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Qu L, Wang F, Wang Y, Li Z. The regulation of LRPs by miRNAs in cancer: influencing cancer characteristics and responses to treatment. Cancer Cell Int 2025; 25:182. [PMID: 40382654 PMCID: PMC12085831 DOI: 10.1186/s12935-025-03804-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 05/04/2025] [Indexed: 05/20/2025] Open
Abstract
The low-density lipoprotein receptor-related protein (LRP) family is a group of cell surface receptors that participate in a variety of biological processes, including lipid metabolism, Wnt signaling, and bone metabolism. miRNAs are small non-coding RNA molecules that regulate gene expression and play a role in many biological processes, including the occurrence and development of tumors. Accumulating evidence demonstrates that LRP members are modulated by miRNAs across multiple cancer types, influencing key oncogenic processes-including tumor cell proliferation, apoptosis suppression, extracellular matrix remodeling, cell adhesion, and angiogenesis. The LRPs, miRNAs, their upstream lncRNAs, and downstream signaling molecules often form complex signaling pathways to regulate the activity of tumor cells. However, the tissue-specific roles and mechanistic underpinnings of these pathways remain incompletely understood. When examining the emerging concept of the interaction between miRNAs and LRPs, we emphasize the significance of these complex regulatory layers in the initiation and progression of cancer. Collectively, these findings are critical for advancing our understanding of the role of the LRPs family in the occurrence and development of tumors, as well as for the development of new strategies for cancer treatment.
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Affiliation(s)
- Lianyue Qu
- Key Laboratory of Diagnostic Imaging and Interventional Radiology of Liaoning Province, Department of Radiology, The First Hospital of China Medical University, Shenyang, P. R. China
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, P. R. China
| | - Fan Wang
- Key Laboratory of Diagnostic Imaging and Interventional Radiology of Liaoning Province, Department of Radiology, The First Hospital of China Medical University, Shenyang, P. R. China
- Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang, P. R. China
| | - Yuxiang Wang
- Key Laboratory of Diagnostic Imaging and Interventional Radiology of Liaoning Province, Department of Radiology, The First Hospital of China Medical University, Shenyang, P. R. China
- Department of Nuclear Medicine, The First Hospital of China Medical University, Shenyang, P. R. China
| | - Zixuan Li
- Key Laboratory of Diagnostic Imaging and Interventional Radiology of Liaoning Province, Department of Radiology, The First Hospital of China Medical University, Shenyang, P. R. China.
- Department of Radiology, The First Hospital of China Medical University, Shenyang, P. R. China.
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Zhao S, Chen F, Hu L, Li X, Gao Z, Chen M, Wang X, Song Z. Long non-coding rnas as key modulators of the immune microenvironment in hepatocellular carcinoma: implications for Immunotherapy. Front Immunol 2025; 16:1523190. [PMID: 40352941 PMCID: PMC12061944 DOI: 10.3389/fimmu.2025.1523190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 04/02/2025] [Indexed: 05/14/2025] Open
Abstract
Hepatocellular carcinoma (HCC) represents a major global health challenge, characterized by its complex immune microenvironment that plays a pivotal role in tumor progression and therapeutic response. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of various biological processes, including gene expression and immune cell function. This review explores the multifaceted roles of lncRNAs in modulating the immune microenvironment of HCC. We discuss how lncRNAs influence the infiltration and activation of immune cells, shape cytokine profiles, and regulate immune checkpoint molecules, thereby affecting the tumor's immunogenicity and response to immunotherapy. Furthermore, we highlight specific lncRNAs implicated in immune evasion mechanisms and their potential as biomarkers and therapeutic targets. By elucidating the intricate interplay between lncRNAs and the immune landscape in HCC, this review aims to provide insights into novel strategies for enhancing immunotherapeutic efficacy and improving patient outcomes.
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Affiliation(s)
| | | | | | | | | | - Minjie Chen
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Xiaoguang Wang
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Zhengwei Song
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
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3
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He GS, Xia JK, Li QH, Zheng Y, Shi CR, Li R, Hong Q, Chen XM. Specnuezhenide: Comprehensive review of pharmacology, pharmacokinetics and ethnomedicinal uses. Fitoterapia 2025; 181:106389. [PMID: 39805507 DOI: 10.1016/j.fitote.2025.106389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 12/24/2024] [Accepted: 01/09/2025] [Indexed: 01/16/2025]
Abstract
BACKGROUND Specnuezhenide (SPN) is a bioactive iridoid terpenoid compound mainly found in Ligustri Lucidi Fructus (LLF), that has a broad spectrum of pharmacological effects, including anti-neoplastic, hepatoprotective, anti-aging, anti-inflammatory, immune-modulatory properties. PURPOSE The present review provides a comprehensive summary of natural medicinal plants, traditional Chinese medicine compounds containing SPN, and their corresponding pharmacological mechanisms. METHODS Using several globally recognized databases such as Web of Science, Google Scholar, PubMed, ScienceDirect, Wiley, ACS, Springer, and CNKI until December 2024, A comprehensive literature search and analysis was carried out with the keywords "Specnuezhenide", " Pharmacology ", "Pharmacokinetics" and " Chinese herbal compound". RESULTS The results indicated that SPN is present in a diverse range of plants, including LLF, Osmanthus fragrans seeds and Naked barley. SPN plays an anti-inflammatory role by regulating the NF-κB and MAPK signaling pathways, down-regulating the expression of TNF-α, IL-1β, IL-6 and other cytokines. Furthermore, many Chinese herbal compounds have been found to contain SPN, such as treatment of spleen and kidney deficiency of compound Shenhua tablet, treatment of liver-kidney Yin deficiency of Er Zhi Wan, treatment of pulmonray abscess of Qidongning and treatment of stagnation of QI due to depression of the liver of Shuganzhi Tablet. SPN is primarily distributed in the stomach, intestine, and liver. However, due to its limited absorption in the gastrointestinal tract and low blood concentration, its bioavailability is significantly reduced. CONCLUSIONS Thereby, SPN holds immense potential in the prevention and treatment of liver, lung and kidney complications. This review intends to provide a novel insight for further development of SPN, hoping to reveal the potential of SPN and necessity of further studies in this field.
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Affiliation(s)
- Guo-Sen He
- The College of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, State Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China
| | - Ji-Kai Xia
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, State Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China; School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Qi-Hu Li
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, State Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China; School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yan Zheng
- The College of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, State Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China
| | - Chun-Ru Shi
- The College of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, State Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China
| | - Run Li
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, State Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China
| | - Quan Hong
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, State Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China.
| | - Xiang-Mei Chen
- The College of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, State Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China.
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Yuan Y, Tang Y, Fang Z, Wen J, Wicha MS, Luo M. Long Non-Coding RNAs: Key Regulators of Tumor Epithelial/Mesenchymal Plasticity and Cancer Stemness. Cells 2025; 14:227. [PMID: 39937018 PMCID: PMC11817775 DOI: 10.3390/cells14030227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/23/2025] [Accepted: 01/27/2025] [Indexed: 02/13/2025] Open
Abstract
Long non-coding RNAs (lncRNAs) are a class of non-coding RNA molecules with transcripts longer than 200 bp, which were initially thought to be noise from genomic transcription without biological function. However, since the discovery of H19 in 1980 and Xist in 1990, increasing evidence has shown that lncRNAs regulate gene expression at epigenetic, transcriptional, and post-transcriptional levels through specific regulatory actions and are involved in the development of cancer and other diseases. Despite many lncRNAs being expressed at lower levels than those of protein-coding genes with less sequence conservation across species, lncRNAs have become an intense area of RNA research. They exert diverse biological functions such as inducing chromatin remodeling, recruiting transcriptional machinery, acting as competitive endogenous RNAs for microRNAs, and modulating protein-protein interactions. Epithelial-mesenchymal transition (EMT) is a developmental process, associated with embryonic development, wound healing, and cancer progression. In the context of oncogenesis, the EMT program is transiently activated and confers migratory/invasive and cancer stem cell (CSC) properties to tumor cells, which are crucial for malignant progression, metastasis, and therapeutic resistance. Accumulating evidence has revealed that lncRNAs play crucial roles in the regulation of tumor epithelial/mesenchymal plasticity (EMP) and cancer stemness. Here, we summarize the emerging roles and molecular mechanisms of lncRNAs in regulating tumor cell EMP and their effects on tumor initiation and progression through regulation of CSCs. We also discuss the potential of lncRNAs as diagnostic and prognostic biomarkers and therapeutic targets.
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Affiliation(s)
- Yuan Yuan
- Department of Breast and Thyroid Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China; (Y.Y.); (Y.T.); (Z.F.)
| | - Yun Tang
- Department of Breast and Thyroid Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China; (Y.Y.); (Y.T.); (Z.F.)
| | - Zeng Fang
- Department of Breast and Thyroid Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China; (Y.Y.); (Y.T.); (Z.F.)
| | - Jian Wen
- Department of Breast Surgery, The Fourth Affiliated Hospital of China Medical University, Shengyang 110032, China;
| | - Max S. Wicha
- Division of Hematology & Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Ming Luo
- Department of Breast and Thyroid Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China; (Y.Y.); (Y.T.); (Z.F.)
- Division of Hematology & Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
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Ghionescu AV, Sorop A, Linioudaki E, Coman C, Savu L, Fogarasi M, Lixandru D, Dima SO. A predicted epithelial-to-mesenchymal transition-associated mRNA/miRNA axis contributes to the progression of diabetic liver disease. Sci Rep 2024; 14:27678. [PMID: 39532948 PMCID: PMC11557572 DOI: 10.1038/s41598-024-77416-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Despite public health measures, type 2 diabetes (T2D) is still a significant concern worldwide, given its associated complications, including hepatic alterations. The role of epithelial-to-mesenchymal transition (EMT) in liver fibrosis is well established. However, its effects on the progression of diabetic liver diseases are not well understood. Therefore, this study aims to investigate the mRNA/miRNA axes involved in this process. Bioinformatic analysis revealed new EMT-associated genes (CDH2, ITGB1, COL4A1, COL1A1, TNC, CCN2, and JUN), which showed higher expression in obese T2D and hepatocellular carcinoma (HCC) patients. In addition, six miRNAs (miR-21-5p, miR-26a-5p, miR-34a-5p, miR-106a-5p, miR-320a-3p and miR-424-5p) have been found as potential targets. Among them, miR-26a-5p and miR-424-5p were significantly downregulated in nonalcoholic steatohepatitis (NASH) and HCC (p < 0.05), being considered potential negative regulators of the EMT process. In our hepatic mesenchymal culture model, miR-26a-5p negatively regulated cadherin 2 (also known as N-cadherin, CDH2) and promoted the cadherin 1 (also known as E-cadherin, CDH1) expression. Our results reveal potential molecules involved in liver tumor development. Moreover, we observe that miR-26a-5p impairs EMT in the initial stages of diabetic liver disease by inhibiting CDH2 and could be a valuable target in this pathology.
