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1
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Li X, Kong D, Hu W, Zheng K, You H, Tang R, Kong F. Insight into the mechanisms regulating liver cancer stem cells by hepatitis B virus X protein. Infect Agent Cancer 2024; 19:56. [PMID: 39529119 PMCID: PMC11555838 DOI: 10.1186/s13027-024-00618-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous disease with high recurrence and mortality. It is well known that a large proportion of HCCs are caused by hepatitis B virus (HBV) infection. In particular, the HBV X protein (HBX), a multifunctional molecule produced by the virus, plays a leading role in hepatocarcinogenesis. However, the molecular mechanisms underlying HBX-mediated HCC remain not fully elucidated. Recently, liver cancer stem cells (LCSCs), a unique heterogeneous subpopulation of the malignancy, have received particular attention owing to their close association with tumorigenesis. Especially, the modulation of LCSCs by HBX by upregulating CD133, CD44, EpCAM, and CD90 plays a significant role in HBV-related HCC development. More importantly, not only multiple signaling pathways, including Wnt/β-catenin signaling, transforming growth factor-β (TGF-β) signaling, phosphatidylinositol-3-kinase (PI-3 K)/AKT signaling, and STAT3 signaling pathways, but also epigenetic regulation, such as DNA and histone methylation, and noncoding RNAs, including lncRNA and microRNA, are discovered to participate in regulating LCSCs mediated by HBX. Here, we summarized the mechanisms underlying different signaling pathways and epigenetic alterations that contribute to the modulation of HBX-induced LCSCs to facilitate hepatocarcinogenesis. Because LCSCs are important in hepatic carcinogenesis, understanding the regulatory factors controlled by HBX might open new avenues for HBV-associated liver cancer treatment.
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Affiliation(s)
- Xiaocui Li
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Delong Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
- Experimental Animal Center, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Wei Hu
- NanJing Drum Tower Hospital Group Suqian Hospital, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, China
| | - Kuiyang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Hongjuan You
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China.
| | - Fanyun Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
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2
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Cai Y, Li L, Shao C, Chen Y, Wang Z. Therapeutic Strategies for Angiogenesis Based on Endothelial Cell Epigenetics. J Cardiovasc Transl Res 2024; 17:816-827. [PMID: 38294628 DOI: 10.1007/s12265-024-10485-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 01/17/2024] [Indexed: 02/01/2024]
Abstract
With the in-depth investigation of various diseases, angiogenesis has gained increasing attention. Among the contributing factors to angiogenesis research, endothelial epigenetics has emerged as an influential player. Endothelial epigenetic therapy exerts its regulatory effects on endothelial cells by controlling gene expression, RNA, and histone modification within these cells, which subsequently promotes or inhibits angiogenesis. As a result, this therapeutic approach offers potential strategies for disease treatment. The purpose of this review is to outline the pertinent mechanisms of endothelial cell epigenetics, encompassing glycolysis, lactation, amino acid metabolism, non-coding RNA, DNA methylation, histone modification, and their connections to specific diseases and clinical applications. We firmly believe that endothelial cell epigenetics has the potential to become an integral component of precision medicine therapy, unveiling novel therapeutic targets and providing new directions and opportunities for disease treatment.
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Affiliation(s)
- Yue Cai
- Department of Cardiology, Affiliated Hospital of Jiangsu University, No. 438 Jiefang Road, Jingkou District, Zhenjiang, 212000, Jiangsu Province, China
| | - Lihua Li
- Department of Pathology, Affiliated Hospital of Jiangsu University, No. 438 Jiefang Road, Jingkou District, Zhenjiang, 212000, Jiangsu Province, China
| | - Chen Shao
- Department of Cardiology, Affiliated Hospital of Jiangsu University, No. 438 Jiefang Road, Jingkou District, Zhenjiang, 212000, Jiangsu Province, China
| | - Yiliu Chen
- Department of Cardiology, Affiliated Hospital of Jiangsu University, No. 438 Jiefang Road, Jingkou District, Zhenjiang, 212000, Jiangsu Province, China
| | - Zhongqun Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, No. 438 Jiefang Road, Jingkou District, Zhenjiang, 212000, Jiangsu Province, China.
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3
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Hussain MS, Moglad E, Afzal M, Gupta G, Hassan Almalki W, Kazmi I, Alzarea SI, Kukreti N, Gupta S, Kumar D, Chellappan DK, Singh SK, Dua K. Non-coding RNA mediated regulation of PI3K/Akt pathway in hepatocellular carcinoma: Therapeutic perspectives. Pathol Res Pract 2024; 258:155303. [PMID: 38728793 DOI: 10.1016/j.prp.2024.155303] [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: 03/04/2024] [Revised: 04/07/2024] [Accepted: 04/08/2024] [Indexed: 05/12/2024]
Abstract
Hepatocellular carcinoma (HCC) is among the primary reasons for fatalities caused by cancer globally, highlighting the need for comprehensive knowledge of its molecular aetiology to develop successful treatment approaches. The PI3K/Akt system is essential in the course of HCC, rendering it an intriguing candidate for treatment. Non-coding RNAs (ncRNAs), such as long ncRNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are important mediators of the PI3K/Akt network in HCC. The article delves into the complex regulatory functions of ncRNAs in influencing the PI3K/Akt system in HCC. The study explores how lncRNAs, miRNAs, and circRNAs impact the expression as well as the function of the PI3K/Akt network, either supporting or preventing HCC growth. Additionally, treatment strategies focusing on ncRNAs in HCC are examined, such as antisense oligonucleotide-based methods, RNA interference, and small molecule inhibitor technologies. Emphasizing the necessity of ensuring safety and effectiveness in clinical settings, limitations, and future approaches in using ncRNAs as therapies for HCC are underlined. The present study offers useful insights into the complex regulation system of ncRNAs and the PI3K/Akt cascade in HCC, suggesting possible opportunities for developing innovative treatment approaches to address this lethal tumor.
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Affiliation(s)
- Md Sadique Hussain
- School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, Jaipur, Rajasthan 302017, India
| | - Ehssan Moglad
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj 11942, Saudi Arabia
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Gaurav Gupta
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India; Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates.
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, 21589, Jeddah, Saudi Arabia
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, 72341, Sakaka, Aljouf, Saudi Arabia
| | - Neelima Kukreti
- School of Pharmacy, Graphic Era Hill University, Dehradun 248007, India
| | - Saurabh Gupta
- Chameli Devi Institute of Pharmacy, Department of Pharmacology, Khandwa Road, Village Umrikheda, Near Toll Booth, Indore, Madhya Pradesh 452020, India
| | - Dinesh Kumar
- School of Pharmacy, Chitkara University, Himachal Pradesh, India
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, Australia; School of Medical and Life Sciences, Sunway University, 47500 Sunway City, Malaysia
| | - Kamal Dua
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia; Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India.
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4
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Agustiningsih A, Rasyak MR, Turyadi, Jayanti S, Sukowati C. The oncogenic role of hepatitis B virus X gene in hepatocarcinogenesis: recent updates. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:120-134. [PMID: 38464387 PMCID: PMC10918233 DOI: 10.37349/etat.2024.00209] [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: 09/15/2023] [Accepted: 11/21/2023] [Indexed: 03/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancers with high mortality rate. Among its various etiological factors, one of the major risk factors for HCC is a chronic infection of hepatitis B virus (HBV). HBV X protein (HBx) has been identified to play an important role in the HBV-induced HCC pathogenesis since it may interfere with several key regulators of many cellular processes. HBx localization within the cells may be beneficial to HBx multiple functions at different phases of HBV infection and associated hepatocarcinogenesis. HBx as a regulatory protein modulates cellular transcription, molecular signal transduction, cell cycle, apoptosis, autophagy, protein degradation pathways, and host genetic stability via interaction with various factors, including its association with various non-coding RNAs. A better understanding on the regulatory mechanism of HBx on various characteristics of HCC would provide an overall picture of HBV-associated HCC. This article addresses recent data on HBx role in the HBV-associated hepatocarcinogenesis.
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Affiliation(s)
- Agustiningsih Agustiningsih
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia
| | - Muhammad Rezki Rasyak
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia
- Post Graduate School, Faculty of Medicine, Universitas Hasanuddin, Makassar 90245, Indonesia
| | - Turyadi
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia
| | - Sri Jayanti
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia
| | - Caecilia Sukowati
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia
- Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, AREA Science Park, Basovizza, 34149 Trieste, Italy
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Ji YL, Kang K, Lv QL, Wang DP. Roles of lncRNA-MALAT1 in the Progression and Prognosis of Gliomas. Mini Rev Med Chem 2024; 24:786-792. [PMID: 37859309 DOI: 10.2174/0113895575253875230922055711] [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: 03/30/2023] [Revised: 08/10/2023] [Accepted: 08/10/2023] [Indexed: 10/21/2023]
Abstract
Long noncoding RNAs (lncRNAs) represent a large subgroup of RNA transcripts that lack the function of coding proteins and may be essential universal genes involved in carcinogenesis and metastasis. LncRNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNAMALAT1) is overexpressed in various human tumors, including gliomas. However, the biological function and molecular mechanism of action of lncRNA-MALAT1 in gliomas have not yet been systematically elucidated. Accumulating evidence suggests that the abnormal expression of lncRNA-MALAT1 in gliomas is associated with various physical properties of the glioma, such as tumor growth, metastasis, apoptosis, drug resistance, and prognosis. Furthermore, lncRNAs, as tumor progression and prognostic markers in gliomas, may affect tumorigenesis, proliferation of glioma stem cells, and drug resistance. In this review, we summarize the knowledge on the biological functions and prognostic value of lncRNA-MALAT1 in gliomas. This mini-review aims to deepen the understanding of lncRNA-MALAT1 as a novel potential therapeutic target for the individualized precision treatment of gliomas.
