuolin Yang
- School of Health Science, Guangdong Pharmaceutical University, Guangzhou, 51006, China
| | - Changlin Zhao
- School of Health Science, Guangdong Pharmaceutical University, Guangzhou, 51006, China
- The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, 51006, China
| |
Collapse
|
|
16
|
Baek M, Kim M, Choi HI, Binas B, Cha J, Jung KH, Choi S, Chai YG. Identification of differentially expressed mRNA/lncRNA modules in acutely regorafenib-treated sorafenib-resistant Huh7 hepatocellular carcinoma cells. PLoS One 2024; 19:e0301663. [PMID: 38603701 PMCID: PMC11008899 DOI: 10.1371/journal.pone.0301663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 03/20/2024] [Indexed: 04/13/2024] Open
Abstract
The multikinase inhibitor sorafenib is the standard first-line treatment for advanced hepatocellular carcinoma (HCC), but many patients become sorafenib-resistant (SR). This study investigated the efficacy of another kinase inhibitor, regorafenib (Rego), as a second-line treatment. We produced SR HCC cells, wherein the PI3K-Akt, TNF, cAMP, and TGF-beta signaling pathways were affected. Acute Rego treatment of these cells reversed the expression of genes involved in TGF-beta signaling but further increased the expression of genes involved in PI3K-Akt signaling. Additionally, Rego reversed the expression of genes involved in nucleosome assembly and epigenetic gene expression. Weighted gene co-expression network analysis (WGCNA) revealed four differentially expressed long non-coding RNA (DElncRNA) modules that were associated with the effectiveness of Rego on SR cells. Eleven putative DElncRNAs with distinct expression patterns were identified. We associated each module with DEmRNAs of the same pattern, thus obtaining DElncRNA/DEmRNA co-expression modules. We discuss the potential significance of each module. These findings provide insights and resources for further investigation into the potential mechanisms underlying the response of SR HCC cells to Rego.
Collapse
Affiliation(s)
- Mina Baek
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea
| | - Minjae Kim
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea
| | - Hae In Choi
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea
| | - Bert Binas
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea
| | - Junho Cha
- Department of Applied Artificial Intelligence, Hanyang University, Ansan, Republic of Korea
| | - Kyoung Hwa Jung
- Department of Biopharmaceutical System, Gwangmyeong Convergence Technology Campus of Korea Polytechnic II, Incheon, Republic of Korea
| | - Sungkyoung Choi
- Department of Applied Artificial Intelligence, Hanyang University, Ansan, Republic of Korea
- Department of Mathematical Data Science, Hanyang University, Ansan, Republic of Korea
| | - Young Gyu Chai
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea
| |
Collapse
|
|
17
|
Ai JH, Wen YZ, Dai SJ, Zhang LD, Huang ZJ, Shi J. Exosomal lncRNA HEIH, an essential communicator for hepatocellular carcinoma cells and macrophage M2 polarization through the miR-98-5p/STAT3 axis. J Biochem Mol Toxicol 2024; 38:e23686. [PMID: 38549433 DOI: 10.1002/jbt.23686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 01/18/2024] [Accepted: 03/07/2024] [Indexed: 04/02/2024]
Abstract
Part of human long noncoding RNAs (lncRNAs) has been elucidated to play an essential role in the carcinogenesis and progression of hepatocellular carcinoma (HCC), a type of malignant tumor with poor outcomes. Tumor-derived exosomes harboring lncRNAs have also been implicated as crucial mediators to orchestrate biological functions among neighbor tumor cells. The recruitment of tumor-associated macrophages (TAMs) exerting M2-like phenotype usually indicates the poor prognosis. Yet, the precise involvement of tumor-derived lncRNAs in cross-talk with environmental macrophages has not been fully identified. In this study, we reported the aberrantly overexpressed HCC upregulated EZH2-associated lncRNA (HEIH) in tumor tissues and cell lines was positively correlated with poor prognosis, as well as enriched exosomal HEIH levels in blood plasma and cell supernatants. Besides, HCC cell-derived exosomes transported HEIH into macrophages for triggering macrophage M2 polarization, thereby in turn promoting the proliferation, migration, and invasion of HCC cells. Mechanistically, HEIH acted as a miRNA sponge for miR-98-5p to up-regulate STAT3, which was then further verified in the tumor xenograft models. Collectively, our study provides the evidence for recognizing tumor-derived exosomal lncRNA HEIH as a novel regulatory function through targeting miR-98-5p/STAT3 axis in environmental macrophages, which may shed light on the complicated tumor microenvironment among tumor and immune cells for HCC treatment.
Collapse
Affiliation(s)
- Jun-Hua Ai
- Department of General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, P.R.China
| | - Yu-Zhong Wen
- Department of General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, P.R.China
| | - Shi-Jie Dai
- Department of General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, P.R.China
| | - Li-Dong Zhang
- Department of General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, P.R.China
| | - Zhong-Jing Huang
- Department of General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, P.R.China
| | - Jun Shi
- Department of General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, P.R.China
| |
Collapse
|
|
18
|
Ren X, Wang X, Song H, Zhang C, Yuan J, He J, Li J, Wang Z. Long non-coding RNA LINC01554 overexpression suppresses viability, migration, and invasion of liver cancer cells through regulating miR-148b-3p/EIF4E3. Heliyon 2024; 10:e27319. [PMID: 38501022 PMCID: PMC10945188 DOI: 10.1016/j.heliyon.2024.e27319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 02/27/2024] [Accepted: 02/27/2024] [Indexed: 03/20/2024] Open
Abstract
Background Long non-coding RNAs (lncRNAs) can be severed as competing endogenous RNAs (ceRNAs) to regulate target genes or mRNAs via sponging microRNAs (miRNAs). This study explored the effect of LINC01554 on liver cancer cells through the ceRNA mechanism. Methods Five significantly down-regulated lncRNAs were selected for further verification, and then through bioinformatics, interactive miRNAs and mRNAs of lncRNAs were identified. The relationship between LINC01554, miR-148b-3p and EIF4E3 was detected by the dual luciferase reporter gene assay. Afterwards, HCCLM3 cells were transfected with pCDH-LINC01554, miR-148b-3p inhibitor and miR-148b-3p mimics. Cell viability, apoptosis, migration and invasion were measured by Cell Counting Kit-8, flow cytometer, and Transwell assays. Real-time quantitative PCR (RT-qPCR) and Western blot were used to measure the expressions of related genes and proteins. Results LINC01554 was significantly down-regulated in the liver cancer cell lines, and was expressed in the cytoplasm of HCCLM3 cells. LINC01554 overexpression inhibited proliferation, migration, and invasion of HCCLM3 cells, and promote their apoptosis (P < 0.05). Besides, LINC01554 overexpression also significantly increased the levels of BAX, BCL2/BAX, P53, cleaved-Caspase3, TIMP3, E-cadherin and EIF4E3 (P < 0.05). Through bioinformatics and dual-luciferase reporter gene assay, LINC01554, miR-148b-3p and EIF4E3 were proved to interact with each other. Furthermore, the effects of miR-148b-3p knockdown on HCCLM3 cells were similar with those of LINC01554 overexpression, and miR-148b-3p mimics could reverse the changes of cell viability, apoptosis, migration, and invasion induced by LINC01554 overexpression. Conclusions LINC01554 overexpression could suppress the growth and metastasis of HCCLM3 cells via miR-148b-3p/EIF4E3.
Collapse
Affiliation(s)
- Xiaojing Ren
- Radiological & Environment Medicine Dept, China Institute for Radiation Protection, Taiyuan, 030032, China
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China
| | - Xiaoxiao Wang
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China
| | - Huangqin Song
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China
| | - Chao Zhang
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China
| | - Junlong Yuan
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China
| | - Jiefeng He
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China
| | - Jianguo Li
- Radiological & Environment Medicine Dept, China Institute for Radiation Protection, Taiyuan, 030032, China
| | - Zhuangqiang Wang
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China
| |
Collapse
|
|
19
|
Dong J, Lv Y, Meng D, Shi R, Li F, Guo R, Wang Y, Guo J, Zhang Y. LncRNA WFDC21P interacts with SEC63 to promote gastric cancer malignant behaviors by regulating calcium homeostasis signaling pathway. Cancer Cell Int 2024; 24:111. [PMID: 38528582 DOI: 10.1186/s12935-024-03297-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 03/06/2024] [Indexed: 03/27/2024] Open
Abstract
BACKGROUND Gastric cancer is currently estimated to be the fifth leading common cancer in the world, and responsible for about one million new cases and an estimated 769,000 cancer-related deaths each year. WFDC21P is long non-coding RNA and has been reported to play critical roles in serval types of cancer. Our research aims to investigate the biological effects and molecular mechanism of WFDC21P in gastric cancer. METHODS Datasets (GSE53137, GSE58828, and GSE109476) in GEO database were used to screen differential expressed lncRNAs in gastric cancer by online GEO2R analysis tool. Quantitative RT-PCR was used to verify the above prediction in ten pairs of gastric cancer and corresponding paracancerous tissues. Pan-cancer analysis was used to analyze the expression of WFDC21P in different types of cancer. Small interfering RNAs were used to WFDC21P knockdown. CCK-8 and colony formation assays were used to measure the proliferation and tumorigenesis abilities. Wound healing and Transwell assay were used to detect the migration and invasion abilities. Proteins that interact with WFDC21P were predicted by catRAPID database. RNA pull down and RNA Immunoprecipitation were used to confirm the interaction. Western blotting was used to detect the key proteins level in calcium homeostasis signaling pathway. Loss-of-function and rescue assays were used to evaluate the biological function of SEC63 at the background of WFDC21P silencing. RESULTS WFDC21P was upregulated in gastric cancer tissues and cell lines. WFDC21P downregulation suppressed proliferation, tumorigenesis, migration, invasion, and promoted apoptosis in gastric cancer. SEC63 protein had the capability to bind with WFDC21P and the expression of SEC63 was regulated by WFDC21P. SEC63 was also upregulated in gastric cancer and exerted effects during tumor growth and metastasis. CONCLUSIONS This study confirmed that lncRNA WFDC21P aggravated gastric cancer malignant behaviors by interacting with SEC63 to regulate the calcium homeostasis signaling pathway.