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Grants
- 629PED/2022 CCCDI-UEFISCDI, project number PN-III-P2-2.1-PED-2021-3180, within PNCDI III
- 629PED/2022 CCCDI-UEFISCDI, project number PN-III-P2-2.1-PED-2021-3180, within PNCDI III
- 629PED/2022 CCCDI-UEFISCDI, project number PN-III-P2-2.1-PED-2021-3180, within PNCDI III
- 629PED/2022 CCCDI-UEFISCDI, project number PN-III-P2-2.1-PED-2021-3180, within PNCDI III
- 629PED/2022 CCCDI-UEFISCDI, project number PN-III-P2-2.1-PED-2021-3180, within PNCDI III
- 629PED/2022 CCCDI-UEFISCDI, project number PN-III-P2-2.1-PED-2021-3180, within PNCDI III
- 629PED/2022 CCCDI-UEFISCDI, project number PN-III-P2-2.1-PED-2021-3180, within PNCDI III
- 28571/02.10.2023 UMFCD
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Affiliation(s)
- Alina-Veronica Ghionescu
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Andrei Sorop
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania
| | - Ekaterini Linioudaki
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Cristin Coman
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- "Cantacuzino" National Medico-Military Institute for Research and Development, Bucharest, Romania
| | - Lorand Savu
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Marton Fogarasi
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Daniela Lixandru
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania.
- University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania.
| | - Simona Olimpia Dima
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
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Ma S, Meng G, Liu T, You J, He R, Zhao X, Cui Y. The Wnt signaling pathway in hepatocellular carcinoma: Regulatory mechanisms and therapeutic prospects. Biomed Pharmacother 2024; 180:117508. [PMID: 39362068 DOI: 10.1016/j.biopha.2024.117508] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 08/26/2024] [Accepted: 09/25/2024] [Indexed: 10/05/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignant tumor that arises from hepatocytes. Multiple signaling pathways play a regulatory role in the occurrence and development of HCC, with the Wnt signaling pathway being one of the primary regulatory pathways. In normal hepatocytes, the Wnt signaling pathway maintains cell regeneration and organ development. However, when aberrant activated, the Wnt pathway is closely associated with invasion, cancer stem cells(CSCs), drug resistance, and immune evasion in HCC. Among these factors, the development of drug resistance is one of the most important factors affecting the efficacy of HCC treatment. These mechanisms form the basis for tumor cell adaptation and evolution within the body, enabling continuous changes in tumor cells, resistance to drugs and immune system attacks, leading to metastasis and recurrence. In recent years, there have been numerous new discoveries regarding these mechanisms. An increasing number of drugs targeting the Wnt signaling pathway have been developed, with some already entering clinical trials. Therefore, this review encompasses the latest research on the role of the Wnt signaling pathway in the onset and progression of HCC, as well as advancements in its therapeutic strategies.
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Affiliation(s)
- Shihui Ma
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150000, China
| | - Guorui Meng
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150000, China
| | - Tong Liu
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150000, China
| | - Junqi You
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150000, China
| | - Risheng He
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150000, China
| | - Xudong Zhao
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150000, China
| | - Yunfu Cui
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150000, China.
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Qiu W, Zhang S, Yu W, Liu J, Wu H. Non-coding RNAs in hepatocellular carcinoma metastasis: Remarkable indicators and potential oncogenic mechanism. Comput Biol Med 2024; 180:108867. [PMID: 39089114 DOI: 10.1016/j.compbiomed.2024.108867] [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: 11/28/2023] [Revised: 06/12/2024] [Accepted: 07/07/2024] [Indexed: 08/03/2024]
Abstract
Non-coding RNAs (ncRNAs), as key regulators involving in intercellular biological processes, are more prominent in many malignancies, especially for hepatocellular carcinoma (HCC). Herein, we conduct a comprehensive review to summarize diverse ncRNAs roles in HCC metastatic mechanism. We focus on four signaling pathways that predominate in HCC metastatic process, including Wnt/β-catenin, HIF-1α, IL-6, and TGF-β pathways. MicroRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) employed different mechanisms to participate in the regulation of the key genes in these pathways, typical as interaction with DNA to control transcription, with RNA to control translation, and with protein to control stability. Therefore, ncRNAs may become potential biomarkers and therapeutic targets for HCC metastasis.
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Affiliation(s)
- Wenqi Qiu
- Department of Plastic and Aesthetic Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Song Zhang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Wei Yu
- 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, Zhejiang, China
| | - Jian Liu
- Department of Intensive Care Unit, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Huiling Wu
- Department of Plastic and Aesthetic Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
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8
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Liu Y, Zhao X, Long Q, Guo Z, Cao X, Wu X, Tu F, Zhang Y, You X, Shi X, Teng Z, Zeng Y. Investigating the role of miR-26b-5p and PTGS2 in schizophrenia treatment using Wendan decoction: Network pharmacology and experimental validation. Eur J Integr Med 2024; 69:102380. [DOI: 10.1016/j.eujim.2024.102380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2025]
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9
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Xue W, Zhu B, Zhao K, Huang Q, Luo H, Shou Y, Huang Z, Guo H. Targeting LRP6: A new strategy for cancer therapy. Pharmacol Res 2024; 204:107200. [PMID: 38710241 DOI: 10.1016/j.phrs.2024.107200] [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: 12/29/2023] [Revised: 04/19/2024] [Accepted: 04/28/2024] [Indexed: 05/08/2024]
Abstract
Targeting specific molecular drivers of tumor growth is a key approach in cancer therapy. Among these targets, the low-density lipoprotein receptor-related protein 6 (LRP6), a vital component of the Wnt signaling pathway, has emerged as an intriguing candidate. As a cell-surface receptor and vital co-receptor, LRP6 is frequently overexpressed in various cancer types, implicating its pivotal role in driving tumor progression. The pursuit of LRP6 as a target for cancer treatment has gained substantial traction, offering a promising avenue for therapeutic intervention. Here, this comprehensive review explores recent breakthroughs in our understanding of LRP6's functions and underlying molecular mechanisms, providing a profound discussion of its involvement in cancer pathogenesis and drug resistance. Importantly, we go beyond discussing LRP6's role in cancer by discussing diverse potential therapeutic approaches targeting this enigmatic protein. These approaches encompass a wide spectrum, including pharmacological agents, natural compounds, non-coding RNAs, epigenetic factors, proteins, and peptides that modulate LRP6 expression or disrupt its interactions. In addition, also discussed the challenges associated with developing LRP6 inhibitors and their advantages over Wnt inhibitors, as well as the drugs that have entered phase II clinical trials. By shedding light on these innovative strategies, we aim to underscore LRP6's significance as a valuable and multifaceted target for cancer treatment, igniting enthusiasm for further research and facilitating translation into clinical applications.
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Affiliation(s)
- Wei Xue
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Key Laboratory of Research and Evaluation of Bioactive Molecules&College of Pharmacy, Guangxi Medical University, Nanning 530021, China; Department of Pharmacy, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 530011, China
| | - Bo Zhu
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry Guangxi Collaborative Innovation Center for Biomedicine, Guangxi Medical University, Nanning 530021, China
| | - Kaili Zhao
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Key Laboratory of Research and Evaluation of Bioactive Molecules&College of Pharmacy, Guangxi Medical University, Nanning 530021, China
| | - Qiuju Huang
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Key Laboratory of Research and Evaluation of Bioactive Molecules&College of Pharmacy, Guangxi Medical University, Nanning 530021, China
| | - Hua Luo
- Macau Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau Special Administrative Region of China
| | - Yiwen Shou
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Key Laboratory of Research and Evaluation of Bioactive Molecules&College of Pharmacy, Guangxi Medical University, Nanning 530021, China
| | - Zhaoquan Huang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China.
| | - Hongwei Guo
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Key Laboratory of Research and Evaluation of Bioactive Molecules&College of Pharmacy, Guangxi Medical University, Nanning 530021, China.
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10
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Zhu J, Wang L. The Role of lncRNA-miR-26a-mRNA Network in Cancer Progression and Treatment. Biochem Genet 2024; 62:1443-1461. [PMID: 37730965 DOI: 10.1007/s10528-023-10475-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 07/24/2023] [Indexed: 09/22/2023]
Abstract
The role of non-coding RNAs in regulating biological processes associated with cancer progression, such as proliferation, migration, and apoptosis, has been extensively studied. Long non-coding RNAs (lncRNAs) play a role in regulating these processes through various mechanisms, including transcriptional and post-transcriptional modifications. In post-transcriptional regulation, lncRNAs can bind to specific miRNAs and affect their function, which can either promote or inhibit cancer development. The interaction between lncRNAs, miRNAs, and mRNAs forms a network known as competitive endogenous RNA (ceRNA), which is involved in cancer progression or inhibition. One specific miRNA called miR-26a-5p has been identified as having tumor-suppressive properties. However, when lncRNAs bind to and inhibit miR-26a-5p, it can lead to cancer progression. Therefore, targeting this ceRNA network could be a promising strategy for preventing cancer development. This review will first discuss the anticancer effects of miR-26a-5p and then explore the involvement of the lncRNA-miR26a-5p-mRNA axis in cancer progression and potential targeted therapies.