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Affiliation(s)
- Yu-Long Ji
- Department of Radiation Oncology, Jiangxi Key Laboratory of Translational Cancer Research, Jiangxi Cancer Hospital, Jiangxi Province, China
| | - Kai Kang
- School of Public Health, Fudan University, Shanghai, 200032, China
- Department of Research and Surveillance Evaluation, Shanghai Municipal Center for Health Promotion, Shanghai, 200040, China
| | - Qiao-Li Lv
- Department of Radiation Oncology, Jiangxi Key Laboratory of Translational Cancer Research, Jiangxi Cancer Hospital, Jiangxi Province, China
| | - Da-Peng Wang
- Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Hu Y, He Y, Luo N, Li X, Guo L, Zhang K. A feedback loop between lncRNA MALAT1 and DNMT1 promotes triple-negative breast cancer stemness and tumorigenesis. Cancer Biol Ther 2023; 24:2235768. [PMID: 37548553 PMCID: PMC10408694 DOI: 10.1080/15384047.2023.2235768] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 09/23/2022] [Accepted: 06/28/2023] [Indexed: 08/08/2023] Open
Abstract
BACKGROUND The function of long non-coding RNA (lncRNA) MALAT1 in regulating triple-negative breast cancer (TNBC) stemness and tumorigenesis was investigated. METHODS Sphere formation and colony formation assays coupled with flow cytometry were employed to evaluate the percentage of CD44high/CD44low cells, and ALDH+ cells were performed to evaluate the stemness. Bisulfite sequencing PCR (BSP) was employed to detect the methylation level of MALAT1. Tumor xenograft experiment was performed to evaluate tumorigenesis in vivo. Finally, dual-luciferase reporter and RIP assays were employed to verify the binding relationship between MALAT1 and miR-137. RESULTS Our results revealed that MALAT1 and BCL11A were highly expressed in TNBC, while miR-137 and DNMT1 were lowly expressed. Our results proved that MALAT1 positively regulated BCL11A expression through targeting miR-137. Functional experiments revealed that MALAT1 inhibited DNMT1 expression through acting on the miR-137/BCL11A pathway to enhance TNBC stemness and tumorigenesis. We also found that high MALAT1 expression in TNBC was related to the DNMT1-mediated hypomethylation of MALAT1. As expected, DNMT1 overexpression could remarkably inhibit TNBC stemness and tumorigenesis, which was eliminated by MALAT1 overexpression. CONCLUSION MALAT1 downregulated DNMT1 by miR-137/BCL11A pathway to enhance TNBC stemness and tumorigenesis; meanwhile, DNMT1/MALAT1 formed a positive feedback loop to continuously promote TNBC malignant behaviors.
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Affiliation(s)
- Yu Hu
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China
- Department of General Surgery, Xiangya Hospital, Central South University, Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan Province, P.R. China
| | - Yuqiong He
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China
- Department of General Surgery, Xiangya Hospital, Central South University, Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan Province, P.R. China
| | - Na Luo
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China
- Department of General Surgery, Xiangya Hospital, Central South University, Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan Province, P.R. China
| | - Xin Li
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China
- Department of General Surgery, Xiangya Hospital, Central South University, Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan Province, P.R. China
| | - Lei Guo
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China
- Department of General Surgery, Xiangya Hospital, Central South University, Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan Province, P.R. China
| | - Kejing Zhang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China
- Department of General Surgery, Xiangya Hospital, Central South University, Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan Province, P.R. China
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7
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Kalantari L, Ghotbabadi ZR, Gholipour A, Ehymayed HM, Najafiyan B, Amirlou P, Yasamineh S, Gholizadeh O, Emtiazi N. A state-of-the-art review on the NRF2 in Hepatitis virus-associated liver cancer. Cell Commun Signal 2023; 21:318. [PMID: 37946175 PMCID: PMC10633941 DOI: 10.1186/s12964-023-01351-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 10/09/2023] [Indexed: 11/12/2023] Open
Abstract
According to a paper released and submitted to WHO by IARC scientists, there would be 905,700 new cases of liver cancer diagnosed globally in 2020, with 830,200 deaths expected as a direct result. Hepatitis B virus (HBV) hepatitis C virus (HCV), and hepatitis D virus (HDV) all play critical roles in the pathogenesis of hepatocellular carcinoma (HCC), despite the rising prevalence of HCC due to non-infectious causes. Liver cirrhosis and HCC are devastating consequences of HBV and HCV infections, which are widespread worldwide. Associated with a high mortality rate, these infections cause about 1.3 million deaths annually and are the primary cause of HCC globally. In addition to causing insertional mutations due to viral gene integration, epigenetic alterations and inducing chronic immunological dysfunction are all methods by which these viruses turn hepatocytes into cancerous ones. While expanding our knowledge of the illness, identifying these pathways also give possibilities for novel diagnostic and treatment methods. Nuclear factor erythroid 2-related factor 2 (NRF2) activation is gaining popularity as a treatment option for oxidative stress (OS), inflammation, and metabolic abnormalities. Numerous studies have shown that elevated Nrf2 expression is linked to HCC, providing more evidence that Nrf2 is a critical factor in HCC. This aberrant Nrf2 signaling drives cell proliferation, initiates angiogenesis and invasion, and imparts drug resistance. As a result, this master regulator may be a promising treatment target for HCC. In addition, the activation of Nrf2 is a common viral effect that contributes to the pathogenesis, development, and chronicity of virus infection. However, certain viruses suppress Nrf2 activity, which is helpful to the virus in maintaining cellular homeostasis. In this paper, we discussed the influence of Nrf2 deregulation on the viral life cycle and the pathogenesis associated with HBV and HCV. We summed up the mechanisms for the modulation of Nrf2 that are deregulated by these viruses. Moreover, we describe the molecular mechanism by which Nrf2 is modulated in liver cancer, liver cancer stem cells (LCSCs), and liver cancer caused by HBV and HCV. Video Abstract.
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Affiliation(s)
- Leila Kalantari
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Arsalan Gholipour
- Nanotechnology Research Institute, School of Chemical Engineering, Babol Noshirvani University of Technology, Babol, Iran
| | | | - Behnam Najafiyan
- Faculty of Pharmacy, Shiraz University of Medical Science, Shiraz, Iran
| | - Parsa Amirlou
- Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | | | - Nikoo Emtiazi
- Department of Pathology, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran.
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Faghihkhorasani A, Dalvand A, Derafsh E, Tavakoli F, Younis NK, Yasamineh S, Gholizadeh O, Shokri P. The role of oncolytic virotherapy and viral oncogenes in the cancer stem cells: a review of virus in cancer stem cells. Cancer Cell Int 2023; 23:250. [PMID: 37880659 PMCID: PMC10599042 DOI: 10.1186/s12935-023-03099-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 10/13/2023] [Indexed: 10/27/2023] Open
Abstract
Cancer Stem Cells (CSCs) are the main "seeds" for the initiation, growth, metastasis, and recurrence of tumors. According to many studies, several viral infections, including the human papillomaviruses, hepatitis B virus, Epstein-Barr virus, and hepatitis C virus, promote the aggressiveness of cancer by encouraging the development of CSC features. Therefore, a better method for the targeted elimination of CSCs and knowledge of their regulatory mechanisms in human carcinogenesis may lead to the development of a future tool for the management and treatment of cancer. Oncolytic viruses (OVs), which include the herpes virus, adenovirus, vaccinia, and reovirus, are also a new class of cancer therapeutics that have favorable properties such as selective replication in tumor cells, delivery of numerous eukaryotic transgene payloads, induction of immunogenic cell death and promotion of antitumor immunity, as well as a tolerable safety profile that essentially differs from that of other cancer therapeutics. The effects of viral infection on the development of CSCs and the suppression of CSCs by OV therapy were examined in this paper. The purpose of this review is to investigate the dual role of viruses in CSCs (oncolytic virotherapy and viral oncogenes).
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Affiliation(s)
| | - Alaleh Dalvand
- Tehran Medical Branch, Islamic Azad University of Medical Sciences, Tehran, Iran
| | - Ehsan Derafsh
- Department of Basic Medical Science, Windsor University School of Medicine, Brighton's Estate, Cayton, St. Kitts And Nevis
| | - Farnaz Tavakoli
- Nephrology and Transplantation Ward, Shariati Hospital Tehran University of Medical Sciences, Tehran, Iran
| | | | - Saman Yasamineh
- Young Researchers and Elite Club, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | | | - Pooria Shokri
- Department of Medical Science, Faculty of Medical Science, Arak University of Medical Sciences, Arak, Iran.
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Zhang MH, Yuan YF, Liu LJ, Wei YX, Yin WY, Zheng LZY, Tang YY, Lv Z, Zhu F. Dysregulated microRNAs as a biomarker for diagnosis and prognosis of hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol 2023; 29:4706-4735. [PMID: 37664153 PMCID: PMC10473924 DOI: 10.3748/wjg.v29.i31.4706] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/29/2023] [Accepted: 08/01/2023] [Indexed: 08/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with a high incidence and fatality rate worldwide. Hepatitis B virus (HBV) infection is one of the most important risk factors for its occurrence and development. Early detection of HBV-associated HCC (HBV-HCC) can improve clinical decision-making and patient outcomes. Biomarkers are extremely helpful, not only for early diagnosis, but also for the development of therapeutics. MicroRNAs (miRNAs), a subset of non-coding RNAs approximately 22 nucleotides in length, have increasingly attracted scientists' attention due to their potential utility as biomarkers for cancer detection and therapy. HBV profoundly impacts the expression of miRNAs potentially involved in the development of hepatocarcinogenesis. In this review, we summarize the current progress on the role of miRNAs in the diagnosis and treatment of HBV-HCC. From a molecular standpoint, we discuss the mechanism by which HBV regulates miRNAs and investigate the exact effect of miRNAs on the promotion of HCC. In the near future, miRNA-based diagnostic, prognostic, and therapeutic applications will make their way into the clinical routine.
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Affiliation(s)
- Ming-He Zhang
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Feng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li-Juan Liu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Xin Wei
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Wan-Yue Yin
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Lan-Zhuo-Yin Zheng
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ying-Ying Tang
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhao Lv
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan 430071, Hubei Province, China
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10
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Liu M, Yu Z, Zhao Z, Yang F, Zhou M, Wang C, Tian X, Zhang B, Liang G, Liu X, Shao J. MiR-24-3p/Dio3 axis is essential for BDE47 to induce local thyroid hormone disorder and neurotoxicity. Toxicology 2023; 491:153527. [PMID: 37116683 DOI: 10.1016/j.tox.2023.153527] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/21/2023] [Accepted: 04/25/2023] [Indexed: 04/30/2023]
Abstract
BDE47 (2,2,4,4-tetrabromodiphenyl ether) is a member of the most important congeners of polybrominated diphenyl ethers (PBDEs) and has been identified as a developmental, reproductive and nervous system toxicant and endocrine system disruptor due to its frequent detection in human tissue and environmental samples. Our preliminary work suggested that high- and low-level of bromodiphenyl ethers have different effects on neuronal cells with differential targets of actions on neural tissues. In this study, we presented the underlying mechanism of BDE47 neurotoxicity from the perspective of thyroid hormone (TH) metabolism using in vitro model of human SK-N-AS neuronal cells. BDE47 could induce local TH metabolism disorder in neuronal cells by inhibiting the expression of the main enzyme, human type III iodothyronine deiodinase (Dio3). Further elucidation revealed that BDE47 effectively up-regulating miR-24-3p, which binds to the 3'-UTR of Dio3 and inhibits its expression. In addition, BDE47 could also inhibit the deiodinase activity of Dio3. Collectively, our study demonstrates the molecular mechanism of BDE47 regulating Dio3-induced TH metabolism disorder through inducing miR-24-3p, providing new clues for the role of miRNAs in neurodevelopmental toxicity mediated by environmental pollutants.