Collapse
Affiliation(s)
- Jinyao Dong
- Hepatobiliary Pancreatogastric Surgery, Shanxi Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University , Taiyuan, Shanxi, 030013, P. R. China
| | - Yongqiang Lv
- Scientific Research Department, Shanxi Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, 030013, P. R. China
| | - Debin Meng
- Hepatobiliary Pancreatogastric Surgery, Shanxi Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University , Taiyuan, Shanxi, 030013, P. R. China
| | - Ruyi Shi
- Department of Cell biology and Genetics, Shanxi Medical University, Taiyuan, Shanxi, 030001, P. R. China
| | - Feng Li
- Central Laboratory, Shanxi Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, 030013, P. R. China
| | - Rui Guo
- Hepatobiliary Pancreatogastric Surgery, Shanxi Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University , Taiyuan, Shanxi, 030013, P. R. China
| | - Yi Wang
- Hepatobiliary Pancreatogastric Surgery, Shanxi Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University , Taiyuan, Shanxi, 030013, P. R. China
| | - Jiansheng Guo
- Gastrointestinal Surgery Department, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030001, P. R. China.
| | - Yanyan Zhang
- Hepatobiliary Pancreatic Surgery and Liver Transplantation Center, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030001, P. R. China.
| |
Collapse
|
|
20
|
Li X, Wu Y, Wang P, Li Y, Gu J, Zhang Y, Yan S, Hu P. LncRNA XXYLT1-AS2 promotes tumor progression via autophagy inhibition through ubiquitinated degradation of TFEB in hepatocellular carcinoma. Clin Transl Oncol 2024; 26:698-708. [PMID: 37540409 DOI: 10.1007/s12094-023-03294-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 07/23/2023] [Indexed: 08/05/2023]
Abstract
PURPOSE There is compelling evidence that long-stranded non-coding RNAs (lncRNAs) play an important role in the progression of hepatocellular carcinoma (HCC). The aim of this study was to investigate the role of lncRNA XXYLT1 antisense-2 (XXYLT1-AS2) in HCC progression. METHODS Real-time PCR was used to assess the levels of XXYLT1-AS2 in plasma from HCC and normal patients. Cell proliferation, apoptosis, migration, and invasion were monitored, and tumor xenografts were established to investigate the biological functions of XXYLT1-AS2 by gain-of-function and loss-of-function studies in vitro and in vivo, the expression of autophagy biomarkers and transcriptional factor EB (TFEB) was examined by immunoprecipitation, ubiquitination assays, and western blotting. Autophagy inhibitor, 3-methyladenine (3MA), and proteasome inhibitor, MG132, were used to verify the role of autophagy in HCC progression and the effect of XXYLT1-AS2 on TFEB ubiquitination, respectively. RESULTS In this study, we identified that lncRNA XXYLT1-AS2 is highly expressed in HCC plasma and promotes tumor growth in vivo. In functional studies, it was found that silent expression of XXYLT1-AS2 inhibited HCC proliferation, migration, invasion, and activated autophagy of HCC cells, which were attenuated by autophagy inhibitor, 3MA. Mechanistically, XXYLT1-AS2 decreased the protein level of TFEB through promoting its degradation by ubiquitin proteasome pathway. CONCLUSION XXYLT1-AS2 plays an oncogenic role in HCC progression through inhibition of autophagy via promoting the degradation of TFEB, and thus could be a novel target for HCC treatment.
Collapse
Affiliation(s)
- Xuejie Li
- Department of Laboratory Medicine, Jinzhou Medical University Graduate Training Base, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
- Biomedical Engineering College, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
| | - Yuqin Wu
- Central Operating Room, Taihe Hospital, Shiyan, 442000, Hubei, People's Republic of China
| | - Pingfeng Wang
- Biomedical Engineering College, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
- Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, No. 32, South Renmin Road, Shiyan City, 442000, Hubei, People's Republic of China
| | - Ying Li
- Blood Transfusion Department, Taihe Hospital, Shiyan, 442000, Hubei, People's Republic of China
| | - Jiangxue Gu
- Biomedical Engineering College, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
| | - Yuan Zhang
- Biomedical Engineering College, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
| | - Shirong Yan
- Department of Laboratory Medicine, Jinzhou Medical University Graduate Training Base, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China.
- Hubei Key Laboratory of Wudang Local Chinese Medicine Research, School of Pharmaceutical Sciences, Hubei University of Medicine, No. 30, South Renmin Road, Shiyan City, 442000, Hubei, People's Republic of China.
| | - Pei Hu
- Department of Laboratory Medicine, Jinzhou Medical University Graduate Training Base, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China.
- Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, No. 32, South Renmin Road, Shiyan City, 442000, Hubei, People's Republic of China.
| |
Collapse
|
|
21
|
Cheng X, Wu C, Xu H, Zou R, Li T, Ye S. miR-557 inhibits hepatocellular carcinoma progression through Wnt/β-catenin signaling pathway by targeting RAB10. Aging (Albany NY) 2024; 16:3716-3733. [PMID: 38364252 PMCID: PMC10929814 DOI: 10.18632/aging.205554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 12/26/2023] [Indexed: 02/18/2024]
Abstract
Accumulating evidence suggests that aberrant miRNAs participate in carcinogenesis and progression of hepatocellular carcinoma (HCC). Abnormal miR-557 expression is reported to interfere with the progression of several human cancers. However, the potential roles of miR-557 in HCC remain largely unknown. In the current study, we found that miR-557 was down-regulated in HCC tissues and cell lines, and was closely related to recurrence and metastasis of HCC. Notably, overexpression of miR-557 inhibited proliferation, migration, invasion, epithelial-to-mesenchymal transition (EMT) progression, blocked cells in G0/G1 phase of MHCC-97H cells in vitro, and suppressed tumor growth in vivo. However, loss of miR-557 facilitated these parameters in Huh7 cells both in vitro and in vivo. Moreover, RAB10 was identified as a direct downstream target of miR-557 through its 3'-UTR. Furthermore, RAB10 re-expression or knockdown partially abolished the effects of miR-557 on proliferation, migration, invasion, and EMT progression of HCC cells. Mechanistically, overexpression of miR-557 suppressed Wnt/β-catenin signaling by inhibiting GSK-3β phosphorylation, increasing β-catenin phosphorylation, and decreasing β-catenin transport to the nucleus, while knockdown of miR-557 activated Wnt/β-catenin signaling. Moreover, the TOP/FOP-Flash reporter assays showed that miR-557 overexpression or knockdown significantly suppressed or activated Wnt signaling activity, respectively. Additionally, low expression of miR-557 and high expression of RAB10 in HCC tissues was closely associated with tumor size, degree of differentiation, TNM stage and poor prognosis in HCC patients. Taken together, these results demonstrate that miR-557 blocks the progression of HCC via the Wnt/β-catenin pathway by targeting RAB10.
Collapse
Affiliation(s)
- Xiaoye Cheng
- Department of Hematology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Can Wu
- Department of General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Haocheng Xu
- Department of General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Ruixiang Zou
- Department of General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Taiyuan Li
- Department of General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Shanping Ye
- Department of General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| |
Collapse
|
|
22
|
Liang W, Zhao Y, Meng Q, Jiang W, Deng S, Xue J. The role of long non-coding RNA in hepatocellular carcinoma. Aging (Albany NY) 2024; 16:4052-4073. [PMID: 38334963 PMCID: PMC10929815 DOI: 10.18632/aging.205523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 12/12/2023] [Indexed: 02/10/2024]
Abstract
Hepatocellular carcinoma (HCC) is a prevalent liver malignancy with complex etiology and generally poor prognosis. Recently, long non-coding RNAs (lncRNAs), non-protein-coding RNA molecules exceeding 200 nucleotides, have emerged as pivotal players in HCC, influencing its initiation, progression, invasion, and metastasis. These lncRNAs modulate gene expression at epigenetic, transcriptional, and post-transcriptional levels, actively participating in the pathological and physiological processes of HCC. Understanding the intricate relationship between lncRNAs and HCC is important for improving prognosis and reducing mortality. This review summarizes advancements in elucidating the role of lncRNAs in HCC pathogenesis.
Collapse
Affiliation(s)
- Weizheng Liang
- Central Laboratory, The First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, Hebei, China
- Department of General Surgery, The First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, Hebei, China
- Tumor Research Institute, The First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, Hebei, China
| | - Yan Zhao
- Department of Mathematics and Computer Science, Free University Berlin, Berlin 14195, Germany
| | - Qingxue Meng
- Technology Department, The First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, Hebei, China
| | - Wenjie Jiang
- Department of Artificial Intelligence and Data Science, Hebei University of Technology, Tianjin 300401, China
| | - Shoulong Deng
- National Health Commission of China (NHC) Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing 100021, China
| | - Jun Xue
- Department of General Surgery, The First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, Hebei, China
- Tumor Research Institute, The First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, Hebei, China
| |
Collapse
|
|
23
|
Wang J, Jiang Z, Wang K, Zheng Q, Jian J, Liu X, Chen Z, Yang R, Wang L. Construction of a necroptosis-related lncRNA signature for predicting prognosis and revealing the immune microenvironment in bladder cancer. Aging (Albany NY) 2024; 16:2812-2827. [PMID: 38319718 PMCID: PMC10911338 DOI: 10.18632/aging.205512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 12/27/2023] [Indexed: 02/07/2024]
Abstract
BACKGROUND Bladder cancer (BCa) is a common malignancy in the urinary system. Necroptosis, a recently discovered form of programmed cell death, is closely associated with the development and progression of various types of tumors. Targeting necroptosis through anti-cancer strategies has shown potential as a therapy for cancer. We aimed to develop a necroptosis-related lncRNAs (NRlncRNAs) risk model that can predict the survival and tumor immunity of BCa patients. METHODS We analyzed sequencing data obtained from the TCGA database, and applied least absolute shrinkage and selection operator (LASSO) and Cox regression analysis to identify crucial NRlncRNAs for building a risk model. Using the risk score, we categorized patients into high- and low-risk groups, and assessed the accuracy with the area under the receiver operating characteristic (AUROC) and Kaplan-Meier curves. We performed the RT-qPCR to detect the expression differences of the genes based on the risk model. RESULTS We identified a total of 296 NRlncRNAs, and 6 of them were included in the prognostic model. The AUC values for 1-, 3-, and 5-year predictions were 0.675, 0.726 and 0.734, respectively. Our risk model demonstrated excellent predictive performance and served as an independent predictor with high predictive power. Additionally, we performed PCA, TMB, GSEA analyses, and evaluated immune cell infiltration, to reveal significant differences between the high- and low-risk groups in functional signaling pathways, immunological status, and mutation profiles. Finally, we assessed the chemotherapeutic response of several drugs. According to the RT-qPCR results, we found that four NRlncRNAs of the risk model were more highly expressed in BCa cell lines than human immortalized uroepithelial cell line and regulated the occurrence and progression of bladder cancer. CONCLUSION We constructed a novel NRlncRNAs-associated risk model, which could predict the prognosis and immune response of BCa patients.
Collapse
Affiliation(s)
- Jingsong Wang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Zhengyu Jiang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Kai Wang
- Department of Urology, People’s Hospital of Hanchuan City, Xiaogan, Hubei 432300, China
| | - Qingyuan Zheng
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Jun Jian
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Xiuheng Liu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Zhiyuan Chen
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Rui Yang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Lei Wang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| |
Collapse
|
|
24
|
Wang Y, Wang P, Wang Q, Chen S, Wang X, Zhong X, Hu W, Thorne RF, Han S, Wu M, Zhang L. The long noncoding RNA HNF1A-AS1 with dual functions in the regulation of cytochrome P450 3A4. Biochem Pharmacol 2024; 220:116016. [PMID: 38176619 DOI: 10.1016/j.bcp.2023.116016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 12/21/2023] [Accepted: 12/28/2023] [Indexed: 01/06/2024]
Abstract
Cytochrome P450 3A4 (CYP3A4) is the most important and abundant drug-metabolizing enzyme in the human liver. Inter-individual differences in the expression and activity of CYP3A4 affect clinical and precision medicine. Increasing evidence indicates that long noncoding RNAs (lncRNAs) play crucial roles in the regulation of CYP3A4 expression. Here, we showed that lncRNA hepatocyte nuclear factor 1 alpha-antisense 1 (HNF1A-AS1) exerted dual functions in regulating CYP3A4 expression in Huh7 and HepG2 cells. Mechanistically, HNF1A-AS1 served as an RNA scaffold to interact with both protein arginine methyltransferase 1 and pregnane X receptor (PXR), thereby facilitating their protein interactions and resulting in the transactivation of PXR and transcriptional alteration of CYP3A4 via histone modifications. Furthermore, HNF1A-AS1 bound to the HNF1A protein, a liver-specific transcription factor, thereby blocking its interaction with the E3 ubiquitin ligase tripartite motif containing 25, ultimately preventing HNF1A ubiquitination and protein degradation, further regulating the expression of CYP3A4. In summary, these results reveal the novel functions of HNF1A-AS1 as the transcriptional and post-translational regulator of CYP3A4; thus, HNF1A-AS1 may serve as a new indicator for establishing or predicting individual differences in CYP3A4 expression.