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Affiliation(s)
- Jun Zhu
- Department of Oncology, Daye People's Hospital, Daye, Hubei, 435100, China.
| | - Liya Wang
- Department of Obstetrics and Gynecology, Pengren Hospital, Daye, Hubei, 435100, China
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11
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Zhang G, Hou S, Li S, Wang Y, Cui W. Role of STAT3 in cancer cell epithelial‑mesenchymal transition (Review). Int J Oncol 2024; 64:48. [PMID: 38488027 PMCID: PMC11000535 DOI: 10.3892/ijo.2024.5636] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 02/29/2024] [Indexed: 03/19/2024] Open
Abstract
Since its discovery, the role of the transcription factor, signal transducer and activator of transcription 3 (STAT3), in both normal physiology and the pathology of numerous diseases, including cancer, has been extensively studied. STAT3 is aberrantly activated in different types of cancer, fulfilling a critical role in cancer progression. The biological process, epithelial‑mesenchymal transition (EMT), is indispensable for embryonic morphogenesis. During the development of cancer, EMT is hijacked to confer motility, tumor cell stemness, drug resistance and adaptation to changes in the microenvironment. The aim of the present review was to outline recent advances in knowledge of the role of STAT3 in EMT, which may contribute to the understanding of the function of STAT3 in EMT in various types of cancer. Delineating the underlying mechanisms associated with the STAT3‑EMT signaling axis may generate novel diagnostic and therapeutic options for cancer treatment.
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Affiliation(s)
- Guoan Zhang
- Department of Forensic Genetics, Institute of Forensic Medicine and Laboratory Medicine, Jining Medical University, Forensic Science Center of Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Sen Hou
- Department of Forensic Genetics, Institute of Forensic Medicine and Laboratory Medicine, Jining Medical University, Forensic Science Center of Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Shuyue Li
- Department of Forensic Genetics, Institute of Forensic Medicine and Laboratory Medicine, Jining Medical University, Forensic Science Center of Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Yequan Wang
- Department of Forensic Genetics, Institute of Forensic Medicine and Laboratory Medicine, Jining Medical University, Forensic Science Center of Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Wen Cui
- Department of Forensic Pathology, Institute of Forensic Medicine and Laboratory Medicine, Jining Medical University, Forensic Science Center of Jining Medical University, Jining, Shandong 272067, P.R. China
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12
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Gajos-Michniewicz A, Czyz M. WNT/β-catenin signaling in hepatocellular carcinoma: The aberrant activation, pathogenic roles, and therapeutic opportunities. Genes Dis 2024; 11:727-746. [PMID: 37692481 PMCID: PMC10491942 DOI: 10.1016/j.gendis.2023.02.050] [Citation(s) in RCA: 25] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 12/28/2022] [Accepted: 02/14/2023] [Indexed: 09/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a liver cancer, highly heterogeneous both at the histopathological and molecular levels. It arises from hepatocytes as the result of the accumulation of numerous genomic alterations in various signaling pathways, including canonical WNT/β-catenin, AKT/mTOR, MAPK pathways as well as signaling associated with telomere maintenance, p53/cell cycle regulation, epigenetic modifiers, and oxidative stress. The role of WNT/β-catenin signaling in liver homeostasis and regeneration is well established, whereas in development and progression of HCC is extensively studied. Herein, we review recent advances in our understanding of how WNT/β-catenin signaling facilitates the HCC development, acquisition of stemness features, metastasis, and resistance to treatment. We outline genetic and epigenetic alterations that lead to activated WNT/β-catenin signaling in HCC. We discuss the pivotal roles of CTNNB1 mutations, aberrantly expressed non-coding RNAs and complexity of crosstalk between WNT/β-catenin signaling and other signaling pathways as challenging or advantageous aspects of therapy development and molecular stratification of HCC patients for treatment.
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Affiliation(s)
- Anna Gajos-Michniewicz
- Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz 92-215, Poland
| | - Malgorzata Czyz
- Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz 92-215, Poland
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13
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Jia Y, Wang W, Jiang J, Zhang X, Li H, Gong S, Li Z, Liu H, Shang C, Wang A, Jin Y, Lin P. LncRNA STAT3-AS regulates endometrial receptivity via the STAT3 signaling pathway. Theriogenology 2024; 216:118-126. [PMID: 38171198 DOI: 10.1016/j.theriogenology.2023.12.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 12/21/2023] [Accepted: 12/27/2023] [Indexed: 01/05/2024]
Abstract
Endometrial receptivity is critical for the successful establishment of pregnancy in ruminants. Interferon tau (IFNT) plays a key role in promoting embryo attachment by activating the Janus kinase/signal transducer and activator of transcription pathway, which induces the expression of a series of interferon-stimulated genes (ISGs). In our previous study, sequencing analysis of goat endometrial epithelial cells (gEECs) treated with 20 ng/mL IFNT revealed a differentially expressed long non-coding RNA located on the STAT3 antisense chain, which we designated STAT3-AS. The aim of this study was to investigate the role and mechanism of STAT3-AS in establishing endometrial receptivity in goats. The results showed that STAT3-AS was expressed in both the nucleus and cytoplasm of gEECs, and its expression increased significantly in the uterus on day 15 of pregnancy. STAT3-AS expression was upregulated in gEECs treated with IFNT alone or in combination with progesterone and estradiol. Knockdown of STAT3-AS using specific short interfering RNA significantly inhibited the expression of classical ISGs such as interferon-stimulated gene 15 and 2',5'-oligodenylate synthetase 2, as well as uterine endometrial receptivity-related genes including homeobox gene A11, integrin beta 3, and vascular endothelial growth factor. Moreover, gEEC proliferation and the STAT3 pathway were suppressed in the absence of STAT3-AS. However, pretreatment with the STAT3 activator RO8191 restored the effect of silencing STAT3-AS on endometrial receptivity. Overall, these results suggest that STAT3-AS is an important regulator of endometrial receptivity in goats and that it regulates endometrial receptivity through the STAT3 pathway.
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Affiliation(s)
- Yanni Jia
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture and Rural Affairs, Northwest A&F University, Yangling, Shaanxi, China
| | - Wei Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Jiaqi Jiang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture and Rural Affairs, Northwest A&F University, Yangling, Shaanxi, China
| | - Xinyan Zhang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture and Rural Affairs, Northwest A&F University, Yangling, Shaanxi, China
| | - Haijing Li
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture and Rural Affairs, Northwest A&F University, Yangling, Shaanxi, China
| | - Suhua Gong
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture and Rural Affairs, Northwest A&F University, Yangling, Shaanxi, China
| | - Zuhui Li
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture and Rural Affairs, Northwest A&F University, Yangling, Shaanxi, China
| | - Haokun Liu
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture and Rural Affairs, Northwest A&F University, Yangling, Shaanxi, China
| | - Chunmei Shang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture and Rural Affairs, Northwest A&F University, Yangling, Shaanxi, China
| | - Aihua Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture and Rural Affairs, Northwest A&F University, Yangling, Shaanxi, China
| | - Yaping Jin
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture and Rural Affairs, Northwest A&F University, Yangling, Shaanxi, China.
| | - Pengfei Lin
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture and Rural Affairs, Northwest A&F University, Yangling, Shaanxi, China.
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14
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Tavakoli Pirzaman A, Alishah A, Babajani B, Ebrahimi P, Sheikhi SA, Moosaei F, Salarfar A, Doostmohamadian S, Kazemi S. The Role of microRNAs in Hepatocellular Cancer: A Narrative Review Focused on Tumor Microenvironment and Drug Resistance. Technol Cancer Res Treat 2024; 23:15330338241239188. [PMID: 38634139 PMCID: PMC11025440 DOI: 10.1177/15330338241239188] [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: 11/22/2023] [Revised: 01/26/2024] [Accepted: 02/26/2024] [Indexed: 04/19/2024] Open
Abstract
Globally, hepatic cancer ranks fourth in terms of cancer-related mortality and is the sixth most frequent kind of cancer. Around 80% of liver cancers are hepatocellular carcinomas (HCC), which are the leading cause of cancer death. It is well known that HCC may develop resistance to the available chemotherapy treatments very fast. One of the biggest obstacles in providing cancer patients with appropriate care is drug resistance. According to reports, more than 90% of cancer-specific fatalities are caused by treatment resistance. By binding to the 3'-untranslated region of target messenger RNAs (mRNAs), microRNAs (miRNAs), a group of noncoding RNAs which are around 17 to 25 nucleotides long, regulate target gene expression. Moreover, they play role in the control of signaling pathways, cell proliferation, and cell death. As a result, miRNAs play an important role in the microenvironment of HCC by changing immune phenotypes, hypoxic conditions, and acidification, as well as angiogenesis and extracellular matrix components. Moreover, changes in miRNA levels in HCC can effectively resist cancer cells to chemotherapy by affecting various cellular processes such as autophagy, apoptosis, and membrane transporter activity. In the current work, we narratively reviewed the role of miRNAs in HCC, with a special focus on tumor microenvironment and drug resistance.
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Affiliation(s)
| | - Ali Alishah
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Bahareh Babajani
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Pouyan Ebrahimi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Seyyed Ali Sheikhi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Farhad Moosaei
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | | | | | - Sohrab Kazemi
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran
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15
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Hu Y, Huang Y, Xie X, Li L, Zhang Y, Zhang X. ARF6 promotes hepatocellular carcinoma proliferation through activating STAT3 signaling. Cancer Cell Int 2023; 23:205. [PMID: 37716993 PMCID: PMC10505330 DOI: 10.1186/s12935-023-03053-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 09/03/2023] [Indexed: 09/18/2023] Open
Abstract
BACKGROUND Hepatocellular Carcinoma (HCC) possesses the high mortality in cancers worldwide. Nevertheless, the concrete mechanism underlying HCC proliferation remains obscure. In this study, we show that high expression of ARF6 is associated with a poor clinical prognosis, which could boost the proliferation of HCC. METHODS Immunohistochemistry and western blotting were used to detect the expression level of ARF6 in HCC tissues. We analyzed the clinical significance of ARF6 in primary HCC patients. We estimated the effect of ARF6 on tumor proliferation with in vitro CCK8, colony formation assay, and in vivo nude mouse xenograft models. Immunofluorescence was conducted to investigate the ARF6 localization. western blotting was used to detect the cell cycle-related proteins with. Additionally, we examined the correlation between ARF6 and STAT3 signaling in HCC with western blotting, immunohistochemistry and xenograft assay. RESULTS ARF6 was upregulated in HCC tissues compared to adjacent normal liver tissues. The increased expression of ARF6 correlated with poor tumor differentiation, incomplete tumor encapsulation, advanced tumor TNM stage and poor prognosis. ARF6 obviously promoted HCC cell proliferation, colony formation, and cell cycle progression. In vivo nude mouse xenograft models showed that ARF6 enhanced tumor growth. Furthermore, ARF6 activated the STAT3 signaling and ARF6 expression was positively correlated with phosphorylated STAT3 level in HCC tissues. Furthermore, after intervening of STAT3, the effect of ARF6 on tumor-promoting was weakened, which demonstrated ARF6 functioned through STAT3 signaling in HCC. CONCLUSIONS Our results indicate that ARF6 promotes HCC proliferation through activating STAT3 signaling, suggesting that ARF6 may serve as potential prognostic and therapeutic targets for HCC patients.