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Affiliation(s)
- Min Liu
- Department of Environmental Health and Toxicology, School of Public Health, Dalian Medical University, Dalian, 116044, China; Neurology Department, Dalian University Affiliated Xinhua Hospital, Dalian, 116021, China
| | - Zhenlong Yu
- College of Pharmacy, Dalian Medical University, Dalian, 116044, China
| | - Zikuang Zhao
- School of Pharmacy, Hangzhou Normal University, Hangzhou, 116000, China
| | - Fangyu Yang
- General Hospital of Northern Theater Command (General Hospital of Shenyang Military Command), Department of Neurosurgery, Shenyang, China
| | - Meirong Zhou
- College of Pharmacy, Dalian Medical University, Dalian, 116044, China
| | - Chao Wang
- College of Pharmacy, Dalian Medical University, Dalian, 116044, China
| | - Xiangge Tian
- College of Pharmacy, Dalian Medical University, Dalian, 116044, China
| | - Baojing Zhang
- College of Pharmacy, Dalian Medical University, Dalian, 116044, China
| | - Guobiao Liang
- General Hospital of Northern Theater Command (General Hospital of Shenyang Military Command), Department of Neurosurgery, Shenyang, China.
| | - Xiaohui Liu
- Department of Environmental Health and Toxicology, School of Public Health, Dalian Medical University, Dalian, 116044, China
| | - Jing Shao
- Department of Environmental Health and Toxicology, School of Public Health, Dalian Medical University, Dalian, 116044, China; Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine; Liaoning Medical Center for Hematopoietic Stem Cell Transplantation; Dalian Key Laboratory of Hematology; Diamond Bay Institute of Hematology; Second Hospital of Dalian Medical University, Dalian, 116027, China.
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11
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Liao X, Chen J, Luo D, Luo B, Huang W, Xie W. Prognostic value of long non-coding RNA MALAT1 in hepatocellular carcinoma: A study based on multi-omics analysis and RT-PCR validation. Pathol Oncol Res 2023; 28:1610808. [PMID: 36685103 PMCID: PMC9845286 DOI: 10.3389/pore.2022.1610808] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 12/16/2022] [Indexed: 01/06/2023]
Abstract
Background: This study aimed to explore the relationship between MALAT1 and the prognosis of patients with hepatocellular carcinoma (HCC). Methods: We constructed a MALAT1 protein-protein interaction network using the STRING database and a network of competing endogenous RNAs (ceRNAs) using the StarBase database. Using data from the GEPIA2 database, we studied the association between genes in these networks and survival of patients with HCC. The potential mechanisms underlying the relationship between MALAT1 and HCC prognosis were studied using combined data from RNA sequencing, DNA methylation, and somatic mutation data from The Cancer Genome Atlas (TCGA) liver cancer cohort. Tumor tissues and 19 paired adjacent non-tumor tissues (PANTs) from HCC patients who underwent radical resection were analyzed for MALAT1 mRNA levels using real-time PCR, and associations of MALAT1 expression with clinicopathological features or prognosis of patients were analyzed using log-rank test and Gehan-Breslow-Wilcoxon test. Results: Five interacting proteins and five target genes of MALAT1 in the ceRNA network significantly correlated with poor survival of patients with HCC (p < 0.05). High MALAT1 expression was associated with mutations in two genes leading to poor prognosis and may upregulate some prognostic risk genes through methylation. MALAT1 was significantly co-expressed with various signatures of genes involved in HCC progression, including the cell cycle, DNA damage repair, mismatch repair, homologous recombination, molecular cancer m6A, exosome, ferroptosis, infiltration of lymphocyte (p < 0.05). The expression of MALAT1 was markedly upregulated in HCC tissues compared with PANTs. In Kaplan-Meier analysis, patients with high MALAT1 expression had significantly shorter progression-free survival (PFS) (p = 0.033) and overall survival (OS) (p = 0.023) than those with low MALAT1 expression. Median PFS was 19.2 months for patients with high MALAT1 expression and 52.8 months for patients with low expression, while the corresponding median OS was 40.5 and 78.3 months. In subgroup analysis of patients with vascular invasion, cirrhosis, and HBsAg positive or AFP positive, MALAT1 overexpression was significantly associated with shorter PFS and OS. Models for predicting PFS and OS constructed based on MALAT1 expression and clinicopathological features had moderate predictive power, with areas under the receiver operating characteristic curves of 0.661-0.731. Additionally, MALAT1 expression level was significantly associated with liver cirrhosis, vascular invasion, and tumor capsular infiltration (p < 0.05 for all). Conclusion: MALAT1 is overexpressed in HCC, and higher expression is associated with worse prognosis. MALAT1 mRNA level may serve as a prognostic marker for patients with HCC after hepatectomy.
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Affiliation(s)
- Xiaoli Liao
- Department of Chemotherapy, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Junming Chen
- Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou, China
| | - DongCheng Luo
- Department of Chemotherapy, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Baohua Luo
- Department of Gastroenterology, Jiangbin Hospital, Nanning, China
| | - Wenfeng Huang
- Department of Medical Oncology, Second Affiliated Hospital of Guangxi Medical University, Nanning, China,*Correspondence: Wenfeng Huang, ; Weimin Xie,
| | - Weimin Xie
- Department of Chemotherapy, Guangxi Medical University Cancer Hospital, Nanning, China,*Correspondence: Wenfeng Huang, ; Weimin Xie,
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12
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Sarfaraz N, Somarowthu S, Bouchard MJ. The interplay of long noncoding RNAs and hepatitis B virus. J Med Virol 2023; 95:e28058. [PMID: 35946066 DOI: 10.1002/jmv.28058] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 08/01/2022] [Accepted: 08/08/2022] [Indexed: 01/11/2023]
Abstract
Hepatitis B Virus (HBV) infections remain a major global health burden with an estimated 296 million people living with a chronic infection and 884,000 HBV-related deaths annually. Notably, patients with a chronic hepatitis B (CHB) infection are at a 30-fold greater risk of developing hepatocellular carcinoma (HCC), the most common type of primary liver cancer, which is the 3rd deadliest cancer worldwide. Several groups have assessed HBV-related aberrant expression of host-cell long noncoding RNAs (lncRNAs) and how altered expression of specific lncRNAs affects HBV replication and progression to associated disease states. Given the challenges in establishing effective HBV models and analyzing transcriptomic data, this review focuses on lncRNA expression data primarily collected from clinical patient samples and primary human hepatocytes, with the subsequent mechanism of action analysis in cell lines or other model systems. Ultimately, understanding HBV-induced lncRNA-expression dysregulation could lead to new treatments and biomarkers for HBV infection and its associated diseases.
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Affiliation(s)
- Nima Sarfaraz
- Graduate Program in Molecular and Cell Biology and Genetics, Graduate School of Biomedical Sciences and Professional Studies, College of Medicine, Drexel University, Philadelphia, Pennsylvania, USA
| | - Srinivas Somarowthu
- Department of Biochemistry and Molecular Biology, College of Medicine, Drexel University, Philadelphia, Pennsylvania, USA
| | - Michael J Bouchard
- Department of Biochemistry and Molecular Biology, College of Medicine, Drexel University, Philadelphia, Pennsylvania, USA
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13
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Niu ZS, Wang WH, Niu XJ. Recent progress in molecular mechanisms of postoperative recurrence and metastasis of hepatocellular carcinoma. World J Gastroenterol 2022; 28:6433-6477. [PMID: 36569275 PMCID: PMC9782839 DOI: 10.3748/wjg.v28.i46.6433] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 10/31/2022] [Accepted: 11/21/2022] [Indexed: 12/08/2022] Open
Abstract
Hepatectomy is currently considered the most effective option for treating patients with early and intermediate hepatocellular carcinoma (HCC). Unfortunately, the postoperative prognosis of patients with HCC remains unsatisfactory, predominantly because of high postoperative metastasis and recurrence rates. Therefore, research on the molecular mechanisms of postoperative HCC metastasis and recurrence will help develop effective intervention measures to prevent or delay HCC metastasis and recurrence and to improve the long-term survival of HCC patients. Herein, we review the latest research progress on the molecular mechanisms underlying postoperative HCC metastasis and recurrence to lay a foundation for improving the understanding of HCC metastasis and recurrence and for developing more precise prevention and intervention strategies.
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Affiliation(s)
- Zhao-Shan Niu
- Laboratory of Micromorphology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Wen-Hong Wang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Xiao-Jun Niu
- Department of Internal Medicine, Qingdao Shibei District People's Hospital, Qingdao 266033, Shandong Province, China
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14
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Braga EA, Fridman MV, Burdennyy AM, Filippova EA, Loginov VI, Pronina IV, Dmitriev AA, Kushlinskii NE. Regulation of the Key Epithelial Cancer Suppressor miR-124 Function by Competing Endogenous RNAs. Int J Mol Sci 2022; 23:13620. [PMID: 36362406 PMCID: PMC9655303 DOI: 10.3390/ijms232113620] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 10/31/2022] [Accepted: 11/02/2022] [Indexed: 12/01/2023] Open
Abstract
A decrease in the miR-124 expression was observed in various epithelial cancers. Like a classical suppressor, miR-124 can inhibit the translation of multiple oncogenic proteins. Epigenetic mechanisms play a significant role in the regulation of miR-124 expression and involve hypermethylation of the MIR-124-1/-2/-3 genes and the effects of long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) according to the model of competing endogenous RNAs (ceRNAs). More than 40 interactomes (lncRNA/miR-124/mRNA) based on competition between lncRNAs and mRNAs for miR-124 binding have been identified in various epithelial cancers. LncRNAs MALAT1, NEAT1, HOXA11-AS, and XIST are the most represented in these axes. Fourteen axes (e.g., SND1-IT1/miR-124/COL4A1) are involved in EMT and/or metastasis. Moreover, eight axes (e.g., OIP5-AS1/miR-124-5p/IDH2) are involved in key pathways, such as Wnt/b-catenin, E2F1, TGF-β, SMAD, ERK/MAPK, HIF-1α, Notch, PI3K/Akt signaling, and cancer cell stemness. Additionally, 15 axes impaired patient survival and three axes reduced chemo- or radiosensitivity. To date, 14 cases of miR-124 regulation by circRNAs have been identified. Half of them involve circHIPK3, which belongs to the exonic ecircRNAs and stimulates cell proliferation, EMT, autophagy, angiogenesis, and multidrug resistance. Thus, miR-124 and its interacting partners may be considered promising targets for cancer therapy.