Collapse
Affiliation(s)
- Yiting Wang
- Department of Pharmacology, School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450001 Zhengzhou, China; Department of Clinical Pharmacology, School of Medicine, Henan University of Chinese Medicine, 450046 Zhengzhou, China
| | - Pei Wang
- Department of Pharmacology, School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450001 Zhengzhou, China
| | - Qi Wang
- Department of Pharmacology, School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450001 Zhengzhou, China
| | - Shitong Chen
- Department of Pharmacology, School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450001 Zhengzhou, China
| | - Xiaofei Wang
- Department of Pharmacology, School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450001 Zhengzhou, China
| | - Xiaobo Zhong
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, 06269 Storrs, CT, USA
| | - Wanglai Hu
- Translational Research Institute, Zhengzhou University People's Hospital, Academy of Medical Science, Zhengzhou University, 450003 Zhengzhou, China
| | - Rick F Thorne
- Translational Research Institute, Zhengzhou University People's Hospital, Academy of Medical Science, Zhengzhou University, 450003 Zhengzhou, China
| | - Shengna Han
- Department of Pharmacology, School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450001 Zhengzhou, China.
| | - Mian Wu
- Translational Research Institute, Zhengzhou University People's Hospital, Academy of Medical Science, Zhengzhou University, 450003 Zhengzhou, China.
| | - Lirong Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450001 Zhengzhou, China.
| |
Collapse
|
|
25
|
Zuo X, Shao Y, Liang Y, Huo C, Wang S. MIR222HG/LIN28B/ATG5 Axis Drives M2 Macrophage Polarization and Proliferation of Hepatocellular Carcinoma Cells. Crit Rev Eukaryot Gene Expr 2024; 34:17-26. [PMID: 38305285 DOI: 10.1615/critreveukaryotgeneexpr.2023049637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2024]
Abstract
Long non-coding RNAs (lncRNAs) are involved in the pathogenesis of hepatocellular carcinoma (HCC). This study aimed to investigate the potential of MIR222HG in HCC. HCC cells were co-cultured with U937 cells. Gene expression was determined using reverse transcription-quantitative (RT-q) PCR and western blot. Functional analysis was performed using Cell Counting Kit 8 (CCK-8), colony formation, and flow cytometry assays. We found that MIR222HG was overexpressed in HCC patients as well as HepG2 and Huh7 cells. MIR222HG-mediated upregulation of autophagy related 5 (ATG5) promoted tumor cell autophagy and the activation of M2-like tumor-associated macrophages (TAM2). Moreover, MIR222HG-mediated the activation of TAM2 drove the proliferation of HCC cells. Additionally, MIR222HG increased the mRNA expression as well as promoted the mRNA stability of ATG5 via binding to lin-28 homolog B (LIN28B). In conclusion, MIR222HG-mediated autophagy and the activation of TAM2 promote the aggressiveness of HCC cells via regulating LIN28B/ATG5 signaling.
Collapse
Affiliation(s)
- Xiao Zuo
- Jingzhou Hospital Affiliated to Yangtze University, Jingzhou City, Hubei Province 434020, China
| | - Yan Shao
- Jingzhou Hospital Affiliated to Yangtze University
| | - Yuhang Liang
- Jingzhou Hospital Affiliated to Yangtze University, Jingzhou City, Hubei Province 434020, China
| | - Chenglong Huo
- Jingzhou Hospital Affiliated to Yangtze University, Jingzhou City, Hubei Province 434020, China
| | - Shuai Wang
- Jingzhou Hospital Affiliated to Yangtze University
| |
Collapse
|
|
26
|
da Cunha Agostini L, Almeida TC, da Silva GN. ANRIL, H19 and TUG1: a review about critical long non-coding RNAs in cardiovascular diseases. Mol Biol Rep 2023; 51:31. [PMID: 38155319 DOI: 10.1007/s11033-023-09007-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 10/30/2023] [Indexed: 12/30/2023]
Abstract
Cardiovascular diseases are the leading cause of death worldwide. They are non-transmissible diseases that affect the cardiovascular system and have different etiologies such as smoking, lipid disorders, diabetes, stress, sedentary lifestyle and genetic factors. To date, lncRNAs have been associated with increased susceptibility to the development of cardiovascular diseases such as hypertension, acute myocardial infarction, stroke, angina and heart failure. In this way, lncRNAs are becoming a very promising point for the prevention and diagnosis of cardiovascular diseases. Therefore, this review highlights the most important and recent discoveries about the mechanisms of action of the lncRNAs ANRIL, H19 and TUG1 and their clinical relevance in these pathologies. This may contribute to early detection of cardiovascular diseases in order to prevent the pathological phenotype from becoming established.
Collapse
Affiliation(s)
- Lívia da Cunha Agostini
- Programa de Pós-Graduação em Ciências Farmacêuticas (CiPharma), Escola de Farmácia, Universidade Federal de Ouro Preto, Morro do Cruzeiro, s/nº, Ouro Prêto, Minas Gerais, CEP 35402-163, Brazil
| | - Tamires Cunha Almeida
- Escola Superior Instituto Butantan (ESIB), Laboratório de Dor e Sinalização, Instituto Butantan, São Paulo, São Paulo, Brazil
| | - Glenda Nicioli da Silva
- Programa de Pós-Graduação em Ciências Farmacêuticas (CiPharma), Escola de Farmácia, Universidade Federal de Ouro Preto, Morro do Cruzeiro, s/nº, Ouro Prêto, Minas Gerais, CEP 35402-163, Brazil.
- Departamento de Análises Clínicas (DEACL), Escola de Farmácia, Universidade Federal de Ouro Preto, Ouro Prêto, Brazil.
| |
Collapse
|
|
27
|
Tang Y, Tian W, Zheng S, Zou Y, Xie J, Zhang J, Li X, Sun Y, Lan J, Li N, Xie X, Tang H. Dissection of FOXO1-Induced LYPLAL1-DT Impeding Triple-Negative Breast Cancer Progression via Mediating hnRNPK/β-Catenin Complex. RESEARCH (WASHINGTON, D.C.) 2023; 6:0289. [PMID: 38111678 PMCID: PMC10726293 DOI: 10.34133/research.0289] [Citation(s) in RCA: 79] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 11/26/2023] [Indexed: 12/20/2023]
Abstract
Triple-negative breast cancer (TNBC) is considered as the most hazardous subtype of breast cancer owing to its accelerated progression, enormous metastatic potential, and refractoriness to standard treatments. Long noncoding RNAs (lncRNAs) are extremely intricate in tumorigenesis and cancerous metastasis. Nonetheless, their roles in the initiation and augmentation of TNBC remain elusive. Here, in silico analysis and validation experiments were utilized to analyze the expression pattern of clinically effective lncRNAs in TNBC, among which a protective lncRNA LYPLAL1-DT was essentially curbed in TNBC samples and indicated a favorable prognosis. Gain- and loss-of-function assays elucidated that LYPLAL1-DT considerably attenuated the proliferative and metastatic properties along with epithelial-mesenchymal transition of TNBC cells. Moreover, forkhead box O1 (FOXO1) was validated to modulate the transcription of LYPLAL1-DT. Mechanistically, LYPLAL1-DT impinged on the malignancy of TNBC mainly by restraining the aberrant reactivation of the Wnt/β-catenin signaling pathway, explicitly destabilizing and diminishing β-catenin protein by interacting with heterogeneous nuclear ribonucleoprotein K (hnRNPK) and constricting the formation of the hnRNPK/β-catenin complex. Conclusively, our present research revealed the anti-oncogenic effects of LYPLAL1-DT in TNBC, unraveling the molecular mechanisms of the FOXO1/LYPLAL1-DT/hnRNPK/β-catenin signaling axis, which shed innovative light on the potential curative medicine of TNBC.
Collapse
Affiliation(s)
- Yuhui Tang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China
| | - Wenwen Tian
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, No.78 Hengzhigang Road, Guangzhou 510095, P. R. China
| | - Shaoquan Zheng
- Breast Disease Center, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Er Road, Guangzhou 510080, P. R. China
| | - Yutian Zou
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China
| | - Jindong Xie
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China
| | - Junsheng Zhang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China
| | - Xing Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China
| | - Yuying Sun
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China
| | - Jing Lan
- Department of General Surgery,
The First Affiliated Hospital of Soochow University, Suzhou 215006, P. R. China
| | - Ning Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China
| | - Xiaoming Xie
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China
| | - Hailin Tang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China
| |
Collapse
|
|
28
|
Zhang L, Kang Q, Kang M, Jiang S, Yang F, Gong J, Ou G, Wang S. Regulation of main ncRNAs by polyphenols: A novel anticancer therapeutic approach. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 120:155072. [PMID: 37714063 DOI: 10.1016/j.phymed.2023.155072] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 08/29/2023] [Accepted: 09/04/2023] [Indexed: 09/17/2023]
Abstract
BACKGROUND Plant polyphenols have shown promising applications in oncotherapy. Increasing evidence reveals that polyphenols possess the antitumor potential for multiple cancers. Non-coding RNAs (ncRNAs), mainly including small ncRNAs (microRNA) and long ncRNAs (lncRNAs), play critical roles in cancer initiation and progression. PURPOSE To establish the modulation of ncRNAs by polyphenols as a novel and promising approach in anticancer treatment. STUDY DESIGN The present research employed ncRNA, miRNA, lncRNA, and regulatory mechanism as keywords to retrieve the literature from PubMed, Web of Science, Science direct, and Google Scholar, in a 20-year period from 2003 to 2023. This study critically reviewed the current literature and presented the regulation of prominent ncRNAs by polyphenols. A comprehensive total of 169 papers were retrieved on polyphenols and their related ncRNAs in cancers. RESULTS NcRNAs, mainly including miRNA and lncRNA, play critical roles in cancer initiation and progression, which are potential modulatory targets of bioactive polyphenols, such as resveratrol, genistein, curcumin, EGCG, quercetin, in cancer management. The mechanism involved in polyphenol-mediated ncRNA regulation includes epigenetic and transcriptional modification, and post-transcriptional processing. CONCLUSION Regulatory ncRNAs are potential therapeutic targets of bioactive polyphenols, and these phytochemicals could modulate the level of these ncRNAs directly and indirectly. A better comprehension of the ncRNA regulation by polyphenols in cancers, their functional outcomes on tumor pathophysiology and regulatory molecular mechanisms, may be helpful to develop effective strategies to fight the devastating disease.