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Affiliation(s)
- Yabing Hu
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Laboratory Medicine, Wuhan No.1 Hospital, Wuhan, China
| | - Yongchu Huang
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaohang Xie
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Longshan Li
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong Zhang
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaochao Zhang
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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16
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Afra F, Mahboobipour AA, Salehi Farid A, Ala M. Recent progress in the immunotherapy of hepatocellular carcinoma: Non-coding RNA-based immunotherapy may improve the outcome. Biomed Pharmacother 2023; 165:115104. [PMID: 37393866 DOI: 10.1016/j.biopha.2023.115104] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/27/2023] [Accepted: 06/28/2023] [Indexed: 07/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the second most lethal cancer and a leading cause of cancer-related mortality worldwide. Immune checkpoint inhibitors (ICIs) significantly improved the prognosis of HCC; however, the therapeutic response remains unsatisfactory in a substantial proportion of patients or needs to be further improved in responders. Herein, other methods of immunotherapy, including vaccine-based immunotherapy, adoptive cell therapy, cytokine delivery, kynurenine pathway inhibition, and gene delivery, have been adopted in clinical trials. Although the results were not encouraging enough to expedite their marketing. A major proportion of human genome is transcribed into non-coding RNAs (ncRNAs). Preclinical studies have extensively investigated the roles of ncRNAs in different aspects of HCC biology. HCC cells reprogram the expression pattern of numerous ncRNAs to decrease the immunogenicity of HCC, exhaust the cytotoxic and anti-cancer function of CD8 + T cells, natural killer (NK) cells, dendritic cells (DCs), and M1 macrophages, and promote the immunosuppressive function of T Reg cells, M2 macrophages, and myeloid-derived suppressor cells (MDSCs). Mechanistically, cancer cells recruit ncRNAs to interact with immune cells, thereby regulating the expression of immune checkpoints, functional receptors of immune cells, cytotoxic enzymes, and inflammatory and anti-inflammatory cytokines. Interestingly, prediction models based on the tissue expression or even serum levels of ncRNAs could predict response to immunotherapy in HCC. Moreover, ncRNAs markedly potentiated the efficacy of ICIs in murine models of HCC. This review article first discusses recent advances in the immunotherapy of HCC, then dissects the involvement and potential application of ncRNAs in the immunotherapy of HCC.
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Affiliation(s)
- Fatemeh Afra
- Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Ali Mahboobipour
- Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Salehi Farid
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Moein Ala
- Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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17
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Moldogazieva NT, Zavadskiy SP, Astakhov DV, Sologova SS, Margaryan AG, Safrygina AA, Smolyarchuk EA. Differentially expressed non-coding RNAs and their regulatory networks in liver cancer. Heliyon 2023; 9:e19223. [PMID: 37662778 PMCID: PMC10474437 DOI: 10.1016/j.heliyon.2023.e19223] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 08/12/2023] [Accepted: 08/16/2023] [Indexed: 09/05/2023] Open
Abstract
The vast majority of human transcriptome is represented by various types of small RNAs with little or no protein-coding capability referred to as non-coding RNAs (ncRNAs). Functional ncRNAs include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), which are expressed at very low, but stable and reproducible levels in a variety of cell types. ncRNAs regulate gene expression due to miRNA capability of complementary base pairing with mRNAs, whereas lncRNAs and circRNAs can sponge miRNAs off their target mRNAs to act as competitive endogenous RNAs (ceRNAs). Each miRNA can target multiple mRNAs and a single mRNA can interact with several miRNAs, thereby creating miRNA-mRNA, lncRNA-miRNA-mRNA, and circRNA-miRNA-mRNA regulatory networks. Over the past few years, a variety of differentially expressed miRNAs, lncRNAs, and circRNAs (DEMs, DELs, and DECs, respectively) have been linked to cancer pathogenesis. They can exert both oncogenic and tumor suppressor roles. In this review, we discuss the recent advancements in uncovering the roles of DEMs, DELs, and DECs and their networks in aberrant cell signaling, cell cycle, transcription, angiogenesis, and apoptosis, as well as tumor microenvironment remodeling and metabolic reprogramming during hepatocarcinogenesis. We highlight the potential and challenges in the use of differentially expressed ncRNAs as biomarkers for liver cancer diagnosis and prognosis.
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Affiliation(s)
- Nurbubu T. Moldogazieva
- Department of Pharmacology, Nelyubin Institute of Pharmacy, I.M. Sechenov First Moscow State Medical University, 119991, 8 Trubetskaya str., Moscow, Russia
| | - Sergey P. Zavadskiy
- Department of Pharmacology, Nelyubin Institute of Pharmacy, I.M. Sechenov First Moscow State Medical University, 119991, 8 Trubetskaya str., Moscow, Russia
| | - Dmitry V. Astakhov
- Department of Biochemistry, Institute of Biodesign and Complex Systems Modelling, I.M. Sechenov First Moscow State Medical University, 119991, 8 Trubetskaya str., Moscow, Russia
| | - Susanna S. Sologova
- Department of Pharmacology, Nelyubin Institute of Pharmacy, I.M. Sechenov First Moscow State Medical University, 119991, 8 Trubetskaya str., Moscow, Russia
| | - Arus G. Margaryan
- Department of Pharmacology, Nelyubin Institute of Pharmacy, I.M. Sechenov First Moscow State Medical University, 119991, 8 Trubetskaya str., Moscow, Russia
| | - Anastasiya A. Safrygina
- Department of Pharmacology, Nelyubin Institute of Pharmacy, I.M. Sechenov First Moscow State Medical University, 119991, 8 Trubetskaya str., Moscow, Russia
| | - Elena A. Smolyarchuk
- Department of Pharmacology, Nelyubin Institute of Pharmacy, I.M. Sechenov First Moscow State Medical University, 119991, 8 Trubetskaya str., Moscow, Russia
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18
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Kim J, Kim Y, Lee B. Identification of Long Non-Coding RNA Profiles and Potential Therapeutic Agents for Fibrolamellar Carcinoma Based on RNA-Sequencing Data. Genes (Basel) 2023; 14:1709. [PMID: 37761849 PMCID: PMC10530820 DOI: 10.3390/genes14091709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 08/21/2023] [Accepted: 08/26/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND Fibrolamellar carcinoma (FLC) is a rare type of liver cancer that primarily affects adolescents and young adults without prior liver disease or viral infections. Patients with FLC generally have non-specific symptoms, are often diagnosed at a later stage, and experience a higher frequency of metastases compared to patients with other liver cancers. A fusion transcript of DNAJB1 and PRKACA, which can lead to increased activity of PKA and cellular proliferation, has been identified in all FLC patients, but the exact mechanism through which FLC develops remains unclear. In this study, we investigated common lncRNA profiles in various FLC samples using bioinformatics analyses. METHODS We analyzed differentially expressed (DE) lncRNAs from three RNA sequencing datasets. Using lncRNAs and DE mRNAs, we predicted potential lncRNA target genes and performed Gene Ontology (GO) and KEGG analyses with the DE lncRNA target genes. Moreover, we screened for small-molecule compounds that could act as therapeutic targets for FLC. RESULTS We identified 308 DE lncRNAs from the RNA sequencing datasets. In addition, we performed a trans-target prediction analysis and identified 454 co-expressed pairs in FLC. The GO analysis showed that the lncRNA-related up-regulated mRNAs were enriched in the regulation of protein kinase C signaling and cAMP catabolic processes, while lncRNA-related down-regulated mRNAs were enriched in steroid, retinol, cholesterol, and xenobiotic metabolic processes. The analysis of small-molecule compounds for FLC treatment identified vitexin, chlorthalidone, triamterene, and amiloride, among other compounds. CONCLUSIONS We identified potential therapeutic targets for FLC, including lncRNA target genes as well as small-molecule compounds that could potentially be used as treatments. Our findings could contribute to furthering our understanding of FLC and providing potential avenues for diagnosis and treatment.
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Affiliation(s)
- Janghyun Kim
- Department of Oral Pathology, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea (Y.K.)
| | - Young Kim
- Department of Oral Pathology, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea (Y.K.)
| | - Bora Lee
- Department of Biochemistry, Chonnam National University Medical School, Hwasun 58128, Republic of Korea
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19
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Luo H, Yang Y, Zhou Y, Bai X, Hou Y. 1,4,5,6,7,8‑Hexahydropyrido[4,3‑d]pyrimidine inhibits HepG2 cell proliferation, migration and invasion, and induces apoptosis through the upregulation of miR‑26b‑5p by targeting CDK8. Oncol Lett 2023; 25:260. [PMID: 37205919 PMCID: PMC10189852 DOI: 10.3892/ol.2023.13846] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 03/28/2023] [Indexed: 05/21/2023] Open
Abstract
1,4,5,6,7,8-Hexahydropyrido[4,3-d]pyrimidine (PPM) promotes apoptosis of HepG2 cells and serves a role in tumor suppression. However, the role of microRNA (miRNA) regulation in initiating apoptosis remains unclear. Therefore, the present study performed reverse transcription-quantitative PCR to investigate the association between PPM and miRNA, which demonstrated that PPM upregulated the expression of miR-26b-5p. Wound healing and Transwell assays showed that PPM inhibited the migration and invasion of HepG2 cells, and EdU staining experiments showed that PPM inhibited the proliferation of HepG2 cells. Transfection with miR-26b-5p inhibitor reversed the effects of PPM on HepG2 cells. Flow cytometry results showed that PPM promoted apoptosis of HepG2 cells by upregulating miRNA (miR)-26b-5p, and Western blotting results showed that PPM promoted the expression of apoptosis-associated protein Bax and inhibited the expression of Bcl-2 by upregulating miR-26b-5p. Using a proteomic approach combined with bioinformatics analysis, CDK8 was identified as a potential target of miR-26b-5p and was downregulated by miR-26b-5p overexpression. However, PPM induced HepG2 cell cycle arrest without the involvement of miR-26b-5p. Western blotting results showed that PPM upregulation of miR-26b-5p suppresses NF-κB/p65 signaling pathway in HepG2 cells by targeting of CDK8. The present results suggested that miR-26b-5p may function as a target gene of PPM and may serve a role in hepatocellular carcinoma treatment.