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Affiliation(s)
- Eleonora A. Braga
- Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia
- Research Centre for Medical Genetics, 115522 Moscow, Russia
| | - Marina V. Fridman
- Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991 Moscow, Russia
| | | | - Elena A. Filippova
- Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia
| | - Vitaly I. Loginov
- Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia
- Research Centre for Medical Genetics, 115522 Moscow, Russia
| | - Irina V. Pronina
- Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia
| | - Alexey A. Dmitriev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
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15
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Sonawala K, Ramalingam S, Sellamuthu I. Influence of Long Non-Coding RNA in the Regulation of Cancer Stem Cell Signaling Pathways. Cells 2022; 11:3492. [PMID: 36359888 PMCID: PMC9656902 DOI: 10.3390/cells11213492] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/01/2022] [Accepted: 11/02/2022] [Indexed: 08/03/2023] Open
Abstract
Over the past two decades, cancer stem cells (CSCs) have emerged as an immensely studied and experimental topic, however a wide range of questions concerning the topic still remain unanswered; in particular, the mechanisms underlying the regulation of tumor stem cells and their characteristics. Understanding the cancer stem-cell signaling pathways may pave the way towards a better comprehension of these mechanisms. Signaling pathways such as WNT, STAT, Hedgehog, NOTCH, PI3K/AKT/mTOR, TGF-β, and NF-κB are responsible not only for modulating various features of CSCs but also their microenvironments. Recently, the prominent roles of various non-coding RNAs such as small non-coding RNAs (sncRNAs) and long non-coding RNAs (lncRNAs) in developing and enhancing the tumor phenotypes have been unfolded. This review attempts to shed light on understanding the influence of long non- coding RNAs in the modulation of various CSC-signaling pathways and its impact on the CSCs and tumor properties; highlighting the protagonistic and antagonistic roles of lncRNAs.
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Affiliation(s)
| | | | - Iyappan Sellamuthu
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chennai 603202, India
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16
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Yang L, Zou T, Chen Y, Zhao Y, Wu X, Li M, Du F, Chen Y, Xiao Z, Shen J. Hepatitis B virus X protein mediated epigenetic alterations in the pathogenesis of hepatocellular carcinoma. Hepatol Int 2022; 16:741-754. [PMID: 35648301 DOI: 10.1007/s12072-022-10351-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 04/25/2022] [Indexed: 12/13/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is a worldwide health problem. Hepatitis B virus X protein (HBx), a pleiotropic regulatory protein encoded by HBV, is necessary for the transcription of HBV covalently closed circular DNA (cccDNA) minichromosomes, and affects the epigenetic regulation of host cells. The epigenetic reprogramming of HBx on host cell genome is strongly involved in HBV-related HCC carcinogenesis. Here, we review the latest findings of the epigenetic regulation induced by HBx protein in hepatocellular carcinoma (HCC), including DNA methylation, histone modification and non-coding RNA expression. The influence of HBx on the epigenetic regulation of cccDNA is also summarized. In addition, preliminary studies of targeted drugs for epigenetic changes induced by HBx are also discussed. The exploration of epigenetic markers as potential targets will help to develop new prevention and/or treatment methods for HBx-related HCC.
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Affiliation(s)
- Liqiong Yang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Tao Zou
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Yao Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China.
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China.
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China.
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China.
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China.
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China.
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17
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Zahra K, Shabbir M, Badshah Y, Trembley JH, Badar Z, Khan K, Afsar T, Almajwal A, Alruwaili NW, Razak S. Determining KLF14 tertiary structure and diagnostic significance in brain cancer progression. Sci Rep 2022; 12:8039. [PMID: 35577881 PMCID: PMC9110742 DOI: 10.1038/s41598-022-12072-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 05/03/2022] [Indexed: 12/14/2022] Open
Abstract
Expression analysis of new protein targets may play a crucial role in the early detection and diagnosis of brain tumor progression. The study aimed to investigate the possible relation of KLF14, TPD52, miR-124, and PKCε in the development and progression of brain cancer and space occupying lesion (SOL) of the brain. One hundred human blood samples comprising varying diagnostic groups (SOL brain, grade I, II, III, IV) were analyzed by real-time quantitative PCR to determine the expression level of KLF14, TPD52, miR-124, and PKCε. TPD52 and PKCε were upregulated in brain cancer by 2.5- and 1.6-fold, respectively, whereas, KLF14 and miR-124 were downregulated in brain cancer. In metastatic and high-grade brain cancer, TPD52 and PKCε expression were up-regulated and KLF14 and miR-124 expression were down-regulated. Further, these genes were found to be differentially expressed in the blood of patients with SOL. Upregulation of TPD52 and PKCε, however, reduced expression of KLF14 and miR-124 in SOL of the brain as compared to healthy controls. Expression analysis of TPD52, KLF14, miR-124, and PKCε provided useful information on the differences existing between the normal brain and SOL, in addition to gliomas; thus, might prove to be useful having diagnostic or prognostic value.
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Affiliation(s)
- Kainat Zahra
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Maria Shabbir
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan.
| | - Yasmin Badshah
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Janeen H Trembley
- Minneapolis VA Health Care System Research Service, Minneapolis, MN, USA
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Zunaira Badar
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Khushbukhat Khan
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Tayyaba Afsar
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Ali Almajwal
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Nawaf W Alruwaili
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Suhail Razak
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia.
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18
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Integrated Analysis of the Altered lncRNA, microRNA, and mRNA Expression in HBV-Positive Hepatocellular Carcinoma. Life (Basel) 2022; 12:life12050701. [PMID: 35629368 PMCID: PMC9146868 DOI: 10.3390/life12050701] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 04/30/2022] [Accepted: 05/02/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatitis B virus (HBV) infection is the most prominent risk factor for developing hepatocellular carcinoma (HCC), which can increase the incidence of HCC by more than 100 times. Accumulated evidence has revealed that non-coding RNAs (ncRNAs) play a regulatory role in various tumors through the long non-coding RNA (lncRNA)–microRNA (miRNA)–mRNA regulation axis. However, the involvement of the ncRNA regulatory network in the progression of HBV infection-induced HCC remains elusive. In the current work, five tumor samples from patients with hepatitis B surface antigen (HBsAg)-positive HCC and three tumor samples from patients with HBsAg-negative HCC were collected for whole-transcriptome sequencing. Between the two groups, 841 lncRNAs, 54 miRNAs, and 1118 mRNAs were identified to be differentially expressed (DE). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that DE genes were mainly involved in cancer-related pathways, including Wnt and MAPK signaling pathways. The Gene Expression Omnibus (GEO) analysis further validated the selected DE mRNAs. The DE lncRNA–miRNA–mRNA network was built to explore the effect of HBV infection on the regulation of ncRNAs in HCC. These findings provide novel insights into the role of HBV infection in the progression of HCC.
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19
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Long Noncoding RNA TFAP2A-AS1 Suppressed Hepatitis B Virus Replication by Modulating miR-933/HDAC11. DISEASE MARKERS 2022; 2022:7733390. [PMID: 35478990 PMCID: PMC9038435 DOI: 10.1155/2022/7733390] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 01/29/2022] [Indexed: 01/21/2023]
Abstract
Objective Studies have shown that long noncoding RNAs (lncRNAs) play crucial roles in multiple tumor types and regulate various biological processes. The present study tried to study lncRNA TFAP2A-AS1 in HBV infection hepatocellular carcinoma. Methods The level of TFAP2A-AS1 and miR-933 in HCC cell and samples were detected by qRT-PCR assay. Luciferase reporter gene assay was carried out to study the mechanism of TFAP2A-AS1 and miR-933. Cell proliferation was measured by CCK-8 assay. HBV DNA replication was detected by RT-qPCR. Results We firstly demonstrated that TFAP2A-AS1 was downregulated in HCC cell lines and HBV-infected HCC samples compared with nontumor tissues. However, miR-933 was upregulated in HCC cell lines and HBV-infected HCC samples compared with nontumor tissues, and miR-933 was negatively associated with the expression of TFAP2A-AS1 in HBV-correlated HCC samples. TFAP2A-AS1 and HDAC11 expression was decreased and miR-933 was upregulated in the HBV-infected cell HepG2.2.15. TFAP2A-AS1 acted as a sponge for miR-933 and HDAC11 was one direct target gene for miR-933. Overexpression of TFAP2A-AS1 suppressed cell growth, HBV DNA replication, HbeAg, and HbsAg expression, while knockdown of TFAP2A-AS1 enhanced cell proliferation, HBV DNA replication, HbeAg, and HbsAg expression in HepG2.2.15 cell. In addition, ectopic expression of miR-933 promoted cell growth, HBV DNA replication, HbeAg, and HbsAg expression in HepG2.2.15 cell. TFAP2A-AS1 suppressed HBV replication and infection through regulating HDAC11. Conclusion These data demonstrated that TFAP2A-AS1 acted crucial roles in the modulation of HbeAg and HbsAg expression and HBV replication and may be one potential target for HBV infection treatment.
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20
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Zhuang H, Ma X, Liu X, Li C, Li X, Wu L, Wen M, Shi W, Yang X. Hyaluronan-mediated motility receptor antisense RNA 1 promotes hepatitis B virus-related hepatocellular carcinoma progression by regulating miR-627-3p/High Mobility Group AT-hook 2 axis. Bioengineered 2022; 13:8617-8630. [PMID: 35322735 PMCID: PMC9162001 DOI: 10.1080/21655979.2022.2054151] [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] [Indexed: 11/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy in the world, with high mortality and poor prognosis. Hepatitis B virus (HBV) is one of the key factors implicated in the occurrence of HCC. Increasing evidence suggests that miRNAs play important roles in the development and metastasis of HBV-associated HCC (HBV-HCC). Here, we performed CCK8 (Cell count kit-8), EdU (5-ethynyl-2’-deoxyuridine) incorporation assay, wound-healing assay, transwell assay to study the changes in the cellular phenotype. Luciferase reporter assay, RNA pull-down experiment, RT-qPCR and western blotting were employed to study molecular mechanism. In addition, we also constructed a mouse HCC xenograft model to verify the functional role of HMMR-AS1/miR-627-3p/HMGA2 signal axis in vivo. Our study demonstrated that HMMR-AS1 was highly expressed in HCC tissues and cell lines, suggesting its implication in the progression of HCC. In addition, in vitro experiments showed that high HMMR-AS1 expression facilitated the migration, invasion, and proliferation of HCC cells. We further revealed that HMMR-AS1 promoted the malignant phenotype of HCC cells by regulating miR-627-3p/HMGA2 axis. Together, our data suggest that HMMR-AS1 regulates HBV-HCC progression via miR-627-3p/HMGA2 axis.