Collapse
Affiliation(s)
- Liang Zhang
- Hubei Superior Discipline Group of Exercise and Brain Science from Hubei Provincial, Wuhan Sports University, Wuhan 430079, China
| | - Qingzheng Kang
- Department of Hematology and Oncology, International Cancer Center, Shenzhen Key Laboratory, Shenzhen University General Hospital, Shenzhen University, Shenzhen 518061, China
| | | | - Suwei Jiang
- School of Medicine, Shenzhen University, Shenzhen 518060, China
| | - Feng Yang
- BGI-Shenzhen, Shenzhen 518103, China
| | - Jun Gong
- Central Laboratory, Yunfu People's Hospital, Yunfu 527399, China
| | - Gaozhi Ou
- School of Physical Education, China University of Geosciences, Wuhan 430074, China
| | - Song Wang
- Hubei Superior Discipline Group of Exercise and Brain Science from Hubei Provincial, Wuhan Sports University, Wuhan 430079, China.
| |
Collapse
|
|
29
|
Hong L, Yang P, Zhang L, Liu X, Wei X, Xiao W, Yu Z, Zhang J, Peng Y, Wu X, Tang W, Zhi F, Li G, Li A, Lin J, Liu S, Zhang H, Xiang L, Wang J. The VAX2-LINC01189-hnRNPF signaling axis regulates cell invasion and migration in gastric cancer. Cell Death Discov 2023; 9:387. [PMID: 37865686 PMCID: PMC10590441 DOI: 10.1038/s41420-023-01688-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 09/28/2023] [Accepted: 10/13/2023] [Indexed: 10/23/2023] Open
Abstract
Transcription factors (TFs) and long noncoding RNAs (lncRNAs) contribute to gastric cancer (GC). However, the roles of TFs and lncRNAs in the invasion and metastasis of GC remain largely unknown. Here, we observed that the transcription factor VAX2 is significantly upregulated in GC cells and tissues and acts as an oncogene. Moreover, high VAX2 expression is associated with the advancement of tumors in GC. In terms of functionality, the enforced expression of VAX2 promotes the proliferation and metastasis of GC cells. Mechanistically, VAX2 specifically interacts with the LINC01189 promoter and represses LINC01189 transcription. Furthermore, LINC01189 exhibits significant downregulation in GC and functions as a suppressor gene. Functionally, it inhibits migratory and invasive abilities in GC cells. In the context of GC metastasis, VAX2 plays a role in modulating it by trans-repressing the expression of LINC01189. Additionally, LINC01189 binds to hnRNPF to enhance hnRNPF degradation through ubiquitination. The cooperation between LINC01189 and hnRNPF regulates GC cell invasion and migration. In addition, both VAX2 and hnRNPF are highly expressed, while LINC01189 is expressed in at low levels in GC tissues compared to normal gastric tissues. Our study suggests that VAX2 expression facilitates, while LINC01189 expression suppresses, metastasis and that the VAX2-LINC01189-hnRNPF axis plays a contributory role in GC development.
Collapse
Grants
- 81974448, 82073066, 82103152, 82103598, 82273354 National Natural Science Foundation of China (National Science Foundation of China)
- 81974448, 82073066, 82103152, 82103598, 82273354 National Natural Science Foundation of China (National Science Foundation of China)
- 81974448, 82073066, 82103152, 82103598, 82273354 National Natural Science Foundation of China (National Science Foundation of China)
- 81974448, 82073066, 82103152, 82103598, 82273354 National Natural Science Foundation of China (National Science Foundation of China)
- 81974448, 82073066, 82103152, 82103598, 82273354 National Natural Science Foundation of China (National Science Foundation of China)
- 81974448, 82073066, 82103152, 82103598, 82273354 National Natural Science Foundation of China (National Science Foundation of China)
- 81974448, 82073066, 82103152, 82103598, 82273354 National Natural Science Foundation of China (National Science Foundation of China)
- 81974448, 82073066, 82103152, 82103598, 82273354 National Natural Science Foundation of China (National Science Foundation of China)
- 81974448, 82073066, 82103152, 82103598, 82273354 National Natural Science Foundation of China (National Science Foundation of China)
- 81974448, 82073066, 82103152, 82103598, 82273354 National Natural Science Foundation of China (National Science Foundation of China)
- 81974448, 82073066, 82103152, 82103598, 82273354 National Natural Science Foundation of China (National Science Foundation of China)
- 2022A1515012464 Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)
- 2022A1515012464 Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)
- 2022A1515012464 Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)
- 2022A1515012464 Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)
- 2022A1515012464 Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)
- 2022A1515012464 Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)
- 2022A1515012464 Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)
- 2022A1515012464 Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)
- 2022A1515012464 Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)
- 2022A1515012464 Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)
- JCYJ20210324135005013 Shenzhen Science and Technology Innovation Commission
- JCYJ20210324135005013 Shenzhen Science and Technology Innovation Commission
- Science and Technology Project of Guangdong Province, 2017B20209003.
- Longgang District Science and Technology Innovation Bureau, LGKCYLWS2021000012, LGKCYLWS2022-005.
Collapse
Affiliation(s)
- Linjie Hong
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Ping Yang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Luyu Zhang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xuehua Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Department of Gastroenterology, Shunde Hospital, Southern Medical University, Foshan, 528300, China
| | - Xiangyang Wei
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Wushuang Xiao
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Zhen Yu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jieming Zhang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Ying Peng
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xiaosheng Wu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Weimei Tang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Fachao Zhi
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Guoxin Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Aimin Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jianjiao Lin
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People's Hospital of Shenzhen, Shenzhen, 518172, China
| | - Side Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People's Hospital of Shenzhen, Shenzhen, 518172, China
| | - Hui Zhang
- Department of Gastroenterology, The Affiliated Hexian Memorial Hospital of Southern Medical University, Guangzhou, 511400, China.
| | - Li Xiang
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People's Hospital of Shenzhen, Shenzhen, 518172, China.
| | - Jide Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People's Hospital of Shenzhen, Shenzhen, 518172, China.
| |
Collapse
|
|
30
|
Li S, Zhu Z, Lu J, Cao W, Song F, Xiao C, Zhang P, He Z, Weng J, Xu J. Prediction of prognosis, immune infiltration, and personalized treatment of hepatocellular carcinoma by analysis of cuproptosis-related long noncoding RNAs and verification in vitro. Front Oncol 2023; 13:1159126. [PMID: 37746284 PMCID: PMC10514553 DOI: 10.3389/fonc.2023.1159126] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 08/18/2023] [Indexed: 09/26/2023] Open
Abstract
Background The correlations between cuproptosis and long noncoding RNAs (lncRNAs) with the tumor microenvironment (TME), immunotherapy, and some other characteristics of hepatocellular carcinoma (HCC) remain unclear. Methods Sixteen cuproptosis regulators and 356 cuproptosis-related lncRNAs (CRLnc) were identified from 374 HCC profiles in The Cancer Genome Atlas (TCGA) database. Six differentially expressed CRLnc were selected, and a prognostic risk model based on the CRLnc signature (CRLncSig) was constructed. The prognostic power of the model was verified. Moreover, a cuproptosis-related gene cluster (CRGC) was generated based on six lncRNAs and differentially expressed genes. The relationship between immune cell infiltration in the TME, immunotherapy, CRLncSig, and CRGC was demonstrated through various algorithms, Tumor Immune Dysfunction and Exclusion (TIDE), tumor mutational burden (TMB), etc. Potential drugs and sensitivity to those agents were evaluated for the risk model. LncRNA AL158166.1 was selected and verified in HCC tissues and cell lines, the impact of its knockdown and overexpression in HCC cells was examined, and the copper (Cu) concentration and the cuproptosis-related gene expression were detected. Results A CRLncSig prognostic risk model with good predictive ability was constructed. The low-risk group had a longer overall survival (OS), lower tumor purity, more extensive immune cell infiltration, higher immune score, enrichment in immune-activated pathways, and more positive response to immunotherapy versus the high-risk group. CRGC-B exhibited the best OS and the lowest tumor stage; the immune cell infiltration analysis was similar to the low-risk group in CRLncSig. CRGC-B belonged to the "immune-high" group of the TME. The low-risk group had a higher TIDE score and susceptibility to antitumor drugs. The lncRNA AL158166.1 had the highest hazard ratio. The levels of AL158166.1 were higher in HCC tissues versus healthy tissues. Knockdown of AL158166.1 could lead to an increase in intracellular Cu concentration, induce DLAT low expression, and inhibit the proliferation and migration of HCC cells, whereas overexpression of AL158166.1 exerted the reverse effect. Conclusion Overall, a new CRLncSig prognostic risk model and a cuproptosis-related molecular signature were constructed and evaluated. The model and signature were associated with the prognosis, immune infiltration, and immunotherapy of HCC. Inhibiting the lncRNA AL158166.1 may induce cuproptosis and showed potential for the inhibition of tumors. Evaluation of the CRLnc, CRLncSig, and CRGC may enhance our understanding of the TME, determine the effectiveness of immunotherapy, and act as a marker for the prognosis of HCC.
Collapse
Affiliation(s)
- Shanbao Li
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhonglin Zhu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jing Lu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wanyue Cao
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fangbin Song
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Cao Xiao
- Department of General Surgery, Fudan University Huashan Hospital, Shanghai, China
| | - Peng Zhang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zeping He
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junyong Weng
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Junming Xu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
31
|
Zhao L, Zang Q, Liang G, Yao X. LncRNA CECR7 boosts hepatocellular carcinoma progression by recruiting RNA binding protein U2AF2 to enhance the stability of EXO1 mRNA. Heliyon 2023; 9:e19862. [PMID: 37809785 PMCID: PMC10559240 DOI: 10.1016/j.heliyon.2023.e19862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 08/30/2023] [Accepted: 09/04/2023] [Indexed: 10/10/2023] Open
Abstract
Objective As an important factor tumor regulator，long non-coding RNAs (lncRNAs) have aroused extensive attention via the diverse functional mechanisms that were associated with the pathological and physiological processes of HCC. Here, the main purpose of this study was to provide a clear understanding about the expression, functions and potential mechanism of lncRNA CECR7 (Cat Eye Syndrome Chromosome Region, Candidate 7) in HCC. Methods RT-qPCR analysis and TCGA database analysis were applied to investigate the expression of CECR7 in HCC cell lines and tissues. Chi-squared Test was employed to explore the correlation between CECR7 expression and HCC clinicopathological features. Besides, Kaplan-Meier curves were constructed to test the effects of CECR7 expression on the prognosis of HCC patients. Transwell assays, MTT assay EdU assay and animal experiments were applied to explore the effects of CECR7 expression on HCC cells migration, invasion, and growth. Furthermore, RNA-seq analysis, luciferase reporter assay and mRNA decay rates assessment were utilized to investigate the mechanism whereby CECR7 regulated EXO1 mRNA. And, rescue experiments were used to determine whether EXO1 was an essential mediator for CECR7 to accelerate HCC cells migration, invasion, and growth. Results CECR7 was determined to be significantly overexpressed in HCC cell lines and tissues. CECR7 expression was closely correlated with the tumor size, venous infiltration, TNM stage, 5-year overall survival and disease-free survival of HCC. And, CECR7 played a catalytic role in HCC cells migration, invasion, and growth. Furthermore, CECR7 enhanced the stability of EXO1 mRNA by recruiting RNA binding protein U2AF2. And, EXO1 was determined to be an essential mediator for CECR7 to accelerate HCC cells migration, invasion, and growth. Conclusion In a word, our findings demonstrates that the cancer-promoting gene lncRNA CECR7 motivates HCC metastasis and growth through enhanced mRNA stability of EXO1 mediated by U2AF2, proposing a new insight for targeted therapy of HCC.