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Affiliation(s)
- Hanlin Luo
- Department of Histology and Embryology, College of Basic Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Yang Yang
- Department of Histology and Embryology, College of Basic Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Yanqiu Zhou
- Department of Histology and Embryology, College of Basic Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Xianyong Bai
- Department of Histology and Embryology, College of Basic Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
- Correspondence to: Professor Yun Hou or Professor Xianyong Bai, Department of Histology and Embryology, College of Basic Medicine, Binzhou Medical University, 346 Guanhai Road, Laishan, Yantai, Shandong 264003, P.R. China, E-mail:
| | - Yun Hou
- Department of Histology and Embryology, College of Basic Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
- Correspondence to: Professor Yun Hou or Professor Xianyong Bai, Department of Histology and Embryology, College of Basic Medicine, Binzhou Medical University, 346 Guanhai Road, Laishan, Yantai, Shandong 264003, P.R. China, E-mail:
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20
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Hashemi M, Sabouni E, Rahmanian P, Entezari M, Mojtabavi M, Raei B, Zandieh MA, Behroozaghdam M, Mirzaei S, Hushmandi K, Nabavi N, Salimimoghadam S, Ren J, Rashidi M, Raesi R, Taheriazam A, Alexiou A, Papadakis M, Tan SC. Deciphering STAT3 signaling potential in hepatocellular carcinoma: tumorigenesis, treatment resistance, and pharmacological significance. Cell Mol Biol Lett 2023; 28:33. [PMID: 37085753 PMCID: PMC10122325 DOI: 10.1186/s11658-023-00438-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 03/15/2023] [Indexed: 04/23/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is considered one of the greatest challenges to human life and is the most common form of liver cancer. Treatment of HCC depends on chemotherapy, radiotherapy, surgery, and immunotherapy, all of which have their own drawbacks, and patients may develop resistance to these therapies due to the aggressive behavior of HCC cells. New and effective therapies for HCC can be developed by targeting molecular signaling pathways. The expression of signal transducer and activator of transcription 3 (STAT3) in human cancer cells changes, and during cancer progression, the expression tends to increase. After induction of STAT3 signaling by growth factors and cytokines, STAT3 is phosphorylated and translocated to the nucleus to regulate cancer progression. The concept of the current review revolves around the expression and phosphorylation status of STAT3 in HCC, and studies show that the expression of STAT3 is high during the progression of HCC. This review addresses the function of STAT3 as an oncogenic factor in HCC, as STAT3 is able to prevent apoptosis and thus promote the progression of HCC. Moreover, STAT3 regulates both survival- and death-inducing autophagy in HCC and promotes cancer metastasis by inducing the epithelial-mesenchymal transition (EMT). In addition, upregulation of STAT3 is associated with the occurrence of chemoresistance and radioresistance in HCC. Specifically, non-protein-coding transcripts regulate STAT3 signaling in HCC, and their inhibition by antitumor agents may affect tumor progression. In this review, all these topics are discussed in detail to provide further insight into the role of STAT3 in tumorigenesis, treatment resistance, and pharmacological regulation of HCC.
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Affiliation(s)
- Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Eisa Sabouni
- Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Parham Rahmanian
- Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Behnaz Raei
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Arad Zandieh
- Division of Epidemiology, Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Mitra Behroozaghdam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Kiavash Hushmandi
- Division of Epidemiology, Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Noushin Nabavi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H3Z6, Canada
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Jun Ren
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, 200032, China
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
- The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Rasoul Raesi
- Department of Health Services Management, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Medical-Surgical Nursing, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, Australia
- AFNP Med Austria, Vienna, Austria
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Heusnerstrasse 40, 42283, Wuppertal, Germany.
| | - Shing Cheng Tan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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Liu Z, Ren C, Cai J, Yin B, Yuan J, Ding R, Ming W, Sun Y, Li Y. A Novel Aging-Related Prognostic lncRNA Signature Correlated with Immune Cell Infiltration and Response to Immunotherapy in Breast Cancer. Molecules 2023; 28:molecules28083283. [PMID: 37110517 PMCID: PMC10141963 DOI: 10.3390/molecules28083283] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/15/2023] [Accepted: 03/21/2023] [Indexed: 04/29/2023] Open
Abstract
Breast cancer (BC) is among the most universal malignant tumors in women worldwide. Aging is a complex phenomenon, caused by a variety of factors, that plays a significant role in tumor development. Consequently, it is crucial to screen for prognostic aging-related long non-coding RNAs (lncRNAs) in BC. The BC samples from the breast-invasive carcinoma cohort were downloaded from The Cancer Genome Atlas (TCGA) database. The differential expression of aging-related lncRNAs (DEarlncRNAs) was screened by Pearson correlation analysis. Univariate Cox regression, LASSO-Cox analysis, and multivariate Cox analysis were performed to construct an aging-related lncRNA signature. The signature was validated in the GSE20685 dataset from the Gene Expression Omnibus (GEO) database. Subsequently, a nomogram was constructed to predict survival in BC patients. The accuracy of prediction performance was assessed through the time-dependent receiver operating characteristic (ROC) curves, Kaplan-Meier analysis, principal component analyses, decision curve analysis, calibration curve, and concordance index. Finally, differences in tumor mutational burden, tumor-infiltrating immune cells, and patients' response to chemotherapy and immunotherapy between the high- and low-risk score groups were explored. Analysis of the TCGA cohort revealed a six aging-related lncRNA signature consisting of MCF2L-AS1, USP30-AS1, OTUD6B-AS1, MAPT-AS1, PRR34-AS1, and DLGAP1-AS1. The time-dependent ROC curve proved the optimal predictability for prognosis in BC patients with areas under curves (AUCs) of 0.753, 0.772, and 0.722 in 1, 3, and 5 years, respectively. Patients in the low-risk group had better overall survival and significantly lower total tumor mutational burden. Meanwhile, the high-risk group had a lower proportion of tumor-killing immune cells. The low-risk group could benefit more from immunotherapy and some chemotherapeutics than the high-risk group. The aging-related lncRNA signature can provide new perspectives and methods for early BC diagnosis and therapeutic targets, especially tumor immunotherapy.
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Affiliation(s)
- Zhixin Liu
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai 264003, China
- Department of Orthopedics, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Chongkang Ren
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai 264003, China
| | - Jinyi Cai
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai 264003, China
| | - Baohui Yin
- Department of Pediatrics, Yantai Affiliated Hospital of Binzhou Medical University, Yantai 264100, China
| | - Jingjie Yuan
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai 264003, China
| | - Rongjuan Ding
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai 264003, China
| | - Wenzhuo Ming
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai 264003, China
| | - Yunxiao Sun
- Department of Pediatrics, Yantai Affiliated Hospital of Binzhou Medical University, Yantai 264100, China
| | - Youjie Li
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai 264003, China
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22
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Interleukin-6 and Hypoxia Synergistically Promote EMT-Mediated Invasion in Epithelial Ovarian Cancer via the IL-6/STAT3/HIF-1 α Feedback Loop. Anal Cell Pathol (Amst) 2023; 2023:8334881. [PMID: 36814597 PMCID: PMC9940980 DOI: 10.1155/2023/8334881] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 12/27/2022] [Accepted: 01/15/2023] [Indexed: 02/15/2023] Open
Abstract
Extensive peritoneal spread and capacity for distant metastasis account for the majority of mortality from epithelial ovarian cancer (EOC). Accumulating evidence shows that interleukin-6 (IL-6) promotes tumor invasion and migration in EOC, although the molecular mechanisms remain to be fully elucidated. Meanwhile, the hypoxic microenvironment has been recognized to cause metastasis by triggering epithelial-mesenchymal transition (EMT) in several types of cancers. Here, we studied the synergy between IL-6 and hypoxia in inducing EMT in two EOC cell lines, A2780 cells and SKOV3 cells. Exogenous recombination of IL-6 and autocrine production of IL-6 regulated by plasmids both induced EMT phenotype in EOC cells characterized by downregulated E-cadherin as well as upregulated expression of vimentin and EMT-related transcription factors. The combined effects of IL-6 and hypoxia were more significant than those of either one treatment on EMT. Suppression of hypoxia-inducible factor-1α (HIF-1α) before IL-6 treatment inhibited the EMT phenotype and invasion ability of EOC cells, indicating that HIF-1α occupies a key position in the regulatory pathway of EMT associated with IL-6. EMT score was found positively correlated with mRNA levels of IL-6, signal transducer and activator of transcription 3 (STAT3), and HIF-1α, respectively, in 489 ovarian samples from The Cancer Genome Atlas dataset. Next, blockade of the abovementioned molecules by chemical inhibitors reversed the alteration in the protein levels of EMT markers induced by either exogenous or endogenous IL-6. These findings indicate a positive feedback loop between IL-6 and HIF-1α, and induce and maintain EMT phenotype through STAT3 signaling, which might provide a novel rationale for prognostic prediction and therapeutic targets in EOC.