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Affiliation(s)
- Hai Zhuang
- Department of Infectious Diseases Ward, Baiyun Hospital Affiliated to Guizhou Medical University, Guiyang, China
| | - Xiaoxia Ma
- Department of Hepato-Biliary Surgery Ward, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Xiaoyan Liu
- Department of Infectious Diseases Ward, Baiyun Hospital Affiliated to Guizhou Medical University, Guiyang, China
| | - Chao Li
- Department of Infectious Diseases Ward, Baiyun Hospital Affiliated to Guizhou Medical University, Guiyang, China
| | - Xinying Li
- Department of Infectious Diseases Ward, Baiyun Hospital Affiliated to Guizhou Medical University, Guiyang, China
| | - Ling Wu
- Department of Infectious Diseases Ward, Baiyun Hospital Affiliated to Guizhou Medical University, Guiyang, China
| | - Maofei Wen
- Department of Infectious Diseases Ward, Baiyun Hospital Affiliated to Guizhou Medical University, Guiyang, China
| | - Wenli Shi
- Department of Infectious Diseases Ward, Baiyun Hospital Affiliated to Guizhou Medical University, Guiyang, China
| | - Xiaozhou Yang
- Department of Infectious Diseases, The Second Affifiliated Hospital of Dalian Medical University, Dalian, China
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21
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Lu J, Guo J, Liu J, Mao X, Xu K. Long Non-coding RNA MALAT1: A Key Player in Liver Diseases. Front Med (Lausanne) 2022; 8:734643. [PMID: 35145971 PMCID: PMC8821149 DOI: 10.3389/fmed.2021.734643] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 12/13/2021] [Indexed: 12/02/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) exceed 200 nucleotides in length are considered to be involved in both developmental processes and various diseases. Here, we focus on lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), which was one of the most important lncRNAs in proliferation, apoptosis, and migration. MALAT1 plays a regulatory role in liver diseases, including hepatic fibrosis, liver regeneration, liver cancer, and fatty liver diseases. In the current review, we summarize the latest literature about the function roles of MALAT1 in liver disorders. Probing the regulatory mechanism and cross talk of MALAT1 with other signaling pathways of pathological processes would improve the prognosis, diagnosis of liver diseases, and offer a promising candidate target for therapeutic interventions.
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Affiliation(s)
- Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Jing Guo
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Jun Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Xiaomin Mao
- Haining People' Hospital, Haining Branch, The First Affiliated Hospital, College of Medicine, Zhejiang University, Haining, China
| | - Kaijin Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
- *Correspondence: Kaijin Xu
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22
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Malakoti F, Targhazeh N, Karimzadeh H, Mohammadi E, Asadi M, Asemi Z, Alemi F. The Multiple Function of lncRNA MALAT1 in Cancer Occurrence and Progression. Chem Biol Drug Des 2021; 101:1113-1137. [PMID: 34918470 DOI: 10.1111/cbdd.14006] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 11/29/2021] [Accepted: 12/09/2021] [Indexed: 11/28/2022]
Abstract
Long non-coding RNAs (lncRNAs) have received particular attention in the last decade due to its engaging in carcinogenesis and tumorigenesis. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a lncRNA that plays physiological and pathological roles in many aspects of genome function as well as biological processes involved in cell development, differentiation, proliferation, invasion, and migration. In this article, we will review the effects of lncRNA MALAT1 on the progression of six prevalent human cancers by focusing on MALAT1 ability to regulate post-transcriptional modification and signaling pathways.
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Affiliation(s)
- Faezeh Malakoti
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Student's Research committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Niloufar Targhazeh
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Haniye Karimzadeh
- Department of Clinical Biochemistry, School of Pharmacy & Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Erfan Mohammadi
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.,Drugs Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Milad Asadi
- Drugs Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Forough Alemi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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23
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Fang Y, Yang Y, Li N, Zhang XL, Huang HF. Emerging role of long noncoding RNAs in recurrent hepatocellular carcinoma. World J Clin Cases 2021; 9:9699-9710. [PMID: 34877309 PMCID: PMC8610931 DOI: 10.12998/wjcc.v9.i32.9699] [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: 04/18/2021] [Revised: 06/08/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) remains one of the most frequent types of liver cancer and is characterized by a high recurrence rate. Recent studies have proposed that long non-coding RNAs (lncRNAs) are potential biomarkers in several recurrent tumor types. It is now well understood that invasion, migration, and metastasis are important factors for tumor recurrence. Moreover, some of the known risk factors for HCC may affect the expression levels of several types of lncRNAs and thus affect the recurrence of liver cancer through lncRNA regulation. In this paper, we review the biological functions, molecular mechanisms, and roles of lncRNAs in HCC and summarize current knowledge about lncRNAs as potential biomarkers in recurrent HCC.
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Affiliation(s)
- Yuan Fang
- Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Yang Yang
- Department of Otorhinolaryngology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Na Li
- Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Xiao-Li Zhang
- Department of Gastrointestinal and Hernia Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Han-Fei Huang
- Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
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24
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Malla RR, Padmaraju V, Marni R, Kamal MA. Natural products: Potential targets of TME related long non-coding RNAs in lung cancer. PHYTOMEDICINE 2021; 93:153782. [PMID: 34627097 DOI: 10.1016/j.phymed.2021.153782] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 09/08/2021] [Accepted: 09/26/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Lung cancer is a significant health concern worldwide due to high mortality and morbidity, despite the advances in diagnosis, treatment, and management. Recent experimental evidence from different models suggested long non-coding RNAs (lncRNAs) as major modulators of cancer stem cells (CSCs) in the tumor microenvironment (TME) to support metastasis and drug resistance in lung cancer. Evidence-based studies demonstrated that natural products interfere with TME functions. PURPOSE OF STUDY To establish lncRNAs of TME as novel targets of natural compounds for lung cancer management. STUDY DESIGN Current study used a combination of TME and lung CSCs, lncRNAs and enrichment and stemness maintenance, natural products and stem cell management, natural products and lncRNAs, natural products and targeted delivery as keywords to retrieve the literature from Scopus, Web of Science, PubMed, and Google Scholar. This study critically reviewed the current literature and presented cancer stem cells' ability in reprogramming lung TME. RESULTS This review found that TME related oncogenic and tumor suppressor lncRNAs and their signaling pathways control the maintenance of stemness in lung TME. This review explored natural phenolic compounds and found that curcumin, genistein, quercetin epigallocatechin gallate and ginsenoside Rh2 are efficient in managing lung CSCs. They modulate lncRNAs and their upstream mediators by targeting signaling and epigenetic pathways. This review also identified relevant nanotechnology-based phytochemical delivery approaches for targeting lung cancer. CONCLUSION By critical literature analysis, TME related lncRNAs were identified as potential therapeutic targets, aiming to develop natural product-based therapeutics to treat metastatic and drug-resistant lung cancers.
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Affiliation(s)
- Rama Rao Malla
- Cancer Biology Lab, Department of Biochemistry and Bioinformatics, GIS, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh 530045, India; Department of Biochemistry and Bioinformatics, GIS, GITAM (Deemed to be) University, Visakhapatnam, Andhra Pradesh 530045, India.
| | - Vasudevaraju Padmaraju
- Department of Biochemistry and Bioinformatics, GIS, GITAM (Deemed to be) University, Visakhapatnam, Andhra Pradesh 530045, India
| | - Rakshmitha Marni
- Cancer Biology Lab, Department of Biochemistry and Bioinformatics, GIS, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh 530045, India; Department of Biochemistry and Bioinformatics, GIS, GITAM (Deemed to be) University, Visakhapatnam, Andhra Pradesh 530045, India
| | - Mohammad Amjad Kamal
- West China School of Nursing / Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia; Enzymoics, Novel Global Community Educational Foundation, Australia
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25
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Ogunleye AJ, Romanova E, Medvedeva YA. Genome-wide regulation of CpG methylation by ecCEBPα in acute myeloid leukemia. F1000Res 2021; 10:204. [PMID: 34557292 PMCID: PMC8444155 DOI: 10.12688/f1000research.28146.2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/23/2021] [Indexed: 01/08/2023] Open
Abstract
Background: Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by genetic and epigenetic aberrations that alter the differentiation capacity of myeloid progenitor cells. The transcription factor
CEBPα is frequently mutated in AML patients leading to an increase in DNA methylation in many genomic locations. Previously, it has been shown that
ecCEBPα (extra coding CEBP
α) - a lncRNA transcribed in the same direction as
CEBPα gene - regulates DNA methylation of
CEBPα promoter in
cis. Here, we hypothesize that
ecCEBPα could participate in the regulation of DNA methylation in
trans. Method: First, we retrieved the methylation profile of AML patients with mutated
CEBPα locus from The Cancer Genome Atlas (TCGA). We then predicted the
ecCEBPα secondary structure in order to check the potential of
ecCEBPα to form triplexes around CpG loci and checked if triplex formation influenced CpG methylation, genome-wide. Results: Using DNA methylation profiles of AML patients with a mutated
CEBPα locus, we show that
ecCEBPα could interact with DNA by forming DNA:RNA triple helices and protect regions near its binding sites from global DNA methylation. Further analysis revealed that triplex-forming oligonucleotides in
ecCEBPα are structurally unpaired supporting the DNA-binding potential of these regions.
ecCEBPα triplexes supported with the RNA-chromatin co-localization data are located in the promoters of leukemia-linked transcriptional factors such as MLF2. Discussion: Overall, these results suggest a novel regulatory mechanism for
ecCEBPα as a genome-wide epigenetic modulator through triple-helix formation which may provide a foundation for sequence-specific engineering of RNA for regulating methylation of specific genes.
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Affiliation(s)
- Adewale J Ogunleye
- Department of Biological and Medical Physics, Moscow Institute of Physics and Technology, Moscow, Russian Federation
| | - Ekaterina Romanova
- Research Center of Biotechnology, Institute of Bioengineering, Russian Academy of Sciences, Moscow, Russian Federation
| | - Yulia A Medvedeva
- Department of Biological and Medical Physics, Moscow Institute of Physics and Technology, Moscow, Russian Federation.,Research Center of Biotechnology, Institute of Bioengineering, Russian Academy of Sciences, Moscow, Russian Federation
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26
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Zhang Q, Cheng M, Fan Z, Jin Q, Cao P, Zhou G. Identification of Cancer Cell Stemness-Associated Long Noncoding RNAs for Predicting Prognosis of Patients with Hepatocellular Carcinoma. DNA Cell Biol 2021; 40:1087-1100. [PMID: 34096799 DOI: 10.1089/dna.2021.0282] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) are emerging as crucial contributors to the development of hepatocellular carcinoma (HCC) and are involved in the stemness regulation of liver cancer stem cells (LCSCs). However, cancer cell stemness-associated lncRNAs and their relevance in prediction of clinical prognosis remain largely unexplored. In this study, through the transcriptome-wide screen, we identified a total of 136 LCSC-associated lncRNAs. We evaluated the prognostic value of these lncRNAs and optimally established an 11-lncRNA (including AC008622.2, AC015908.3, AC020915.2, AC025176.1, AC026356.2, AC099850.3, CYTOR, DDX11-AS1, HTR2A-AS1, LINC02870, and SNHG3) prognostic risk model. Multivariate analysis revealed that the risk score is an independent prognostic predictor for HCC patients, which outperforms the traditional clinical pathological factors. Gene set enrichment analysis suggested that the high-risk score reflects the alteration of pathways involved in cell cycle, oxidative phosphorylation, and metabolism. Furthermore, functional studies on SNHG12, the leading candidate of the risk lncRNAs, revealed that knockdown of SNHG12 reduces the abilities of HCC cells stemness, proliferation, migration, and invasion. In summary, we constructed a prognostic risk model based on 11 LCSC-associated lncRNAs, which might be a promising prognostic predictor for HCC patients and highlight the involvement of lncRNAs in LCSC-associated treatment strategy in clinical practice.