Collapse
Affiliation(s)
- Liang Zhao
- Department of General Surgery, Gansu Gem Flower Hospital, Lanzhou 730060, Gansu, China
| | - Qing Zang
- Department of Emergency, Gansu Gem Flower Hospital, Lanzhou 730060, Gansu, China
| | - Guodong Liang
- Department of Emergency, Gansu Gem Flower Hospital, Lanzhou 730060, Gansu, China
| | - Xiaobin Yao
- Department of General Surgery, Gansu Gem Flower Hospital, Lanzhou 730060, Gansu, China
| |
Collapse
|
|
32
|
Zhou W, Feng Y, Lin C, CHAO CK, He Z, Zhao S, Xue J, Zhao X, Cao W. Yin Yang 1-Induced Long Noncoding RNA DUXAP9 Drives the Progression of Oral Squamous Cell Carcinoma by Blocking CDK1-Mediated EZH2 Degradation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2207549. [PMID: 37401236 PMCID: PMC10477890 DOI: 10.1002/advs.202207549] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 04/04/2023] [Indexed: 07/05/2023]
Abstract
LncRNAs play a critical role in oral squamous cell carcinoma (OSCC) progression. However, the function and detailed molecular mechanism of most lncRNAs in OSCC are not fully understood. Here, a novel nuclear-localized lncRNA, DUXAP9 (DUXAP9), that is highly expressed in OSCC is identified. A high level of DUXAP9 is positively associated with lymph node metastasis, poor pathological differentiation, advanced clinical stage, worse overall survival, and worse disease-specific survival in OSCC patients. Overexpression of DUXAP9 significantly promotes OSCC cell proliferation, migration, invasion, and xenograft tumor growth and metastasis, and upregulates N-cadherin, Vimentin, Ki67, PCNA, and EZH2 expression and downregulates E-cadherin in vitro and in vivo, whereas knockdown of DUXAP9 remarkably suppresses OSCC cell proliferation, migration, invasion, and xenograft tumor growth in vitro and in vivo in an EZH2-dependent manner. Yin Yang 1 (YY1) is found to activate the transcriptional expression of DUXAP9 in OSCC. Furthermore, DUXAP9 physically interacts with EZH2 and inhibits EZH2 degradation via the suppression of EZH2 phosphorylation, thereby blocking EZH2 translocation from the nucleus to the cytoplasm. Thus, DUXAP9 can serve as a promising target for OSCC therapy.
Collapse
Affiliation(s)
- Wenkai Zhou
- Department of Oral and Maxillofacial & Head and Neck OncologyShanghai Ninth People's HospitalCollege of StomatologyShanghai Jiao Tong University School of MedicineShanghai200011China
- National Center for StomatologyNational Clinical Research Center for Oral DiseasesShanghai Key Laboratory of StomatologyShanghai200011China
| | - Yisheng Feng
- National Center for StomatologyNational Clinical Research Center for Oral DiseasesShanghai Key Laboratory of StomatologyShanghai200011China
| | - Chengzhong Lin
- National Center for StomatologyNational Clinical Research Center for Oral DiseasesShanghai Key Laboratory of StomatologyShanghai200011China
- The 2nd Dental CenterShanghai Ninth People's HospitalCollege of StomatologyShanghai Jiao Tong University School of MedicineCollege of StomatologyShanghai Jiao Tong UniversityShanghai200011China
| | - Chi Kuan CHAO
- National Center for StomatologyNational Clinical Research Center for Oral DiseasesShanghai Key Laboratory of StomatologyShanghai200011China
| | - Ziqi He
- National Center for StomatologyNational Clinical Research Center for Oral DiseasesShanghai Key Laboratory of StomatologyShanghai200011China
| | - Shiyao Zhao
- National Center for StomatologyNational Clinical Research Center for Oral DiseasesShanghai Key Laboratory of StomatologyShanghai200011China
| | - Jieyuan Xue
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong UniversityShanghai200030China
| | - Xu‐Yun Zhao
- Department of Biochemistry and Molecular Cell BiologyShanghai Key Laboratory for Tumor Microenvironment and InflammationKey Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of EducationShanghai Jiao Tong University School of MedicineShanghai200025China
| | - Wei Cao
- Department of Oral and Maxillofacial & Head and Neck OncologyShanghai Ninth People's HospitalCollege of StomatologyShanghai Jiao Tong University School of MedicineShanghai200011China
- National Center for StomatologyNational Clinical Research Center for Oral DiseasesShanghai Key Laboratory of StomatologyShanghai200011China
| |
Collapse
|
|
33
|
Zhao Y, Liu Y, Shi X. LncRNA AC012360.1 facilitates growth and metastasis by regulating the miR-139-5p/LPCAT1 axis in hepatocellular carcinoma. ENVIRONMENTAL TOXICOLOGY 2023; 38:2192-2203. [PMID: 37300846 DOI: 10.1002/tox.23856] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 04/27/2023] [Accepted: 05/28/2023] [Indexed: 06/12/2023]
Abstract
Long noncoding RNAs (lncRNAs) participate in tumorigenesis and tumor progression. However, whether lncRNA AC012360.1 contributes to hepatocellular carcinoma (HCC) is unknown. In HCC tissues, differentially expressed lncRNAs were identified by bioinformatics. AC012360.1 level was validated and its role in HCC progression was investigated. Among the top 10 upregulated lncRNAs, AC012360.1 exhibited the greatest increase in HCC tissues. Additionally, AC012360.1 was upregulated in HCC tissues/cells. Moreover, AC012360.1 knockdown refrained cell proliferation/metastasis and tumor growth. Conversely, AC012360.1 overexpression showed an oncogenic role. AC012360.1 and lysophosphatidylcholine acyltransferase 1 (LPCAT1) contained miR-139-5p binding sites. Furthermore, miR-139-5p silencing partially mitigated the role of AC012360.1 knockdown, while LPCAT1 knockdown partially abolished the tumor-promoting effect of AC012360.1 overexpression. In conclusion, AC012360.1 exhibited its oncogenic function in HCC through sponging miR-139-5p and upregulating LPCAT1 expression.
Collapse
Affiliation(s)
- Yun Zhao
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ying Liu
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xue Shi
- Department of Hematology, Shengjing Hospital of China Medical University, Shenyang, China
| |
Collapse
|
|
34
|
Afra F, Mahboobipour AA, Salehi Farid A, Ala M. Recent progress in the immunotherapy of hepatocellular carcinoma: Non-coding RNA-based immunotherapy may improve the outcome. Biomed Pharmacother 2023; 165:115104. [PMID: 37393866 DOI: 10.1016/j.biopha.2023.115104] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/27/2023] [Accepted: 06/28/2023] [Indexed: 07/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the second most lethal cancer and a leading cause of cancer-related mortality worldwide. Immune checkpoint inhibitors (ICIs) significantly improved the prognosis of HCC; however, the therapeutic response remains unsatisfactory in a substantial proportion of patients or needs to be further improved in responders. Herein, other methods of immunotherapy, including vaccine-based immunotherapy, adoptive cell therapy, cytokine delivery, kynurenine pathway inhibition, and gene delivery, have been adopted in clinical trials. Although the results were not encouraging enough to expedite their marketing. A major proportion of human genome is transcribed into non-coding RNAs (ncRNAs). Preclinical studies have extensively investigated the roles of ncRNAs in different aspects of HCC biology. HCC cells reprogram the expression pattern of numerous ncRNAs to decrease the immunogenicity of HCC, exhaust the cytotoxic and anti-cancer function of CD8 + T cells, natural killer (NK) cells, dendritic cells (DCs), and M1 macrophages, and promote the immunosuppressive function of T Reg cells, M2 macrophages, and myeloid-derived suppressor cells (MDSCs). Mechanistically, cancer cells recruit ncRNAs to interact with immune cells, thereby regulating the expression of immune checkpoints, functional receptors of immune cells, cytotoxic enzymes, and inflammatory and anti-inflammatory cytokines. Interestingly, prediction models based on the tissue expression or even serum levels of ncRNAs could predict response to immunotherapy in HCC. Moreover, ncRNAs markedly potentiated the efficacy of ICIs in murine models of HCC. This review article first discusses recent advances in the immunotherapy of HCC, then dissects the involvement and potential application of ncRNAs in the immunotherapy of HCC.
Collapse
Affiliation(s)
- Fatemeh Afra
- Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Ali Mahboobipour
- Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Salehi Farid
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Moein Ala
- Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
35
|
Chen W, Ruan M, Zou M, Liu F, Liu H. Clinical Significance of Non-Coding RNA Regulation of Programmed Cell Death in Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:4187. [PMID: 37627215 PMCID: PMC10452865 DOI: 10.3390/cancers15164187] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/02/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a widely prevalent and malignantly progressive tumor. Most patients are typically diagnosed with HCC at an advanced stage, posing significant challenges in the execution of curative surgical interventions. Non-coding RNAs (ncRNAs) represent a distinct category of RNA molecules not directly involved in protein synthesis. However, they possess the remarkable ability to regulate gene expression, thereby exerting significant regulatory control over cellular processes. Notably, ncRNAs have been implicated in the modulation of programmed cell death (PCD), a crucial mechanism that various therapeutic agents target in the fight against HCC. This review summarizes the clinical significance of ncRNA regulation of PCD in HCC, including patient diagnosis, prognosis, drug resistance, and side effects. The aim of this study is to provide new insights and directions for the diagnosis and drug treatment strategies of HCC.
Collapse
Affiliation(s)
| | | | | | - Fuchen Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China; (W.C.); (M.R.)
| | - Hui Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China; (W.C.); (M.R.)
| |
Collapse
|
|
36
|
Li L, Ai R, Yuan X, Dong S, Zhao D, Sun X, Miao T, Guan W, Guo P, Yu S, Nan Y. LINC00886 Facilitates Hepatocellular Carcinoma Tumorigenesis by Sequestering microRNA-409-3p and microRNA-214-5p. J Hepatocell Carcinoma 2023; 10:863-881. [PMID: 37313303 PMCID: PMC10259583 DOI: 10.2147/jhc.s410891] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 06/01/2023] [Indexed: 06/15/2023] Open
Abstract
Purpose As the major subtype of liver cancer, hepatocellular carcinoma (HCC) suffers from high mortality and is prone to recurrence. Long non-coding RNAs (lncRNAs) are well characterized to be pivotal players contributing to HCC pathogenesis and progression. Therefore, this study intended to probe the biological functions of LINC00886 in hepatocarcinogenesis. Patients and Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to analysis of LINC00886, microRNA-409-3p (miR-409-3p), microRNA-214-5p (miR-214-5p), RAB10 and E2F2 expression. Subcellular localization of LINC00886 was identified through a fluorescent in situ hybridization (FISH) kit and a subcellular assay. Additionally, proliferated cells were determined with EdU as well as cell counting kit-8 (CCK-8) assays. Scratch and Transwell assays were applied to detect migratory and invasive cells. Apoptotic cells were measured via TUNEL staining assay. Furthermore, targeted binding between LINC00886 and miR-409-3p or miR-214-5p was validated utilizing dual-luciferase reporter assays. RAB10, E2F2 and NF-κB signaling-associated protein levels were evaluated utilizing Western blot. Results LINC00886, RAB10 and E2F2 levels were aberrantly increased, with the abnormal expressed decline of miR-409-3p and miR-214-5p, in HCC tissues, cells and peripheral blood mononuclear cells (PBMCs). Silencing LINC00886 attenuated the proliferative, migratory, invasive, and anti-apoptotic potential of HCC cells, while LINC00886 overexpression proceeded in the contrary direction. Mechanistically, miR-409-3p and miR-214-5p were validated as binding targets for LINC00886 and inverted the biological functions of LINC00886 during HCC progression. Furthermore, the LINC00886-miR-409-3p/miR-214-5p axis could regulate RAB10 and E2F2 expression via mediating NF-κB pathway activation in hepatocarcinogenesis. Conclusion Our findings indicated that LINC00886 facilitated HCC progression via absorbing miR-409-3p or miR-214-5p to upregulate RAB10 and E2F2 through activation of NF-κB pathway, offering a promising novel target for HCC therapy.