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23
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Xu T, Xie M, Jing X, Jiang H, Wu X, Wang X, Shu Y. Loss of miR-26b-5p promotes gastric cancer progression via miR-26b-5p-PDE4B/CDK8-STAT3 feedback loop. J Transl Med 2023; 21:77. [PMID: 36737782 PMCID: PMC9898947 DOI: 10.1186/s12967-023-03933-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Accepted: 01/26/2023] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Chronic inflammation is a well-known risk factor for the development of gastric cancer (GC). Nevertheless, the molecular mechanisms underlying inflammation-related GC progression are incompletely defined. METHODS Bioinformatic analysis was performed based on data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), and the expression of miR-26b-5p in GC cells and tissues was validated by quantitative real-time PCR (qRT-PCR). Cell proliferation was examined through Cell Counting Kit-8 (CCK8), 5-Ethynyl-2'-deoxyuridine (EdU), colony formation, flow cytometry, and tumor xenografts. Correlation between miR-26b-5p and Cyclin dependent kinase 8 (CDK8) or Phosphodiesterase 4B (PDE4B) was analyzed by dual-luciferase reporter assays, qRT-PCR, and Western blot. The effect of miR-26b-5p on the Signal transducer and activator of transcription 3 (STAT3) pathway was investigated using Western blot, immunofluorescence (IF), and immunohistochemistry (IHC). The impact of STAT3 on miR-26b-5p was determined by dual-luciferase reporter assays and qRT-PCR. RESULTS The expression of miR-26b-5p was significantly downregulated in Helicobacter Pylori (H. pylori)-infected GC cells. The decreased expression of miR-26b-5p was also detected in GC cells and tissues compared to normal gastric epithelium cells (GES1) and normal adjacent gastric tissues. The low expression of miR-26b-5p promoted GC proliferation in vitro and in vivo and was related to the poor outcome of GC patients. In terms of mechanism, miR-26b-5p directly targeted PDE4B and CDK8, resulting in decreased phosphorylation and nuclear translocation of STAT3, which was associated with the regulation of GC proliferation by miR-26b-5p. Notably, miR-26b-5p was transcriptionally suppressed by STAT3, thus forming the miR-26b-5p-PDE4B/CDK8-STAT3 positive feedback loop. CONCLUSION The newly identified miR-26b-5p-PDE4B/CDK8-STAT3 feedback loop plays an important role in inflammation-related GC progression and may serve as a promising therapeutic target for GC.
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Affiliation(s)
- Tingting Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department of Oncology, Gusu School, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Mengyan Xie
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xinming Jing
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Huning Jiang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xi Wu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xinzhu Wang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yongqian Shu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
- Department of Oncology, Gusu School, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.
- Department of Oncology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
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24
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Hashemi M, Mirzaei S, Zandieh MA, Rezaei S, Amirabbas Kakavand, Dehghanpour A, Esmaeili N, Ghahremanzade A, Saebfar H, Heidari H, Salimimoghadam S, Taheriazam A, Entezari M, Ahn KS. Long non-coding RNAs (lncRNAs) in hepatocellular carcinoma progression: Biological functions and new therapeutic targets. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2023; 177:207-228. [PMID: 36584761 DOI: 10.1016/j.pbiomolbio.2022.12.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 11/29/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022]
Abstract
Liver is an important organ in body that performs vital functions such as detoxification. Liver is susceptible to development of cancers, and hepatocellular carcinoma (HCC) is among them. 75-85% of liver cancer cases are related to HCC. Therefore, much attention has been directed towards understanding factors mediating HCC progression. LncRNAs are epigenetic factors with more than 200 nucleotides in length located in both nucleus and cytoplasm and they are promising candidates in cancer therapy. Directing studies towards understanding function of lncRNAs in HCC is of importance. LncRNAs regulate cell cycle progression and growth of HCC cells, and they can also induce/inhibit apoptosis in tumor cells. LncRNAs affect invasion and metastasis in HCC mainly by epithelial-mesenchymal transition (EMT) mechanism. Revealing the association between lncRNAs and downstream signaling pathways in HCC is discussed in the current manuscript. Infectious diseases can affect lncRNA expression in mediating HCC development and then, altered expression level of lncRNA is associated with drug resistance and radio-resistance. Biomarker application of lncRNAs and their role in prognosis and diagnosis of HCC are also discussed to pave the way for treatment of HCC patients.
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Affiliation(s)
- Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Mohammad Arad Zandieh
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Sahar Rezaei
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Amirabbas Kakavand
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amir Dehghanpour
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Negin Esmaeili
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Azin Ghahremanzade
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Hamidreza Saebfar
- European University Association, League of European Research Universities, University of Milan, Italy
| | - Hajar Heidari
- Department of Biomedical Sciences, School of Public Health University at Albany State University of New York, Albany, NY, 12208, USA
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Kwang Seok Ahn
- College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
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25
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Huang B, Lang X, Li X. The role of IL-6/JAK2/STAT3 signaling pathway in cancers. Front Oncol 2022; 12:1023177. [PMID: 36591515 PMCID: PMC9800921 DOI: 10.3389/fonc.2022.1023177] [Citation(s) in RCA: 191] [Impact Index Per Article: 63.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
Interleukin-6 (IL-6) is a pleiotropic cytokine involved in immune regulation. It can activate janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) signaling pathway. As one of the important signal transduction pathways in cells, JAK2/STAT3 signaling pathway plays a critical role in cell proliferation and differentiation by affecting the activation state of downstream effector molecules. The activation of JAK2/STAT3 signaling pathway is involved in tumorigenesis and development. It contributes to the formation of tumor inflammatory microenvironment and is closely related to the occurrence and development of many human tumors. This article focuses on the relationship between IL-6/JAK2/STAT3 signaling pathway and liver cancer, breast cancer, colorectal cancer, gastric cancer, lung cancer, pancreatic cancer and ovarian cancer, hoping to provide references for the research of cancer treatment targeting key molecules in IL-6/JAK2/STAT3 signaling pathway.
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Affiliation(s)
- Bei Huang
- Operational Management Office, West China Second University Hospital, Sichuan University, Chengdu, China,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Xiaoling Lang
- Operational Management Office, West China Second University Hospital, Sichuan University, Chengdu, China,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China,*Correspondence: Xiaoling Lang, ; Xihong Li,
| | - Xihong Li
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China,Emergency Department, West China Second University Hospital, Sichuan University, Chengdu, China,*Correspondence: Xiaoling Lang, ; Xihong Li,
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26
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Leung RWH, Lee TKW. Wnt/β-Catenin Signaling as a Driver of Stemness and Metabolic Reprogramming in Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14215468. [PMID: 36358885 PMCID: PMC9656505 DOI: 10.3390/cancers14215468] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 10/30/2022] [Accepted: 11/03/2022] [Indexed: 11/09/2022] Open
Abstract
Simple Summary Aberrant Wnt/β-catenin signaling has been reported to play crucial role in pathogenesis of hepatocellular carcinoma (HCC). In this review, we focus on the regulatory role of Wnt/β-catenin signaling in cancer stemness and metabolic reprogramming, which are two emerging hallmarks of cancer. Understanding the role of Wnt/β-catenin signaling in regulation of the above processes reveals novel therapeutic strategy against this deadly disease. Abstract Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide due to its high rates of tumor recurrence and metastasis. Aberrant Wnt/β-catenin signaling has been shown to play a significant role in HCC development, progression and clinical impact on tumor behavior. Accumulating evidence has revealed the critical involvement of Wnt/β-catenin signaling in driving cancer stemness and metabolic reprogramming, which are regarded as emerging cancer hallmarks. In this review, we summarize the regulatory mechanism of Wnt/β-catenin signaling and its role in HCC. Furthermore, we provide an update on the regulatory roles of Wnt/β-catenin signaling in metabolic reprogramming, cancer stemness and drug resistance in HCC. We also provide an update on preclinical and clinical studies targeting Wnt/β-catenin signaling alone or in combination with current therapies for effective cancer therapy. This review provides insights into the current opportunities and challenges of targeting this signaling pathway in HCC.
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Affiliation(s)
- Rainbow Wing Hei Leung
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
| | - Terence Kin Wah Lee
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
- State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hong Kong, China
- Correspondence: ; Tel.: +852-3400-8799; Fax: +852-2364-9932
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Long non-coding RNA DLGAP1-AS1 modulates the development of non-small-cell lung cancer via the microRNA-193a-5p/DTL axis. J Transl Med 2022; 102:1182-1191. [PMID: 36775444 DOI: 10.1038/s41374-022-00831-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 08/23/2021] [Accepted: 10/15/2021] [Indexed: 12/25/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is one of the most malignant cancers worldwide. A growing number of studies have suggested that long noncoding RNAs (lncRNAs) play a key role in the progression of non-small cell lung cancer (NSCLC). Here, we report a novel lncRNA DLGAP1 antisense RNA 1 (DLGAP1-AS1) that exhibits oncogenic properties in NSCLC. The lncRNA DLGAP1-AS1 and denticleless protein homolog (DTL) presented upregulated expression, but microRNA-193a-5p (miR-193a-5p) showed downregulated expression in cancerous tissues of human lung samples from 48 patients with NSCLC. Partial loss of lncRNA DLGAP1-AS1 reduced malignant cell viability, migration, and invasion but induced apoptosis. Dual-luciferase reporter gene, RNA pull-down and RNA binding protein immunoprecipitation assays demonstrated enrichment of lncRNA DLGAP1-AS1 in miR-193a-5p and Argonaute 2, suggesting that lncRNA DLGAP1-AS1 modulated DTL, a putative target of miR-193a-5p. We also found that restoration of miR-193a-5p rescued NSCLC cell biological functions affected by overexpression of lncRNA DLGAP1-AS1. Silencing lncRNA DLGAP1-AS1 was found to reduce the tumorigenesis of NSCLC cells xenografted into nude mice, which was rescued by DTL overexpression. In conclusion, our study highlights a novel regulatory network of the lncRNA DLGAP1-AS1/miR-193a-5p/DTL axis in NSCLC, providing a potential therapeutic strategy for NSCLC.
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28
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Han Q, Wang M, Dong X, Wei F, Luo Y, Sun X. Non-coding RNAs in hepatocellular carcinoma: Insights into regulatory mechanisms, clinical significance, and therapeutic potential. Front Immunol 2022; 13:985815. [PMID: 36300115 PMCID: PMC9590653 DOI: 10.3389/fimmu.2022.985815] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 09/23/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a complex and heterogeneous malignancy with high incidence and poor prognosis. In addition, owing to the lack of diagnostic and prognostic markers, current multimodal treatment options fail to achieve satisfactory outcomes. Tumor immune microenvironment (TIME), angiogenesis, epithelial-mesenchymal transition (EMT), invasion, metastasis, metabolism, and drug resistance are important factors influencing tumor development and therapy. The intercellular communication of these important processes is mediated by a variety of bioactive molecules to regulate pathophysiological processes in recipient cells. Among these bioactive molecules, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), account for a large part of the human transcriptome, and their dysregulation affects the progression of HCC. The purpose of this review is to evaluate the potential regulatory mechanisms of ncRNAs in HCC, summarize novel biomarkers from somatic fluids (plasma/serum/urine), and explore the potential of some small-molecule modulators as drugs. Thus, through this review, we aim to contribute to a deeper understanding of the regulatory mechanisms, early diagnosis, prognosis, and precise treatment of HCC.