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Affiliation(s)
- Qian Zhang
- Medical College of Guizhou University, Guiyang City, China.,State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing Institute of Radiation Medicine, Beijing, China
| | - Min Cheng
- State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing Institute of Radiation Medicine, Beijing, China.,Collaborative Innovation Center for Personalized Cancer Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing City, China
| | - Zhijuan Fan
- Clinical Lab of Tianjin Third Central Hospital, Tianjin, China
| | - Qian Jin
- State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing Institute of Radiation Medicine, Beijing, China
| | - Pengbo Cao
- State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing Institute of Radiation Medicine, Beijing, China
| | - Gangqiao Zhou
- Medical College of Guizhou University, Guiyang City, China.,State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing Institute of Radiation Medicine, Beijing, China.,Collaborative Innovation Center for Personalized Cancer Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing City, China
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27
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Nong W, Ma L, Lan B, Liu N, Yang H, Lao X, Deng Q, Huang Z. Comprehensive Identification of Bridge Genes to Explain the Progression from Chronic Hepatitis B Virus Infection to Hepatocellular Carcinoma. J Inflamm Res 2021; 14:1613-1624. [PMID: 33907440 PMCID: PMC8071210 DOI: 10.2147/jir.s298977] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 03/16/2021] [Indexed: 12/16/2022] Open
Abstract
Background Hepatitis B virus infection co-occurs in 33% of individuals with hepatocellular carcinoma worldwide. However, the molecular link between hepatitis B virus and hepatocellular carcinoma is unknown. Thus, we aimed to elucidate molecular linkages underlying pathogenesis through in-depth data mining analysis. Materials and Methods Differentially expressed genes were identified from patients with chronic hepatitis B virus infection, hepatocellular carcinoma, or both. Gene set enrichment analysis revealed signaling pathways involving differentially expressed genes. Protein-protein interaction networks, protein crosstalk, and enrichment were analyzed to determine whether differentially expressed gene products might serve as a bridge from hepatitis B virus infection to hepatocellular carcinoma pathogenesis. Prognostic potential and transcriptional and post-transcriptional regulators of bridge genes were also examined. Results We identified vital bridge factors in hepatitis B virus infection-associated hepatocellular carcinoma. Differentially expressed genes were clustered into modules based on relative protein function. Signaling pathways associated with cancer, inflammation, immune system, and microenvironment showed significant crosstalk between modules. Thirty-two genes were dysregulated in hepatitis B virus infection-mediated hepatocellular carcinoma. CPEB3, RAB26, SLCO1B1, ST3GAL6 and XK had higher connectivity in the modular network, suggesting significant associations with survival. CDC20 and NUP107 were identified as driver genes as well as markers of poor prognosis. Conclusion Our results suggest that the sustained inflammatory environment created by hepatitis B virus infection is a risk factor for hepatocellular carcinoma. The identification of hepatitis B virus infection-related hepatocellular carcinoma bridge genes provides testable hypotheses about the pathogenesis of hepatocellular carcinoma.
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Affiliation(s)
- Wenwei Nong
- Department of General Surgery, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Liping Ma
- Department of Clinical Laboratory, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Biyang Lan
- Department of General Surgery, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Ning Liu
- Department of General Surgery, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Hongzhi Yang
- Department of General Surgery, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Xiaoxia Lao
- Department of Clinical Laboratory, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Qiaomei Deng
- Department of Clinical Laboratory, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Zhihu Huang
- Department of Clinical Laboratory, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, People's Republic of China
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28
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Zhao L, Shen J, Jia K, Shi F, Hao Q, Gao F. MicroRNA-24-3p Inhibits Microglia Inflammation by Regulating MK2 Following Spinal Cord Injury. Neurochem Res 2021; 46:843-852. [PMID: 33439430 DOI: 10.1007/s11064-020-03211-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 06/30/2020] [Accepted: 12/18/2020] [Indexed: 11/27/2022]
Abstract
Spinal cord injury (SCI) is a functional impairment of the spinal cord caused by external forces, accompanied by limb movement disorders and permanent paralysis, which seriously lowers the life quality of SCI patients. Secondary injury caused by inflammation attenuated the therapeutic effects of SCI. Therefore, the exploration of biomarkers associated with the inflammatory response following SCI might provide novel therapy strategy against SCI.SCI rat model was established as previously reported and evaluated by BBB score. The expression of microRNA-24-3p (miR-24-3p) and MAPK-activated protein kinase 2 (MK2) in spinal cord tissues of SCI rats and HAPI cells was analyzed by qRT-PCR. Protein expression of MK2, ionized calcium-binding adapter molecule-1 (Iba-1), tumor necrosis factor-alpha (TNF-α), and interleukin-1β (IL-1β) was assessed by western blot assay. The release of inflammatory cytokines TNF-α and IL-1β was measured by enzyme-linked immunosorbent assay (ELISA). The interaction between miR-24-3p and MK2 was examined by the luciferase reporter system. Basso-Beattie-Bresnahan (BBB) score dramatically reduced in rats following SCI compared with sham rats. Moreover, the expression of miR-24-3p was down-regulated, while MK2 was up-regulated in the spinal cord tissues of SCI rats and LPS-induced microglia cells compared with the corresponding control group. Luciferase reporter system confirmed the interaction between miR-24-3p and MK2. In addition, miR-24-3p upregulation or MK2 knockdown attenuated LPS induced activation of microglial cells and expression of inflammatory cytokine TNF-α and IL-1β. Besides, we discovered that miR-24-3p regulated inflammation of highly aggressively proliferating immortalized (HAPI) cells by targeting MK2.In our study, we clarified that miR-24-3p repressed inflammation of microglia cells following SCI by regulating MK2, thereby providing promising biomarkers for SCI therapy.
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Affiliation(s)
- Lin Zhao
- Department of Human Anatomy, Medical College of Yan'an University, Yan'an, 716000, Shaanxi, China
| | - Juan Shen
- Department of Human Anatomy, Medical College of Yan'an University, Yan'an, 716000, Shaanxi, China
| | - Kunpeng Jia
- Department of Pediatrics, Affiliated Hospital of Yan'an University, Yan'an, 716000, Shaanxi, China
| | - Fangfang Shi
- Department of Human Anatomy, Medical College of Yan'an University, Yan'an, 716000, Shaanxi, China
| | - Qin Hao
- Department of Nursing, Medical College of Yan'an University, Guanghua Road, Baota District, Yan'an, 716000, Shaanxi, China.
| | - Feng Gao
- Department of Physiology, Medical College of Yan'an University, Guanghua Road, Baota District, Yan'an, 716000, Shaanxi, China.
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29
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Host-virus interactions mediated by long non-coding RNAs. Virus Res 2021; 298:198402. [PMID: 33771610 DOI: 10.1016/j.virusres.2021.198402] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 03/17/2021] [Accepted: 03/18/2021] [Indexed: 11/21/2022]
Abstract
Viruses are obligate pathogens that cause a wide range of diseases across all kingdoms of life. They have a colossal impact on the economy and healthcare infrastructure world-wide. Plants and animals have developed sophisticated molecular mechanisms to defend themselves against viruses and viruses in turn hijack host mechanisms to ensure their survival inside their hosts. Long non-coding (lnc) RNAs have emerged as important macromolecules that regulate plant-virus and animal-virus interactions. Both pro-viral and anti-viral lncRNAs have been reported and they show immense potential to be used as markers and in therapeutics. The current review is focussed on the recent developments that have been made in viral interactions of animals and plants.
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30
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Abstract
Chronic infection of the liver by the hepatitis B virus (HBV) is associated with increased risk for developing hepatocellular carcinoma (HCC). A multitude of studies have investigated the mechanism of liver cancer pathogenesis due to chronic HBV infection. Chronic inflammation, expression of specific viral proteins such as HBx, the integration site of the viral genome into the host genome, and the viral genotype, are key players contributing to HCC pathogenesis. In addition, the genetic background of the host and exposure to environmental carcinogens are also predisposing parameters in hepatocarcinogenesis. Despite the plethora of studies, the molecular mechanism of HCC pathogenesis remains incompletely understood. In this review, the focus is on epigenetic mechanisms involved in the pathogenesis of HBV-associated HCC. Epigenetic mechanisms are dynamic molecular processes that regulate gene expression without altering the host DNA, acting by modifying the host chromatin structure via covalent post-translational histone modifications, changing the DNA methylation status, expression of non-coding RNAs such as microRNAs and long noncoding RNAs, and altering the spatial, 3-D organization of the chromatin of the virus-infected cell. Herein, studies are described that provide evidence in support of deregulation of epigenetic mechanisms in the HBV-infected/-replicating hepatocyte and their contribution to hepatocyte transformation. In contrast to genetic mutations which are permanent, epigenetic alterations are dynamic and reversible. Accordingly, the identification of essential molecular epigenetic targets involved in HBV-mediated HCC pathogenesis offers the opportunity for the design and development of novel epigenetic therapeutic approaches.
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Affiliation(s)
- Ourania Andrisani
- Department of Basic Medical Sciences and Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA
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31
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Goyal B, Yadav SRM, Awasthee N, Gupta S, Kunnumakkara AB, Gupta SC. Diagnostic, prognostic, and therapeutic significance of long non-coding RNA MALAT1 in cancer. Biochim Biophys Acta Rev Cancer 2021; 1875:188502. [PMID: 33428963 DOI: 10.1016/j.bbcan.2021.188502] [Citation(s) in RCA: 190] [Impact Index Per Article: 47.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/30/2020] [Accepted: 01/02/2021] [Indexed: 12/20/2022]
Abstract
Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) is a widely studied lncRNA in cancer. Although dispensable for normal physiology, MALAT1 is important for cancer-related pathways regulation. It is localized in the nuclear speckles periphery along with centrally located pre-RNA splicing factors. MALAT1 associated cancer signaling pathways include MAPK/ERK, PI3K/AKT, β-catenin/Wnt, Hippo, VEGF, YAP, etc. Molecular tools such as immunoprecipitation, RNA pull-down, reporter assay, Northern blotting, microarray, and q-RT-PCR has been used to elucidate MALAT1's function in cancer pathogenesis. MALAT1 can regulate multiple steps in the development of tumours. The diagnostic and prognostic significance of MALAT1 has been demonstrated in cancers of the breast, cervix, colorectum, gallbladder, lung, ovary, pancreas, prostate, glioma, hepatocellular carcinoma, and multiple myeloma. MALAT1 has also emerged as a novel therapeutic target for solid as well as hematological malignancies. In experimental models, siRNA and antisense oligonucleotide (ASO) based strategy has been used for targeting MALAT1. The lncRNA has also been targeted for the chemosensitization and radiosensitization of cancer cells. However, most studies have been performed in preclinical models. How the cross-talk of MALAT1 with other signaling pathways affect cancer pathogenesis is the focus of this article. The diagnostic, prognostic, and therapeutic significance of MALAT1 in multiple cancer types are discussed.