Collapse
Affiliation(s)
- Lu Li
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, Hebei, 050051, People’s Republic of China
| | - Rong Ai
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, Hebei, 050051, People’s Republic of China
| | - Xiwei Yuan
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, Hebei, 050051, People’s Republic of China
| | - Shiming Dong
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, Hebei, 050051, People’s Republic of China
| | - Dandan Zhao
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, Hebei, 050051, People’s Republic of China
| | - Xiaoye Sun
- Department of Organ Transplant Center, Tianjin First Central Hospital, Tianjin, 300192, People’s Republic of China
| | - Tongguo Miao
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, Hebei, 050051, People’s Republic of China
| | - Weiwei Guan
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, Hebei, 050051, People’s Republic of China
| | - Peilin Guo
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, Hebei, 050051, People’s Republic of China
| | - Songhao Yu
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, Hebei, 050051, People’s Republic of China
| | - Yuemin Nan
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, Hebei, 050051, People’s Republic of China
| |
Collapse
|
|
37
|
Du X, Zhou P, Zhang H, Peng H, Mao X, Liu S, Xu W, Feng K, Zhang Y. Downregulated liver-elevated long intergenic noncoding RNA (LINC02428) is a tumor suppressor that blocks KDM5B/IGF2BP1 positive feedback loop in hepatocellular carcinoma. Cell Death Dis 2023; 14:301. [PMID: 37137887 PMCID: PMC10156739 DOI: 10.1038/s41419-023-05831-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 03/30/2023] [Accepted: 04/24/2023] [Indexed: 05/05/2023]
Abstract
Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality and poor prognoses worldwide. Many studies have reported that long noncoding RNAs (lncRNAs) are related to the progression and prognosis of HCC. However, the functions of downregulated liver-elevated (LE) lncRNAs in HCC remain elusive. Here we report the roles and mechanisms of downregulated LE LINC02428 in HCC. Downregulated LE lncRNAs played significant roles in HCC genesis and development. LINC02428 was upregulated in liver tissues compared with other normal tissues and showed low expression in HCC. The low expression of LINC02428 was attributed to poor HCC prognosis. Overexpressed LINC02428 suppressed the proliferation and metastasis of HCC in vitro and in vivo. LINC02428 was predominantly located in the cytoplasm and bound to insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) to prevent it from binding to lysine demethylase 5B (KDM5B) mRNA, which decreased the stability of KDM5B mRNA. KDM5B was found to preferentially bind to the promoter region of IGF2BP1 to upregulate its transcription. Therefore, LINC02428 interrupts the KDM5B/IGF2BP1 positive feedback loops to inhibit HCC progression. The KDM5B/IGF2BP1 positive feedback loop is involved in tumorigenesis and progression of HCC.
Collapse
Affiliation(s)
- Xuanlong Du
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Pengcheng Zhou
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Haidong Zhang
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Hao Peng
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Xinyu Mao
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China
| | - Shiwei Liu
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Wenjing Xu
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Kun Feng
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China
| | - Yewei Zhang
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China.
| |
Collapse
|
|
38
|
Han XY, Li X, Zhao RY, Ma HZ, Yu M, Niu XD, Jin HJ, Wang YF, Liu DM, Cai H. Comprehensive analysis of prognostic value and immunotherapy prospect of brain cytoplasmic RNA1 in hepatocellular carcinoma. World J Gastrointest Oncol 2023; 15:644-664. [PMID: 37123057 PMCID: PMC10134208 DOI: 10.4251/wjgo.v15.i4.644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 02/18/2023] [Accepted: 03/16/2023] [Indexed: 04/12/2023] Open
Abstract
BACKGROUND The expression of brain cytoplasmic RNA1 (BCYRN1) is linked to the clinicopathology and prognosis of several types of cancers, among which hepatocellular carcinoma (HCC) is one of the most frequent types of cancer worldwide.
AIM To explore the prognostic value and immunotherapeutic potential of BCYRN1 in HCC by bioinformatics and meta-analysis.
METHODS Information was obtained from the Cancer Genome Atlas database. First, the correlation between BCYRN1 expression and prognosis and clinicopathologic characteristics of HCC patients was explored. Univariate and multivariate regression analyses were employed to examine the relationship between BCYRN1 and HCC prognosis. Secondly, potential functions and pathways were explored by means of enrichment analysis of differentially-expressed genes. The relationships between BCYRN1 expression and tumor microenvironment, immune cell infiltration, immune checkpoint, drug sensitivity and immunotherapy effect were also investigated. Finally, three major databases were searched and used to conduct a meta-analysis on the relationship between BCYRN1 expression and patient prognosis.
RESULTS BCYRN1 expression was significantly higher in HCC compared to normal tissues and was linked to a poor prognosis and clinicopathological characteristics. Enrichment analysis showed that BCYRN1 regulates the extracellular matrix and transmission of signaling molecules, participates in the metabolism of nutrients, such as proteins, and participates in tumor-related pathways. BCYRN1 expression was linked to the tumor microenvironment, immune cell infiltration, drug sensitivity and the efficacy of immunotherapy. Furthermore, the meta-analysis in this study showed that BCYRN1 overexpression was related to a worse outcome in HCC patients.
CONCLUSION Overexpression of BCYRN1 relates to poor prognosis and may be a potential prognostic factor and immunotherapeutic target in HCC.
Collapse
Affiliation(s)
- Xiao-Yong Han
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Graduate School, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Xiong Li
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Graduate School, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Rang-Yin Zhao
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Hai-Zhong Ma
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- The First Clinical College of Medicine, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Miao Yu
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Xiang-Dong Niu
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Hao-Jie Jin
- The First Clinical College of Medicine, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Yong-Feng Wang
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- The First Clinical College of Medicine, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - De-Ming Liu
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Hui Cai
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou 730000, Gansu Province, China
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| |
Collapse
|
|
39
|
Kouroumalis E, Tsomidis I, Voumvouraki A. Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy. Biomedicines 2023; 11:1166. [PMID: 37189787 PMCID: PMC10135776 DOI: 10.3390/biomedicines11041166] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/09/2023] [Accepted: 04/12/2023] [Indexed: 05/17/2023] Open
Abstract
The pathogenesis of hepatocellular carcinoma (HCC) is a multifactorial process that has not yet been fully investigated. Autophagy and apoptosis are two important cellular pathways that are critical for cell survival or death. The balance between apoptosis and autophagy regulates liver cell turnover and maintains intracellular homeostasis. However, the balance is often dysregulated in many cancers, including HCC. Autophagy and apoptosis pathways may be either independent or parallel or one may influence the other. Autophagy may either inhibit or promote apoptosis, thus regulating the fate of the liver cancer cells. In this review, a concise overview of the pathogenesis of HCC is presented, with emphasis on new developments, including the role of endoplasmic reticulum stress, the implication of microRNAs and the role of gut microbiota. The characteristics of HCC associated with a specific liver disease are also described and a brief description of autophagy and apoptosis is provided. The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. The role of ferroptosis, a recently described specific pathway of regulated cell death, is presented. Finally, the potential therapeutic implications of autophagy and apoptosis in drug resistance are examined.
Collapse
Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, PAGNI University Hospital, University of Crete School of Medicine, 71500 Heraklion, Crete, Greece
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
| | - Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Central Macedonia, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Central Macedonia, Greece
| |
Collapse
|
|
40
|
Yan C, Jin Y. Silencing of long noncoding RNA MIAT inhibits the viability and proliferation of breast cancer cells by promoting miR-378a-5p expression. Open Med (Wars) 2023; 18:20230676. [PMID: 37025425 PMCID: PMC10071813 DOI: 10.1515/med-2023-0676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 01/10/2023] [Accepted: 02/06/2023] [Indexed: 04/05/2023] Open
Abstract
Myocardial infarction–associated transcript (MIAT) is a long noncoding RNA that plays a critical role in a variety of diseases. Accordingly, this study probed into the possible interaction mechanism between MIAT and miR-378a-5p in breast cancer. Concretely, MIAT and miR-378a-5p expressions in breast cancer tissues and cells were measured. After transfection with siMIAT and miR-378a-5p inhibitor, the viability and proliferation of breast cancer cells were examined by cell counting kit-8 and colony formation assays. The expressions of apoptosis-related proteins were detected. According to the results, MIAT was highly expressed in breast cancer tissues and cells. MIAT silencing could decrease Bcl-2 expression, viability, and proliferation of breast cancer cells and increase the expressions of cleaved caspase-3 and Bax. MIAT and miR-378a-5p could directly bind to each other, and MIAT silencing promoted the expression of miR-378a-5p. miR-378a-5p expression was low in breast cancer tissues. The miR-378a-5p inhibitor enhanced the viability and proliferation of breast cancer cells and partially reversed the effects of MIAT silencing on the breast cancer cells. In conclusion, MIAT silencing inhibits the viability and proliferation of breast cancer cells by promoting miR-378a-5p, indicating the potential of MIAT as a new target for the treatment of breast cancer.
Collapse
Affiliation(s)
- Chao Yan
- Medical Laboratory, The Affiliated Huai’an Hospital of Xuzhou Medical University and The Second People’s Hospital of Huai’an, Huai’an 223003, Jiangsu, China
| | - Yue Jin
- Medical Laboratory, The Affiliated Huai’an Hospital of Xuzhou Medical University and The Second People’s Hospital of Huai’an, No. 62, Huaihai South Road, Qingjiangpu District, Huai’an 223003, Jiangsu, China
| |
Collapse
|
|
41
|
Wang X, Chen J, Lin L, Li Y, Tao Q, Lang Z, Zheng J, Yu Z. Machine learning integrations develop an antigen-presenting-cells and T-Cells-Infiltration derived LncRNA signature for improving clinical outcomes in hepatocellular carcinoma. BMC Cancer 2023; 23:284. [PMID: 36978017 PMCID: PMC10053113 DOI: 10.1186/s12885-023-10766-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 03/23/2023] [Indexed: 03/30/2023] Open
Abstract
As a highly heterogeneous cancer, the prognostic stratification and personalized management of hepatocellular carcinoma (HCC) are still challenging. Recently, Antigen-presenting-cells (APCs) and T-cells-infiltration (TCI) have been reported to be implicated in modifying immunology in HCC. Nevertheless, the clinical value of APCs and TCI-related long non-coding RNAs (LncRNAs) in the clinical outcomes and precision treatment of HCC is still obscure. In this study, a total of 805 HCC patients were enrolled from three public datasets and an external clinical cohort. 5 machine learning (ML) algorithms were transformed into 15 kinds of ML integrations, which was used to construct the preliminary APC-TCI related LncRNA signature (ATLS). According to the criterion with the largest average C-index in the validation sets, the optimal ML integration was selected to construct the optimal ATLS. By incorporating several vital clinical characteristics and molecular features for comparison, ATLS was demonstrated to have a relatively more significantly superior predictive capacity. Additionally, it was found that the patients with high ATLS score had dismal prognosis, relatively high frequency of tumor mutation, remarkable immune activation, high expression levels of T cell proliferation regulators and anti-PD-L1 response as well as extraordinary sensitivity to Oxaliplatin/Fluorouracil/Lenvatinib. In conclusion, ATLS may serve as a robust and powerful biomarker for improving the clinical outcomes and precision treatment of HCC.