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Affiliation(s)
- Qin Han
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Mengchen Wang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xi Dong
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Fei Wei
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yun Luo
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- *Correspondence: Yun Luo, ; Xiaobo Sun,
| | - Xiaobo Sun
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- *Correspondence: Yun Luo, ; Xiaobo Sun,
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Cheng C, Liu D, Liu Z, Li M, Wang Y, Sun B, Kong R, Chen H, Wang G, Li L, Hu J, Li Y, Chen H, Zhao Z, Zhang T, Zhu S, Pan S. Positive feedback regulation of lncRNA TPT1-AS1 and ITGB3 promotes cell growth and metastasis in pancreatic cancer. Cancer Sci 2022; 113:2986-3001. [PMID: 35534983 PMCID: PMC9459417 DOI: 10.1111/cas.15388] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 04/08/2022] [Accepted: 04/18/2022] [Indexed: 11/29/2022] Open
Abstract
Emerging evidence has indicated that long noncoding RNAs (lncRNAs) are potential biomarkers and play crucial roles in cancer development. However, the functions and underlying mechanisms of lncRNA TPT1-AS1 in pancreatic ductal adenocarcinoma (PDAC) remain elusive. RNAseq data of PDAC tissues and normal tissues were analyzed, and lncRNAs which were associated with PDAC prognosis were identified. The clinical relevance of TPT1-AS1 for PDAC patients was explored, and the effects of TPT1-AS1 in PDAC progression were investigated in vitro and in vivo. LncRNA TPT1-AS1 was highly expressed in PDAC, and high TPT1-AS1 levels predicted a poor prognosis. Moreover, functional experiments revealed that TPT1-AS1 promoted pancreatic cancer cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) process in vitro and in vivo. Mechanistically, TPT1-AS1 functioned as an endogenous sponge for miR-30a-5p, which increased integrin β3 (ITGB3) level in pancreatic cancer cells. Conversely, our data revealed that ITGB3 could activate the transcription factor signal transducer and activator of transcription 3 (STAT3), which in turn bound directly to the TPT1-AS1 promoter and affected the expression of TPT1-AS1, thus forming a positive feedback loop with TPT1-AS1. Taken together, our results uncovered a reciprocal loop of TPT1-AS1 and ITGB3 which contributed to pancreatic cancer growth and development, and indicated that TPT1-AS1 might serve as a novel potential diagnostic biomarker and therapeutic target for PDAC patients.
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Affiliation(s)
- Chundong Cheng
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Danxi Liu
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Zonglin Liu
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Mengyang Li
- Department of Medical OncologyThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Yongwei Wang
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Bei Sun
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Rui Kong
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Hua Chen
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Gang Wang
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Le Li
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Jisheng Hu
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Yilong Li
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Hongze Chen
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Zhongjie Zhao
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Tao Zhang
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Siqiang Zhu
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Shangha Pan
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
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30
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Khan A, Zhang X. Function of the Long Noncoding RNAs in Hepatocellular Carcinoma: Classification, Molecular Mechanisms, and Significant Therapeutic Potentials. Bioengineering (Basel) 2022; 9:406. [PMID: 36004931 PMCID: PMC9405066 DOI: 10.3390/bioengineering9080406] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 08/15/2022] [Accepted: 08/16/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common and serious type of primary liver cancer. HCC patients have a high death rate and poor prognosis due to the lack of clear signs and inadequate treatment interventions. However, the molecular pathways that underpin HCC pathogenesis remain unclear. Long non-coding RNAs (lncRNAs), a new type of RNAs, have been found to play important roles in HCC. LncRNAs have the ability to influence gene expression and protein activity. Dysregulation of lncRNAs has been linked to a growing number of liver disorders, including HCC. As a result, improved understanding of lncRNAs could lead to new insights into HCC etiology, as well as new approaches for the early detection and treatment of HCC. The latest results with respect to the role of lncRNAs in controlling multiple pathways of HCC were summarized in this study. The processes by which lncRNAs influence HCC advancement by interacting with chromatin, RNAs, and proteins at the epigenetic, transcriptional, and post-transcriptional levels were examined. This critical review also highlights recent breakthroughs in lncRNA signaling pathways in HCC progression, shedding light on the potential applications of lncRNAs for HCC diagnosis and therapy.
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Affiliation(s)
| | - Xiaobo Zhang
- College of Life Sciences, Zhejiang University, Hangzhou 310058, China
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31
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Li M, Xiao Y, Liu M, Ning Q, Xiang Z, Zheng X, Tang S, Mo Z. MiR-26a-5p regulates proliferation, apoptosis, migration and invasion via inhibiting hydroxysteroid dehydrogenase like-2 in cervical cancer cell. BMC Cancer 2022; 22:876. [PMID: 35948893 PMCID: PMC9367141 DOI: 10.1186/s12885-022-09970-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 08/02/2022] [Indexed: 12/18/2022] Open
Abstract
Background Evidences have indicated that miR-26a-5p regulates the malignant properties of various tumor cells. However, the influences of miR-26a-5p on proliferation, apoptosis and invasion are still vague in the cervical cancer (CC) cells. Methods The miRNA microarray and real-time quantitative PCR (RT-qPCR) analysis were utilized to detect the expression of miR-26a-5p in the patients with CC. Kaplan–Meier plotter was performed to evaluate the overall survival (OS) of the patients with CC. The CCK-8, flow cytometry, transwell and wound healing analyses were respectively used to analyze proliferation, migration and invasion in the CC cells. RT-qPCR, western blot and IHC analysis were executed to measure the expression of hydroxysteroid dehydrogenase like-2 (HSDL2) in the patients with CC. Bioinformatics and luciferase reporter assay were carried out to verify the relationship of miR-26a-5p and HSDL2. Results The expression of miR-26a-5p was downregulated and low expression of miR-26a-5p indicated a poor OS in patients with CC. Overexpression of miR-26a-5p significantly inhibited proliferation, migration and invasion, accelerated apoptosis in the Hela and C33A cells. The expression of HSDL2 was upregulated, and negatively correlated with miR-26a-5p in the patients with CC. HSDL2 was directly targeted by miR-26a-5p and rescue experiments displayed that HSDL2 partially abolished proliferation, apoptosis, migration, and invasion induced by miR-26a-5p in CC cells. Conclusions MiR-26a-5p alleviated progression of CC by suppressing proliferation, migration and invasion, promoting apoptosis through downregulating HSDL2. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09970-x.
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Affiliation(s)
- Ming Li
- Hunan Province Key Laboratory for Antibody-Based Drug and Intelligent Delivery System, Hunan University of Medicine, Huaihua, 418000, Hunan, China.,Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Guilin Medical University, Guilin, 541001, Guangxi, China
| | - Yubo Xiao
- Hunan Province Key Laboratory for Antibody-Based Drug and Intelligent Delivery System, Hunan University of Medicine, Huaihua, 418000, Hunan, China
| | - Minqi Liu
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Guilin Medical University, Guilin, 541001, Guangxi, China.,Guangxi Province Postgraduate Co-Training Base for Cooperative Innovation in Basic Medicine (Guilin Medical University and Yueyang Women & Children's Medical Center), Yueyang, 414000, China
| | - Qian Ning
- Hunan Province Key Laboratory for Antibody-Based Drug and Intelligent Delivery System, Hunan University of Medicine, Huaihua, 418000, Hunan, China
| | - Ziye Xiang
- School of Medical Laboratory Science, Changsha Medical University, Changsha, 410000, Hunan, China
| | - Xiang Zheng
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Guilin Medical University, Guilin, 541001, Guangxi, China
| | - Shengsong Tang
- Hunan Province Key Laboratory for Antibody-Based Drug and Intelligent Delivery System, Hunan University of Medicine, Huaihua, 418000, Hunan, China. .,College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, 410128, Hunan, China.
| | - Zhongcheng Mo
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Guilin Medical University, Guilin, 541001, Guangxi, China. .,Guangxi Province Postgraduate Co-Training Base for Cooperative Innovation in Basic Medicine (Guilin Medical University and Yueyang Women & Children's Medical Center), Yueyang, 414000, China.
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32
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Fu T, Lin Y, Lin L, Yang Y, Guo Q, Long Y, He H, Bao Y, Lin T, Chen J, Chen Z, Du L, Liao G, Liao B, Huang J. Network architecture of non-coding RNAs provides insights into the pathogenesis of upper tract urothelial carcinoma. Urol Oncol 2022; 40:383.e11-383.e21. [DOI: 10.1016/j.urolonc.2022.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 04/18/2022] [Accepted: 05/03/2022] [Indexed: 10/18/2022]
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33
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Ma Y, Di Y, Li Q, Zhan Q, He X, Liu S, Zou H, Corpe C, Chen L, Wang J. LncRNAs as epigenetic regulators of epithelial to mesenchymal transition in pancreatic cancer. Discov Oncol 2022; 13:61. [PMID: 35819532 PMCID: PMC9276894 DOI: 10.1007/s12672-022-00522-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 07/01/2022] [Indexed: 11/04/2022] Open
Abstract
Pancreatic cancer is the leading cause of cancer-related mortality because of tumor metastasis. Activation of the epithelial-to-mesenchymal transition (EMT) pathway has been confirmed to be an important driver of pancreatic cancer progression from initiation to metastasis. Long noncoding RNAs (lncRNAs) have been reported to exert essential physiological functions in pancreatic cancer progression by regulating the EMT program. In this review, we have summarized the role of EMT-related lncRNAs in human pancreatic cancer and the potential molecular mechanisms by which lncRNAs can be vital epigenetic regulators of epithelial to mesenchymal transition. Specifically, EMT-activating transcription factors (EMT-TFs) regulate EMT via TGF-β/Smad, Wnt/β-catenin, and JAK/STAT pathways. In addition, the interaction between lncRNAs and HIF-1α and m6A RNA methylation also have an impact on tumor metastasis and EMT in pancreatic cancer. This review will provide insights into lncRNAs as promising biomarkers for tumor metastasis and potential therapeutic strategies for pancreatic cancer.