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Affiliation(s)
- Bela Goyal
- Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Shashi Ranjan Mani Yadav
- Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Nikee Awasthee
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
| | - Sweety Gupta
- Department of Radiation Oncology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Ajaikumar B Kunnumakkara
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, 781039, India
| | - Subash Chandra Gupta
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India.
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32
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Xia Q, Shu Z, Ye T, Zhang M. Identification and Analysis of the Blood lncRNA Signature for Liver Cirrhosis and Hepatocellular Carcinoma. Front Genet 2020; 11:595699. [PMID: 33365048 PMCID: PMC7750531 DOI: 10.3389/fgene.2020.595699] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 10/13/2020] [Indexed: 12/12/2022] Open
Abstract
As one of the most common malignant tumors, hepatocellular carcinoma (HCC) is the fifth major cause of cancer-associated mortality worldwide. In 90% of cases, HCC develops in the context of liver cirrhosis and chronic hepatitis B virus (HBV) infection is an important etiology for cirrhosis and HCC, accounting for 53% of all HCC cases. To understand the underlying mechanisms of the dynamic chain reactions from normal to HBV infection, from HBV infection to liver cirrhosis, from liver cirrhosis to HCC, we analyzed the blood lncRNA expression profiles from 38 healthy control samples, 45 chronic hepatitis B patients, 46 liver cirrhosis patients, and 46 HCC patients. Advanced machine-learning methods including Monte Carlo feature selection, incremental feature selection (IFS), and support vector machine (SVM) were applied to discover the signature associated with HCC progression and construct the prediction model. One hundred seventy-one key HCC progression-associated lncRNAs were identified and their overall accuracy was 0.823 as evaluated with leave-one-out cross validation (LOOCV). The accuracies of the lncRNA signature for healthy control, chronic hepatitis B, liver cirrhosis, and HCC were 0.895, 0.711, 0.870, and 0.826, respectively. The 171-lncRNA signature is not only useful for early detection and intervention of HCC, but also helpful for understanding the multistage tumorigenic processes of HCC.
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Affiliation(s)
- Qi Xia
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory for Biomedical Engineering of Ministry of Education, Zhejiang University, Hangzhou, China.,Zhejiang University, Hangzhou, China
| | - Zheyue Shu
- Zhejiang University, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China
| | - Ting Ye
- Zhejiang University, Hangzhou, China
| | - Min Zhang
- Zhejiang University, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China
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Hu W, Liu W, Liang H, Zhang C, Zou M, Zou B. Silencing of methyltransferase-like 3 inhibits oesophageal squamous cell carcinoma. Exp Ther Med 2020; 20:138. [PMID: 33082869 PMCID: PMC7557329 DOI: 10.3892/etm.2020.9267] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 10/22/2019] [Indexed: 12/13/2022] Open
Abstract
Methyltransferase-like 3 (METTL3) is a methyltransferase responsible for N6-methyladenosine mRNA modifications, which has been demonstrated to serve oncogenic roles in various types of cancer; however, the exact function of METTL3 in oesophageal squamous cell carcinoma (ESCC) has not been determined. The present study aimed to explore the regulatory role of METTL3 in ESCC. In the present study, reverse transcription-quantitative PCR and western blotting were used to examine mRNA and protein expression, CCK-8 assays and flow cytometry were used to determine cellular viability and apoptosis, and wound healing and Transwell assays were conducted to study cellular migration and invasion. The expression levels of METTL3 were significantly higher in ESCC tissues and cell lines compared with adjacent non-tumour tissues and the normal oesophageal epithelial cell line HET-1A, respectively. Increased METTL3 expression was associated with an advanced clinical stage of ESCC and poorer prognosis. Furthermore, the genetic knockdown of METTL3 using small interfering RNA significantly suppressed ESCC growth, invasion and migration in vitro, and induced cellular apoptosis, in addition to reducing the phosphorylation levels of PI3K and AKT. In conclusion, the present study demonstrated that the upregulation of METTL3 promoted ESCC progression, and that inhibition of METTL3 significantly suppressed the malignant phenotypes of ESCC cells, at least in part, by downregulating PI3K/AKT signalling activity. Thus, it is suggested that METTL3 may be a promising therapeutic target for ESCC.
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Affiliation(s)
- Wen Hu
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Wei Liu
- Department of Cardiac Major Vascular Surgery, Xiangya Hospital of Central South University, Changsha, Hunan 410008, P.R. China
| | - Hengxing Liang
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Chunmin Zhang
- Institute of Foreign Languages, Central South University, Changsha, Hunan 410075, P.R. China
| | - Min Zou
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Bibo Zou
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
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Wu Y, Zhang Y, Qin X, Geng H, Zuo D, Zhao Q. PI3K/AKT/mTOR pathway-related long non-coding RNAs: roles and mechanisms in hepatocellular carcinoma. Pharmacol Res 2020; 160:105195. [PMID: 32916254 DOI: 10.1016/j.phrs.2020.105195] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 08/30/2020] [Accepted: 09/03/2020] [Indexed: 01/27/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide with high prevalence and lethality. The oncogenic phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is a classic dysregulated pathway involved in the pathogenesis of HCC. However, the underlying mechanism for how PI3K/AKT/mTOR pathway aberrantly activates HCC has not been entirely elucidated. The recognition of the functional roles of long non-coding RNAs (lncRNAs) in PI3K/AKT/mTOR signaling axis sheds light on a new dimension to our understanding of hepatocarcinogenesis. In this review, we comprehensively summarize 67 dysregulated PI3K/AKT/mTOR pathway-related lncRNAs in HCC. Many studies have indicated that the 67 dysregulated lncRNAs show oncogenic or anti-oncogenic effects in HCC by regulation on epigenetic, transcriptional and post-transcriptional levels and they play pivotal roles in the initiation of HCC in diverse biological processes like proliferation, metastasis, drug resistance, radio-resistance, energy metabolism, autophagy and so on. Besides, many of these lncRNAs are associated with clinicopathological features and clinical prognosis in HCC, which may provide a potential future application in the diagnosis and therapy of HCC.
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Affiliation(s)
- Yuting Wu
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
| | - Yingshi Zhang
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
| | - Xiaochun Qin
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
| | - Haobin Geng
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
| | - Daiying Zuo
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
| | - Qingchun Zhao
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China; Department of Pharmacy, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenhe District, Shenyang 110840, China.
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Niu ZS, Wang WH, Dong XN, Tian LML. Role of long noncoding RNA-mediated competing endogenous RNA regulatory network in hepatocellular carcinoma. World J Gastroenterol 2020; 26:4240-4260. [PMID: 32848331 PMCID: PMC7422540 DOI: 10.3748/wjg.v26.i29.4240] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 07/05/2020] [Accepted: 07/15/2020] [Indexed: 02/06/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) are noncoding RNAs (ncRNAs) that occupy over 90% of the human genome, and their main function is to directly or indirectly regulate messenger RNA (mRNA) expression and participate in the tumorigenesis and progression of malignances. In particular, some lncRNAs can interact with miRNAs as competing endogenous RNAs (ceRNAs) to modulate mRNA expression. Accordingly, these RNA molecules are interrelated and coordinate to form a dynamic lncRNA-mediated ceRNA regulatory network. Mounting evidence has revealed that lncRNAs that act as ceRNAs are closely related to tumorigenesis. To date, numerous studies have established many different regulatory networks in hepatocellular carcinoma (HCC), and perturbations in these ceRNA interactions may result in the initiation and progression of HCC. Herein, we emphasize recent advances concerning the biological function of lncRNAs as ceRNAs in HCC, with the aim of elucidating the molecular mechanism underlying these HCC-related RNA molecules and providing novel insights into the diagnosis and treatment of HCC.
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Affiliation(s)
- Zhao-Shan Niu
- Laboratory of Micromorphology, School of Basic Medicine, Medical Department of Qingdao University, Qingdao 266071, Shandong Province, China
| | - Wen-Hong Wang
- Department of Pathology, School of Basic Medicine, Medical Department of Qingdao University, Qingdao 266071, Shandong Province, China
| | - Xian-Ning Dong
- Department of Pathology, the Affiliated Hospital of Qingdao University, Qingdao 266061, Shandong Province, China
| | - Li-Mei-Li Tian
- BGI Gene Innovation Class, School of Basic Medicine, Medical Department of Qingdao University, Qingdao 266071, Shandong Province, China
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36
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Piao L, Li H, Feng Y, Yang Z, Kim S, Xuan Y. SET domain-containing 5 is a potential prognostic biomarker that promotes esophageal squamous cell carcinoma stemness. Exp Cell Res 2020; 389:111861. [PMID: 31981592 DOI: 10.1016/j.yexcr.2020.111861] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 01/20/2020] [Accepted: 01/21/2020] [Indexed: 02/07/2023]
Abstract
SET domain-containing 5 (SETD5) is an uncharacterized member of the protein lysine methyltransferase family. Although it was reported that SETD5 gene mutations are associated with the several types of human cancer, its functional role in esophageal squamous cell carcinoma (ESCC) progression has not been fully elucidated. In the present study, we used tissue samples from 147 patients with ESCC and ESCC cell lines to determine the clinicopathological significance of SETD5 in ESCC and its effects on ESCC stemness. We performed immunohistochemical staining, immunofluorescence imaging, and tumor sphere formation, colony formation, flow cytometry, wound healing, Transwell, and western blotting assays. SETD5 expression was upregulated in ESCC tissue and associated with primary tumor (pT) stage, clinical stage, lymph node metastasis, shorter overall survival rate, and disease-free survival rate. Cox regression analyses indicated that SETD5 is an independent poor prognostic factor of ESCC. In addition, SETD5 expression was correlated with cancer stemness-related protein, hypoxia-inducible factor-1α (HIF-1α), and CD68 expression. Moreover, immunofluorescence analysis revealed that SETD5 was co-localized with CD44 and SOX2 in TE10 and TE11 cells and that exposing cells to cobalt chloride increased HIF-1α, SETD5, and stemness-related protein expression in a time-dependent manner. Furthermore, SETD5 expression was significantly correlated with the expression of cell cycle-related genes and PI3K/Akt signaling pathway-related proteins. Finally, knocking down SETD5 downregulated the expression of stemness-related and PI3K/Akt signaling pathway proteins, while inhibiting tumor spheroid formation, cell proliferation, migration, and invasion in ESCC cells. These results indicate that SETD5 expression is associated with cancer stemness and that SETD5 is a potential prognostic biomarker and therapeutic target for ESCC.