Collapse
Affiliation(s)
- Xiaodong Wang
- Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Ji Chen
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, No.2 Fuxue Lane, Wenzhou, Zhejiang, P.R. China
| | - Lifan Lin
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, No.2 Fuxue Lane, Wenzhou, Zhejiang, P.R. China
| | - Yifei Li
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, No.2 Fuxue Lane, Wenzhou, Zhejiang, P.R. China
| | - Qiqi Tao
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, No.2 Fuxue Lane, Wenzhou, Zhejiang, P.R. China
| | - Zhichao Lang
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, No.2 Fuxue Lane, Wenzhou, Zhejiang, P.R. China
| | - Jianjian Zheng
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, No.2 Fuxue Lane, Wenzhou, Zhejiang, P.R. China.
| | - Zhengping Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, No.2 Fuxue Lane, Wenzhou, Zhejiang, P.R. China.
| |
Collapse
|
|
42
|
Tuo H, Liu R, Wang Y, Yang W, Liu Q. Hypoxia-induced lncRNA MRVI1-AS1 accelerates hepatocellular carcinoma progression by recruiting RNA-binding protein CELF2 to stabilize SKA1 mRNA. World J Surg Oncol 2023; 21:111. [PMID: 36973749 PMCID: PMC10044719 DOI: 10.1186/s12957-023-02993-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 03/18/2023] [Indexed: 03/29/2023] Open
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs) perform a vital role during the progression of hepatocellular carcinoma (HCC). Here, we aimed to identify a novel lncRNA involved in HCC development and elucidate the underlying molecular mechanism. METHODS The RT-qPCR and TCGA dataset analysis were applied to explore the expressions of MRVI1-AS1 in HCC tissues and cell lines. Statistical analysis was applied to analyze the clinical significance of MRVI1-AS1 in HCC. The functions of MRVI1-AS1 in HCC cells metastasis and growth were explored by transwell assays, wound healing assay, MTT assay, EdU assay, the intravenous transplantation tumor model, and the subcutaneous xenograft tumor model. Microarray mRNA expression analysis, dual luciferase assays, and actinomycin D treatment were used to explore the downstream target of MRVI1-AS1 in HCC cells. RIP assay was applied to assess the direct interactions between CELF2 and MRVI1-AS1 or SKA1 mRNA. Rescue experiments were employed to validate the functional effects of MRVI1-AS1, CELF2, and SKA1 on HCC cells. RESULTS MRVI1-AS1 was found to be dramatically upregulated in HCC and the expression was strongly linked to tumor size, venous infiltration, TNM stage, as well as HCC patients' outcome. Cytological experiments and animal experiments showed that MRVI1-AS1 promoted HCC cells metastasis and growth. Furthermore, SKA1 was identified as the downstream targeted mRNA of MRVI1-AS1 in HCC cells, and MRVI1-AS1 increased SKA1 expression by recruiting CELF2 protein to stabilize SKA1 mRNA. In addition, we found that MRVI1-AS1 expression was stimulated by hypoxia through a HIF-1-dependent manner, which meant that MRVI1-AS was a direct downstream target gene of HIF-1 in HCC. CONCLUSION In a word, our findings elucidated that hypoxia-induced MRVI1-AS1 promotes metastasis and growth of HCC cells via recruiting CELF2 protein to stabilize SKA1 mRNA, pointing to MRVI1-AS1 as a promising clinical application target for HCC therapy.
Collapse
Affiliation(s)
- Hang Tuo
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, People's Republic of China
| | - Runkun Liu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, People's Republic of China
| | - Yufeng Wang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, People's Republic of China
| | - Wei Yang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, People's Republic of China.
| | - Qingguang Liu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, People's Republic of China.
| |
Collapse
|
|
43
|
Sun W, Lei X, Lu Q, Wu Q, Ma Q, Huang D, Zhang Y. LncRNA FRMD6-AS1 promotes hepatocellular carcinoma cell migration and stemness by regulating SENP1/HIF-1α axis. Pathol Res Pract 2023; 243:154377. [PMID: 36827886 DOI: 10.1016/j.prp.2023.154377] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 02/07/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023]
Abstract
BACKGROUND Long non-cording RNAs (lncRNAs) drive the malignant progression of hepatocellular carcinoma (HCC), a cancer with high mortality rates but the function of FERM Domain Containing 6 antisense RNA 1 (FRMD6-AS1) in HCC has not been fully addressed. Hypoxia-inducible factors (HIFs) are transcription factors relevant to HCC under hypoxia and are regulated by SUMO-specific protease 1 (SENP1) through its deSUMOylation of HIF-1α. The current study investigated the role of FRMD6-AS1 in the regulation of SENP1-mediated deSUMOylation of HIF-1α. METHODS HUH7 and MHCC97H cells were treated with CoCl2 to mimic hypoxia in vitro and lentiviral vector-mediated FRMD6-AS1 overexpressing HCC cells were established. Wound-healing, Transwell, sphere formation assay, Western blotting analysis and animal experiments were performed. Expression of FRMD6-AS1, SENP1 mRNA and HIF-1α mRNA was assessed by RT-qPCR and of HIF-1α and SENP1 protein by Western blot. DeSUMOylation of HIF-1α was detected by immunoprecipitation. RNA immunoprecipitation with SENP1 antibody or IgG was performed to assess endogenous interactions between SENP1 and FRMD6-AS1. RESULTS FRMD6-AS1 was upregulated in HCC tissues and cells and its upregulation indicated poor prognosis for HCC patients. FRMD6-AS1 promoted HCC cells migration and stemness in vitro and also promoted tumor growth in an in vivo mouse xenograft model. Mechanistic studies showed that FRMD6-AS1 regulated the level of HIF-1α protein but not the mRNA and this effect was achieved by binding to SENP1 protein and enhancing its protease activity. Rescue experiments demonstrated the oncogenic role of the FRMD6-AS1/SENP1/ HIF-1α axis in HCC cells. CONCLUSIONS High FRMD6-AS1 expression was associated with poor prognosis of HCC patients. FRMD6-AS1 may have an oncogenic role in HCC via regulation of the SENP1/HIF-1α axis and may be a prognostic biomarker for HCC. Blockade of FRMD6-AS1 may offer a novel therapeutic approach to restrict HCC progression.
Collapse
Affiliation(s)
- Wen Sun
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310014, China
| | - Xiangxiang Lei
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou 310053, China
| | - Qiliang Lu
- Qingdao medical college, Qingdao university, Qingdao 266000, China
| | - Qingsong Wu
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310014, China
| | - Qiancheng Ma
- College of Bioscience Engineering, Zhejiang University of Technology, Hangzhou 310014, China
| | - Dongsheng Huang
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, No. 8, Yikang Street, Lin'an District, Hangzhou 310014, China.
| | - Yaping Zhang
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, No. 8, Yikang Street, Lin'an District, Hangzhou 310014, China.
| |
Collapse
|
|
44
|
Heidarzadehpilehrood R, Pirhoushiaran M, Binti Osman M, Abdul Hamid H, Ling KH. Weighted Gene Co-Expression Network Analysis (WGCNA) Discovered Novel Long Non-Coding RNAs for Polycystic Ovary Syndrome. Biomedicines 2023; 11:biomedicines11020518. [PMID: 36831054 PMCID: PMC9953234 DOI: 10.3390/biomedicines11020518] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/03/2023] [Accepted: 02/06/2023] [Indexed: 02/15/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) affects reproductive-age women. This condition causes infertility, insulin resistance, obesity, and heart difficulties. The molecular basis and mechanism of PCOS might potentially generate effective treatments. Long non-coding RNAs (lncRNAs) show control over multifactorial disorders' growth and incidence. Numerous studies have emphasized its significance and alterations in PCOS. We used bioinformatic methods to find novel dysregulated lncRNAs in PCOS. To achieve this objective, the gene expression profile of GSE48301, comprising PCOS patients and normal control tissue samples, was evaluated using the R limma package with the following cut-off criterion: p-value < 0.05. Firstly, weighted gene co-expression network analysis (WGCNA) was used to determine the co-expression genes of lncRNAs; subsequently, hub gene identification and pathway enrichment analysis were used. With the defined criteria, nine novel dysregulated lncRNAs were identified. In WGCNA, different colors represent different modules. In the current study, WGCNA resulted in turquoise, gray, blue, and black co-expression modules with dysregulated lncRNAs. The pathway enrichment analysis of these co-expressed modules revealed enrichment in PCOS-associated pathways, including gene expression, signal transduction, metabolism, and apoptosis. In addition, CCT7, EFTUD2, ESR1, JUN, NDUFAB1, CTTNB1, GRB2, and CTNNB1 were identified as hub genes, and some of them have been investigated in PCOS. This study uncovered nine novel PCOS-related lncRNAs. To confirm how these lncRNAs control translational modification in PCOS, functional studies are required.
Collapse
Affiliation(s)
- Roozbeh Heidarzadehpilehrood
- Department of Obstetrics & Gynaecology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Malaysia
| | - Maryam Pirhoushiaran
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran
| | - Malina Binti Osman
- Department of Medical Microbiology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Malaysia
| | - Habibah Abdul Hamid
- Department of Obstetrics & Gynaecology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Malaysia
- Correspondence: (H.A.H.); (K.-H.L.)
| | - King-Hwa Ling
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Malaysia
- Correspondence: (H.A.H.); (K.-H.L.)
| |
Collapse
|
|
45
|
Huang XF, Fu LS, Cai QQ, Fan F. Prognostic and immunological role of sulfatide-related lncRNAs in hepatocellular carcinoma. Front Oncol 2023; 13:1091132. [PMID: 36816914 PMCID: PMC9929346 DOI: 10.3389/fonc.2023.1091132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 01/18/2023] [Indexed: 02/04/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. Long non-coding RNAs (lncRNAs) play important roles in the occurrence and development of HCC through multiple pathways. Our previous study reported the specific molecular mechanism for sulfatide regulation of integrin αV expression and cell adhesion in HCC cells through lncRNA AY927503. Next, it is necessary to identify more sulfatide-related lncRNAs, explore their clinical signifcance, and determine new targeted treatment strategies. Methods Microarrays were used to screen a complete set of lncRNAs with different expression profiles in sulfatide-treated cells. Sulfatide-related lncRNAs expression data and corresponding HCC patient survival information were obtained from the The Cancer Genome Atlas (TCGA) database, and the prognosis prediction model was constructed based on Cox regression analysis. Methylated RNA immunoprecipitation with next generation sequencing (MeRIP-seq) was used to detemine the effect of sulfatide on lncRNAs m6A modification. Tumor Immune Estimation Resource (TIMER) and Gene set nnrichment analysis (GSEA) were utilized to enrich the immune and functional pathways of sulfatide-related lncRNAs. Results A total of 85 differentially expressed lncRNAs (|Fold Change (FC)|>2, P<0.05) were screened in sulfatide-treated HCC cells. As a result, 24 sulfatide-related lncRNAs were highly expressed in HCC tissues, six of which were associated with poor prognosis in HCC patients. Based on thses data, a sulfatide-related lncRNAs prognosis assessment model for HCC was constructed. According to this risk score analysis, the overall survival (OS) curve showed that the OS of high-risk patients was significantly lower than that of low-risk patients (P<0.05). Notably, the expression difference in sulfatide-related lncRNA NRSN2-AS1 may be related to sulfatide-induced RNA m6A methylation. In addition, the expression level of NRSN2-AS1 was significantly positively correlated with immune cell infiltration in HCC and participated in the peroxisome and Peroxisome proliferator-activated receptor (PPAR) signaling pathways. Conclusions In conclusion, sulfatide-related lncRNAs might be promising prognostic and therapeutic targets for HCC.
Collapse
Affiliation(s)
- Xing Feng Huang
- Department of Biliary Tract Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Li Sheng Fu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Key Lab of Glycoconjugate Research, Ministry of Public Health, Shanghai, China
| | - Qian Qian Cai
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Fei Fan
- Department of The Second Ward of Special Treatment, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| |
Collapse
|
|
46
|
Kouroumalis E, Tsomidis I, Voumvouraki A. Iron as a therapeutic target in chronic liver disease. World J Gastroenterol 2023; 29:616-655. [PMID: 36742167 PMCID: PMC9896614 DOI: 10.3748/wjg.v29.i4.616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/03/2022] [Accepted: 12/31/2022] [Indexed: 01/20/2023] Open
Abstract
It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease. The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver. In this review, we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin, transferrin, and ferritin in iron homeostasis. The regulation of ferroptosis by endogenous and exogenous mod-ulators will be examined. Furthermore, the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease, chronic hepatitis B and C, liver fibrosis, and hepatocellular carcinoma (HCC) will be analyzed. Finally, experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented. Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC, where induction of ferroptosis is the desired effect. Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.
Collapse
Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71003, Greece
| | - Ioannis Tsomidis
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
| |
Collapse
|
|
47
|
Long J, Liu L, Yang X, Zhou X, Lu X, Qin L. LncRNA NUTM2A-AS1 aggravates the progression of hepatocellular carcinoma by activating the miR-186-5p/KLF7-mediated Wnt/beta-catenin pathway. Hum Cell 2023; 36:312-328. [PMID: 36242728 DOI: 10.1007/s13577-022-00802-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 09/28/2022] [Indexed: 01/20/2023]
Abstract
Emerging evidence has uncovered that noncoding RNAs (ncRNAs) contribute to the development of hepatocellular carcinoma (HCC). Nevertheless, the functions of the majority of long ncRNAs (lncRNAs) in HCC are unknown. Here, we intend to probe the function of lncRNA NUTM2A-AS1 in the evolvement of HCC and the related mechanism. Expression levels of lncRNA NUTM2A-AS1, miR-186-5p and KLF7 mRNA in HCC tissues and adjacent non-tumor tissues were monitored. Gain- or loss-of-function assays were utilized to investigate the biological functions of lncRNA NUTM2A-AS1, miR-186-5p and KLF7 in HCC cell lines (including HCCLM3 and Huh7). Western blot was implemented for the detection of the epithelial-mesenchymal transition (EMT)-related proteins (including E-cadherin, Vimentin and Snail), KLF7, Wnt, β-catenin, and stemness-related proteins (Nanog, OCT4, YKL40, and CD133). Furthermore, the targeted associations between lncRNA NUTM2A-AS1, miR-186-5p, and KLF7 were verified by bioinformatics analysis, dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. As a result, lncRNA NUTM2A-AS1 and KLF7 profiles were heightened in the HCC tissues versus adjacent normal tissues, while miR-186-5p had the opposite expression tendency. Up-regulation of lncRNA NUTM2A-AS1 was related to tumor size, advanced tumor stage, and lymph node metastasis of HCC patients. Functionally, overexpression of lncRNA NUTM2A-AS1 heightened HCC cells' growth, invasion, EMT, and stemness and repressed their apoptosis by activating the Wnt/β-catenin pathway. In contrast, up-regulation of miR-186-5p or inhibition of KLF7 had reverse effects. In vivo, lncRNA NUTM2A-AS1 overexpression facilitated tumor growth and EMT, accompanied by declined miR-186-5p levels and enhanced KLF7 expression. The mechanistic studies revealed that miR-186-5p served as a common target of lncRNA NUTM2A-AS1 and KLF7. As hinted by the rescue experiments, NUTM2A-AS1 partly abated miR-186-5p-mediated anti-tumor effects in HCC cells, whereas KLF7 knockdown reversed the promotive effects of NUTM2A-AS1. LncRNA NUTM2A-AS1 accelerated the evolution of HCC by up-regulating the KLF7/Wnt/beta-catenin pathway through sponging miR-186-5p.
Collapse
Affiliation(s)
- Jianwu Long
- Department of Hepatobiliary Surgery, Hengyang Medical School, The Affiliated Nanhua Hospital, University of South China, No. 336, Dongfeng South Road, Zhuhui District, Hengyang City, 421000, China.,Department of General Surgery, The First Affiliated Hospital of Soochow University, No. 899 Pinghai Road, Gusu District, Suzhou City, 215000, Jiangsu, China
| | - Longfei Liu
- Department of Hepatobiliary Surgery, Hengyang Medical School, The Affiliated Nanhua Hospital, University of South China, No. 336, Dongfeng South Road, Zhuhui District, Hengyang City, 421000, China
| | - Xuefeng Yang
- Hunan Provincial Clinical Research Center for Metabolic Associated Fatty Liver Disease, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Xiaojun Zhou
- Department of Hepatobiliary Surgery, Hengyang Medical School, The Affiliated Nanhua Hospital, University of South China, No. 336, Dongfeng South Road, Zhuhui District, Hengyang City, 421000, China
| | - Xianzhou Lu
- Department of Hepatobiliary Surgery, Hengyang Medical School, The Affiliated Nanhua Hospital, University of South China, No. 336, Dongfeng South Road, Zhuhui District, Hengyang City, 421000, China.
| | - Lei Qin
- Department of General Surgery, The First Affiliated Hospital of Soochow University, No. 899 Pinghai Road, Gusu District, Suzhou City, 215000, Jiangsu, China.
| |
Collapse
|
|
48
|
Hong Y, Zhang Y, Zhao H, Chen H, Yu QQ, Cui H. The roles of lncRNA functions and regulatory mechanisms in the diagnosis and treatment of hepatocellular carcinoma. Front Cell Dev Biol 2022; 10:1051306. [PMID: 36467404 PMCID: PMC9716033 DOI: 10.3389/fcell.2022.1051306] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 11/07/2022] [Indexed: 10/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent and deadly type of liver cancer. While the underlying molecular mechanisms are poorly understood, it is documented that lncRNAs may play key roles. Many HCC-associated lncRNAs have been linked to HBV and HCV infection, mediating gene expression, cell growth, development, and death. Studying the regulatory mechanisms and biological functions of HCC-related lncRNAs will assist our understanding of HCC pathogenesis as well as its diagnosis and management. Here, we address the potential of dysregulated lncRNAs in HCC as diagnostic and therapeutic biomarkers, and we evaluate the oncogenic or tumor-suppressive properties of these lncRNAs.
Collapse
Affiliation(s)
- Yuling Hong
- School of Clinical Medicine, Jining Medical University, Jining, China
| | - Yunxing Zhang
- Jining First People’s Hospital, Jining Medical College, Jining, China
| | - Haibo Zhao
- Jining First People’s Hospital, Jining Medical College, Jining, China
| | - Hailing Chen
- School of Clinical Medicine, Jining Medical University, Jining, China
| | - Qing-Qing Yu
- Jining First People’s Hospital, Jining Medical College, Jining, China
| | - Hongxia Cui
- Jining First People’s Hospital, Jining Medical College, Jining, China
| |
Collapse
|
|
49
|
Li R, Jin C, Zhao W, Liang R, Xiong H. Development of a novel immune-related lncRNA prognostic signature for patients with hepatocellular carcinoma. BMC Gastroenterol 2022; 22:450. [PMID: 36344926 PMCID: PMC9639314 DOI: 10.1186/s12876-022-02540-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 10/14/2022] [Indexed: 11/09/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common neoplasm and the major cause of cancer-associated death worldwide. The high mortality rate of HCC is mainly attributed to its widespread prevalence and the lack of effective treatment. Immunotherapy as a promising, innovative approach has revolutionised the treatment of solid tumours. However, owing to the heterogeneity and complex tumour microenvironment of HCC, an efficient biomarker for immunotherapy has yet to be identified. We investigated the role of immune-related long non-coding RNAs (lncRNAs) as prognostic biomarkers in patients with HCC from The Cancer Genome Atlas (TCGA) database. Spearman correlation, univariate and multivariate Cox, and lasso regression analyses were utilised to screen lncRNAs associated with prognosis. Four lncRNAs were filtered out to develop an immune-associated lncRNA prognostic signature in TCGA training as well as validation cohorts. Patients with HCC were then categorised into low- and high-risk groups according to the median value of the risk scores to evaluate the ability of the prognostic model between training and validation cohorts. A nomogram (based on risk score and stage) was constructed to appraise the general overall survival (OS) of patients with HCC. Differences in immune cell infiltration, immune checkpoint inhibitor (ICI) treatment response, gene mutation, and drug sensitivity were observed between the two groups. Thus, the lncRNA prognostic signature can serve as a sensitive prognostic biomarker with potential in individualised immunotherapy for HCC patients.
Collapse
Affiliation(s)
- Rui Li
- grid.33199.310000 0004 0368 7223Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei China
| | - Chen Jin
- grid.268099.c0000 0001 0348 3990Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, Zhejiang China
| | - Weiheng Zhao
- grid.33199.310000 0004 0368 7223Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei China
| | - Rui Liang
- grid.190737.b0000 0001 0154 0904Biological Engineering Academy, Chongqing University, Chongqing, China
| | - Huihua Xiong
- grid.33199.310000 0004 0368 7223Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei China
| |
Collapse
|
|
50
|
LINC01468 drives NAFLD-HCC progression through CUL4A-linked degradation of SHIP2. Cell Death Dis 2022; 8:449. [DOI: 10.1038/s41420-022-01234-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 10/19/2022] [Accepted: 10/20/2022] [Indexed: 11/09/2022]
Abstract
AbstractAccumulating evidence suggests that long noncoding RNAs (lncRNAs) are deregulated in hepatocellular carcinoma (HCC) and play a role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the current understanding of the role of lncRNAs in NAFLD-associated HCC is limited. In this study, transcriptomic profiling analysis of three paired human liver samples from patients with NAFLD-driven HCC and adjacent samples showed that LINC01468 expression was significantly upregulated. In vitro and in vivo gain- and loss-of-function experiments showed that LINC01468 promotes the proliferation of HCC cells through lipogenesis. Mechanistically, LINC01468 binds SHIP2 and promotes cullin 4 A (CUL4A)-linked ubiquitin degradation, thereby activating the PI3K/AKT/mTOR signaling pathway, resulting in the promotion of de novo lipid biosynthesis and HCC progression. Importantly, the SHIP2 inhibitor reversed the sorafenib resistance induced by LINC01468 overexpression. Moreover, ALKBH5-mediated N6-methyladenosine (m6A) modification led to stabilization and upregulation of LINC01468 RNA. Taken together, the findings indicated a novel mechanism by which LINC01468-mediated lipogenesis promotes HCC progression through CUL4A-linked degradation of SHIP2. LINC01468 acts as a driver of HCC progression from NAFLD, highlights the potential of the LINC01468-SHIP2 axis as a therapeutic target for HCC.
Collapse
|