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Affiliation(s)
- Lihua Piao
- Institute for Regenerative Medicine, Yanbian University College of Medicine, Yanji, 133002, Jilin Province, PR China
| | - Haoyue Li
- Institute for Regenerative Medicine, Yanbian University College of Medicine, Yanji, 133002, Jilin Province, PR China; Department of Pathology, Yanbian University College of Medicine, Yanji, 133002, Jilin Province, PR China
| | - Ying Feng
- Institute for Regenerative Medicine, Yanbian University College of Medicine, Yanji, 133002, Jilin Province, PR China; Department of Pathology, Yanbian University College of Medicine, Yanji, 133002, Jilin Province, PR China
| | - Zhaoting Yang
- Institute for Regenerative Medicine, Yanbian University College of Medicine, Yanji, 133002, Jilin Province, PR China; Department of Pathology, Yanbian University College of Medicine, Yanji, 133002, Jilin Province, PR China
| | - Seokhyung Kim
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University College of Medicine, Seoul, 110-745, South Korea
| | - Yanhua Xuan
- Institute for Regenerative Medicine, Yanbian University College of Medicine, Yanji, 133002, Jilin Province, PR China; Department of Pathology, Yanbian University College of Medicine, Yanji, 133002, Jilin Province, PR China.
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The Regulatory Role of MicroRNA in Hepatitis-B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) Pathogenesis. Cells 2019; 8:cells8121504. [PMID: 31771261 PMCID: PMC6953055 DOI: 10.3390/cells8121504] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/11/2019] [Accepted: 11/12/2019] [Indexed: 02/06/2023] Open
Abstract
The incidence and mortality of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) is an intractable public health problem in developing countries that is compounded by limited early detection and therapeutic options. Despite the early promise of utilizing the regulatory role of miRNA in liver cancer, this field remains largely in the work-in-progress phase. This exploratory review paper adopts a broad focus in order to collate evidence of the regulatory role of miRNA in each stage of the HBV-HCC continuum. This includes the regulatory role of miRNA in early HBV infection, chronic inflammation, fibrosis/cirrhosis, and the onset of HCC. The paper specifically investigates HBV dysregulated miRNA that influence the expression of the host/HBV genome in HBV-HCC pathogenesis and fully acknowledges that this does not cover the full spectrum of dysregulated miRNA. The sheer number of dysregulated miRNA in each phase support a hypothesis that future therapeutic interventions will need to consider incorporating multiple miRNA panels.
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38
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Zhang H, Chen X, Zhang J, Wang X, Chen H, Liu L, Liu S. Long non‑coding RNAs in HBV‑related hepatocellular carcinoma (Review). Int J Oncol 2019; 56:18-32. [PMID: 31746420 DOI: 10.3892/ijo.2019.4909] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 09/02/2019] [Indexed: 12/25/2022] Open
Abstract
Hepatitis B virus (HBV)‑related hepatocellular carcinoma (HCC) is a global health problem that accounts for more than half of total liver cancer cases in developing countries. Despite the growing number of researches conducted, the molecular mechanism underlying the development of HCC remains elusive. Long non‑coding RNAs (lncRNAs), which are non‑coding RNAs >200 nt in length that were previously considered to be transcriptional noise, have been found to be dysregulated in HBV‑related HCC with the help of high‑throughput omics techniques. Subsequent investigations revealed that aberrant expression of lncRNAs may affect the risk of HBV‑related HCC through diverse mechanisms, including epigenetic silencing of transcriptional activation, alternative splicing, molecular sponging, modulating protein stability, and by serving as precursors of miRNAs. Although the sensitivity and specificity of lncRNAs must be further validated, a number of circulating lncRNAs have been identified as useful biomarkers for HBV‑related HCC. In addition to these findings, recent studies also unveiled that certain genetic polymorphisms in lncRNAs may affect the occurrence and prognosis of HBV‑related HCC. The aim of the present review was to provide an overview of the mechanisms underlying the involvement of lncRNAs in HBV‑related HCC. Subsequently, lncRNAs found to be dysregulated in HBV‑related HCC were focused on and current findings on circulating lncRNAs and their genetic polymorphisms were discussed.
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Affiliation(s)
- Hao Zhang
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Sichuan 610000, P.R. China
| | - Xuebing Chen
- Department of Infectious Diseases, People's Hospital of Deyang City, Deyang, Sichuan 618000, P.R. China
| | - Jian Zhang
- Department of Pathology, People's Hospital of Deyang City, Deyang, Sichuan 618000, P.R. China
| | - Xianwei Wang
- Department of Pathology, People's Hospital of Deyang City, Deyang, Sichuan 618000, P.R. China
| | - Huijuan Chen
- Department of Pathology, People's Hospital of Deyang City, Deyang, Sichuan 618000, P.R. China
| | - Lin Liu
- Department of Pathology, People's Hospital of Deyang City, Deyang, Sichuan 618000, P.R. China
| | - Shanling Liu
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Sichuan 610000, P.R. China
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39
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Metastasis Associated Lung Adenocarcinoma Transcript 1: An update on expression pattern and functions in carcinogenesis. Exp Mol Pathol 2019; 112:104330. [PMID: 31712117 DOI: 10.1016/j.yexmp.2019.104330] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 11/03/2019] [Indexed: 12/28/2022]
Abstract
The Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) is among long non-coding RNAs (lncRNAs) which has disapproved the old term of "junk DNA" which was used for majority of human genome which are not transcribed to proteins. An extensive portion of literature points to the fundamental role of this lncRNA in tumorigenesis process of diverse cancers ranging from solid tumors to leukemia. Being firstly identified in lung cancer, it has prognostic and diagnostic values in several cancer types. Consistent with the proposed oncogenic roles for this lncRNA, most of studies have shown up-regulation of MALAT1 in malignant tissues compared with non-malignant/normal tissues of the same source. However, few studies have shown down-regulation of MALAT1 in breast cancer, endometrial cancer, colorectal cancer and glioma. In the current study, we have conducted a comprehensive literature search and provided an up-date on the role of MALAT1 in cancer biology. Our investigation underscores a potential role as a diagnostic/prognostic marker and a putative therapeutic target for MALAT1.
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40
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Akula SM, Abrams SL, Steelman LS, Emma MR, Augello G, Cusimano A, Azzolina A, Montalto G, Cervello M, McCubrey JA. RAS/RAF/MEK/ERK, PI3K/PTEN/AKT/mTORC1 and TP53 pathways and regulatory miRs as therapeutic targets in hepatocellular carcinoma. Expert Opin Ther Targets 2019; 23:915-929. [PMID: 31657972 DOI: 10.1080/14728222.2019.1685501] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Hepatocellular carcinoma (HCC) is a significant problem globally because of viral infections and the increasing incidence of obesity and fatty liver disease. However, it is difficult to treat because its inherent genetic heterogeneity results in activation of numerous signaling pathways. Kinases have been targeted for decades with varying results, but the development of therapeutic resistance is a major challenge.Areas covered: The key roles of the RAS/RAF/MEK/ERK, PI3K/PTEN/AKT/mTORC1, TP53 microRNAs (miRs) as therapeutic targets are discussed and we suggests novel approaches for targeting miRs or their downstream targets to combat HCC. We performed literature searches using the Medline Database from 2000 to the present.Expert opinion: The involvement of RAS/RAF/MEK/ERK, PI3K/PTEN/AKT/mTORC and TP53 pathways as drivers of the disease and drug resistance is a challenge. Moreover, miRs regulate the expression of key genes in these pathways. What we and others are proposing is the prospect of targeting miRs and their downstream targets to improve conventional approaches to treat HCC. Combination approaches are often promising because multiple signaling pathways are deregulated due to diverse mutations and events.
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Affiliation(s)
- Shaw M Akula
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA
| | - Stephen L Abrams
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA
| | - Linda S Steelman
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA
| | - Maria R Emma
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Giuseppa Augello
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Antonella Cusimano
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Antonina Azzolina
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Giuseppe Montalto
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy.,Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Melchiorre Cervello
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - James A McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA
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41
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Liu S, Liu X, Li J, Zhou H, Carr MJ, Zhang Z, Shi W. Long noncoding RNAs: Novel regulators of virus-host interactions. Rev Med Virol 2019; 29:e2046. [PMID: 31016795 PMCID: PMC7169114 DOI: 10.1002/rmv.2046] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 02/26/2019] [Accepted: 03/01/2019] [Indexed: 12/16/2022]
Abstract
Long noncoding RNAs (lncRNAs) represent a key class of cellular regulators, involved in the modulation and control of multiple biological processes. Distinct classes of lncRNAs are now known to be induced by host cytokines following viral infections. Current evidence demonstrates that lncRNAs play essential roles at the host‐pathogen interface regulating viral infections by either innate immune responses at various levels including activation of pathogen recognition receptors or by epigenetic, transcriptional, and posttranscriptional effects. We review the newly described mechanisms underlying the interactions between lncRNAs, cytokines, and metabolites differentially expressed following viral infections; we highlight the regulatory networks of host antiviral responses and emphasize the need for interdisciplinary research between lncRNA biology and immunology to deepen understanding of viral pathogenesis.
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Affiliation(s)
- Shaoqiong Liu
- Key Laboratory of Etiology and Epidemiology of Emerging Infectious Diseases in Universities of Shandong Province, Taishan Medical University, Taian, China
| | - Xia Liu
- Key Laboratory of Etiology and Epidemiology of Emerging Infectious Diseases in Universities of Shandong Province, Taishan Medical University, Taian, China
| | - Juan Li
- Key Laboratory of Etiology and Epidemiology of Emerging Infectious Diseases in Universities of Shandong Province, Taishan Medical University, Taian, China
| | - Hong Zhou
- Key Laboratory of Etiology and Epidemiology of Emerging Infectious Diseases in Universities of Shandong Province, Taishan Medical University, Taian, China
| | - Michael J Carr
- Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan.,National Virus Reference Laboratory, School of Medicine, University College Dublin, Dublin 4, Ireland
| | - Zhenjie Zhang
- Key Laboratory of Etiology and Epidemiology of Emerging Infectious Diseases in Universities of Shandong Province, Taishan Medical University, Taian, China
| | - Weifeng Shi
- Key Laboratory of Etiology and Epidemiology of Emerging Infectious Diseases in Universities of Shandong Province, Taishan Medical University, Taian, China
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42
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Yang J, Nie J, Ma X, Wei Y, Peng Y, Wei X. Targeting PI3K in cancer: mechanisms and advances in clinical trials. Mol Cancer 2019; 18:26. [PMID: 30782187 PMCID: PMC6379961 DOI: 10.1186/s12943-019-0954-x] [Citation(s) in RCA: 1023] [Impact Index Per Article: 170.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 02/06/2019] [Indexed: 02/07/2023] Open
Abstract
Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is one of the most important intracellular pathways, which can be considered as a master regulator for cancer. Enormous efforts have been dedicated to the development of drugs targeting PI3K signaling, many of which are currently employed in clinical trials evaluation, and it is becoming increasingly clear that PI3K inhibitors are effective in inhibiting tumor progression. PI3K inhibitors are subdivided into dual PI3K/mTOR inhibitors, pan-PI3K inhibitors and isoform-specific inhibitors. In this review, we performed a critical review to summarize the role of the PI3K pathway in tumor development, recent PI3K inhibitors development based on clinical trials, and the mechanisms of resistance to PI3K inhibition.
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Affiliation(s)
- Jing Yang
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Ji Nie
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xuelei Ma
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Yuquan Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Yong Peng
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
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