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Affiliation(s)
- Yan Ma
- Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Jinshan District, Shanghai, 201508, People's Republic of China
| | - Yang Di
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Qiuyue Li
- Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Jinshan District, Shanghai, 201508, People's Republic of China
| | - Qilin Zhan
- Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Jinshan District, Shanghai, 201508, People's Republic of China
| | - Xiaomeng He
- Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Jinshan District, Shanghai, 201508, People's Republic of China
| | - Shanshan Liu
- Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Jinshan District, Shanghai, 201508, People's Republic of China
| | - Heng Zou
- Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Jinshan District, Shanghai, 201508, People's Republic of China
| | - Christopher Corpe
- King's College London, Nutritional Science Department, 150 Stamford Street, Waterloo, London, SE19NH, UK
| | - Litian Chen
- Department of Hepatobiliary Surgery, Shanghai Jiaotong University School of Medicine Xinhua Hospital, Kongjiang Road 1665, Shanghai, China.
| | - Jin Wang
- Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Jinshan District, Shanghai, 201508, People's Republic of China.
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Liu Z, Nan Y, Luo Q, Wu X, Liu S, Zhao P, Chang W, Zhou A. DLGAP1-AS2-Mediated Phosphatidic Acid Synthesis Activates YAP Signaling and Confers Chemoresistance in Squamous Cell Carcinoma. Cancer Res 2022; 82:2887-2903. [PMID: 35731019 DOI: 10.1158/0008-5472.can-22-0717] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/25/2022] [Accepted: 06/20/2022] [Indexed: 11/16/2022]
Abstract
Squamous cell carcinomas (SCC) constitute a group of human malignancies that originate from the squamous epithelium. Most SCC patients experience treatment failure and relapse and have a poor prognosis due to de novo and acquired resistance to first-line chemotherapeutic agents. To identify chemoresistance mechanisms and explore novel targets for chemosensitization, we performed whole-transcriptome sequencing of paired resistant and parental SCC cells. We identified DLGAP1 antisense RNA 2 (D-AS2) as a crucial noncoding RNA that contributes to chemoresistance in SCC. Mechanistically, D-AS2 affected chromatin accessibility around the histone mark H3K27ac of FAM3 metabolism regulating signaling molecule D (FAM3D), reducing FAM3D mRNA transcription and extracellular protein secretion. FAM3D interacted with the Gαi-coupled G protein-coupled receptors (GPCRs) formyl peptide receptor 1 (FPR1) and FPR2 to suppress phospholipase D (PLD) activity, and reduced FAM3D increased PLD signaling. Moreover, activated PLD promoted phosphatidic acid (PA) production and subsequent nuclear translocation of yes-associated protein (YAP). Accordingly, in vivo administration of a D-AS2-targeting antisense oligonucleotide sensitized SCC to cisplatin treatment. In summary, this study shows that D-AS2/FAM3D-mediated PLD/PA lipid signaling is essential for SCC chemoresistance, suggesting D-AS2 can be targeted to sensitize SCC to cytotoxic chemotherapeutic agents.
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Affiliation(s)
- Zhihua Liu
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yabing Nan
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qingyu Luo
- Dana-Farber Cancer Institute, Boston, MA, United States
| | - Xiaowei Wu
- Dana-Farber Cancer Institute, Boston, MA, United States
| | - Shi Liu
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Pengfei Zhao
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wan Chang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Aiping Zhou
- National Cancer Center / National Clinical Research Center for Cancer / Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Yang X, Jiang Z, Li Y, Zhang Y, Han Y, Gao L. Non-coding RNAs regulating epithelial-mesenchymal transition: Research progress in liver disease. Biomed Pharmacother 2022; 150:112972. [PMID: 35447551 DOI: 10.1016/j.biopha.2022.112972] [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: 03/11/2022] [Revised: 04/12/2022] [Accepted: 04/12/2022] [Indexed: 11/18/2022] Open
Abstract
Chronic liver injury could gradually progress to liver fibrosis, cirrhosis, and even hepatic carcinoma without effective treatment. The massive production and activation of abnormal cell differentiation is vital to the procession of liver diseases. Epithelial-mesenchymal transformation (EMT) is a biological process in which differentiated epithelial cells lose their epithelial characteristics and acquire mesenchymal cell migration capacity. Emerging evidence suggests that EMT not only occurs in the process of hepatocellular carcinogenesis, but also appears in liver cells transforming to myofibroblasts, a core event of liver disease. Non-coding RNA (ncRNA) such as microRNA (miRNA), long non-coding RNA (lncRNA) and circular RNA (circRNA) are important regulatory factors in EMT, which can regulate target gene expression by binding with RNA single-stranded. Various studies had shown that ncRNA regulation of EMT plays a key role in liver disease development, and many effective ncRNAs have been identified as promising biomarkers for the diagnosis and treatment of liver disease. In this review, we focus on the relationship between the different ncRNAs and EMT as well as the specific molecular mechanism in the liver diseases to enrich the pathological progress of liver diseases and provide reference for the treatment of liver diseases.
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Affiliation(s)
- Xiang Yang
- Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China.
| | - Zhitao Jiang
- Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Yang Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yingchun Zhang
- Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Yi Han
- Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Liyuan Gao
- Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China.
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36
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Zhou B, Zhang W, Yan Z, Zhao B, Zhao J, Feng W, Chen X, Li C, Liu KX. MicroRNA-26b-5p Targets DAPK1 to Reduce Intestinal Ischemia/Reperfusion Injury via Inhibition of Intestinal Mucosal Cell Apoptosis. Dig Dis Sci 2022; 67:1794-1805. [PMID: 33839982 PMCID: PMC9142477 DOI: 10.1007/s10620-021-06975-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 03/26/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Emerging evidence has suggested that miRNAs are important regulators of intestinal I/R injury, but their function in this context remains elusive. AIMS To evaluate the role of miR-26b-5p in intestinal I/R injury. METHODS We utilized in vivo murine models of intestinal I/R and in vitro Mode-K cell-based models of oxygen and glucose deprivation/reperfusion (OGD/R) to examine the function of miR-26b-5p in intestinal I/R injury. The expression of miR-26b-5p in intestinal mucosa and Mode-K cell was detected by RT-PCR. HE staining and Chiu's score were used to evaluate intestinal mucosa injury severity. Apoptosis was detected by TUNEL stain, flow cytometry, and western blot. TargetScan and StarBase prediction algorithms were applied to predict putative target genes of miR-26b-5p and validated by luciferase reporter analyses. RESULTS We found that the expression of miR-26b-5p in intestinal mucosa was markedly decreased during I/R injury. We additionally found miR-26b-5p overexpression to markedly disrupt intestinal I/R- or OGD/R-induced injury in vivo and in vitro, whereas inhibiting this miRNA had an adverse impact and resulted in increased intestinal tissue injury and Mode-K cell damage. From a mechanistic perspective, miR-26b-5p was predicted to target DAPK1, which was related to cellular apoptosis. Luciferase reporter assay results confirmed that miR-26b-5p directly targets DAPK1 in Mode-K cells, thereby suppressing OGD/R-induced cell apoptosis. CONCLUSION Our findings show that miR-26b-5p may prevent intestinal I/R injury via targeting DAPK1 and inhibiting intestinal mucosal cell apoptosis, suggesting that this miRNA may be a viable target for the treatment of intestinal I/R injury.
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Affiliation(s)
- Bowei Zhou
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Wenjuan Zhang
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Zhengzheng Yan
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Bingcheng Zhao
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Jin Zhao
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Weijie Feng
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Xiaodong Chen
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Cai Li
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Ke-Xuan Liu
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China.
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37
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Chen S, Zhang Y, Ding X, Li W. Identification of lncRNA/circRNA-miRNA-mRNA ceRNA Network as Biomarkers for Hepatocellular Carcinoma. Front Genet 2022; 13:838869. [PMID: 35386284 PMCID: PMC8977626 DOI: 10.3389/fgene.2022.838869] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 02/24/2022] [Indexed: 12/24/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC) accounts for the majority of liver cancer, with the incidence and mortality rates increasing every year. Despite the improvement of clinical management, substantial challenges remain due to its high recurrence rates and short survival period. This study aimed to identify potential diagnostic and prognostic biomarkers in HCC through bioinformatic analysis. Methods: Datasets from GEO and TCGA databases were used for the bioinformatic analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were carried out by WebGestalt website and clusterProfiler package of R. The STRING database and Cytoscape software were used to establish the protein-protein interaction (PPI) network. The GEPIA website was used to perform expression analyses of the genes. The miRDB, miRWalk, and TargetScan were employed to predict miRNAs and the expression levels of the predicted miRNAs were explored via OncomiR database. LncRNAs were predicted in the StarBase and LncBase while circRNA prediction was performed by the circBank. ROC curve analysis and Kaplan-Meier (KM) survival analysis were performed to evaluate the diagnostic and prognostic value of the gene expression, respectively. Results: A total of 327 upregulated and 422 downregulated overlapping DEGs were identified between HCC tissues and noncancerous liver tissues. The PPI network was constructed with 89 nodes and 178 edges and eight hub genes were selected to predict upstream miRNAs and ceRNAs. A lncRNA/circRNA-miRNA-mRNA network was successfully constructed based on the ceRNA hypothesis, including five lncRNAs (DLGAP1-AS1, GAS5, LINC00665, TYMSOS, and ZFAS1), six circRNAs (hsa_circ_0003209, hsa_circ_0008128, hsa_circ_0020396, hsa_circ_0030051, hsa_circ_0034049, and hsa_circ_0082333), eight miRNAs (hsa-miR-150-5p, hsa-miR-19b-3p, hsa-miR-23b-3p, hsa-miR-26a-5p, hsa-miR-651-5p, hsa-miR-10a-5p, hsa-miR-214-5p and hsa-miR-486-5p), and five mRNAs (CDC6, GINS1, MCM4, MCM6, and MCM7). The ceRNA network can promote HCC progression via cell cycle, DNA replication, and other pathways. Clinical diagnostic and survival analyses demonstrated that the ZFAS1/hsa-miR-150-5p/GINS1 ceRNA regulatory axis had a high diagnostic and prognostic value. Conclusion: These results revealed that cell cycle and DNA replication pathway could be potential pathways to participate in HCC development. The ceRNA network is expected to provide potential biomarkers and therapeutic targets for HCC management, especially the ZFAS1/hsa-miR-150-5p/GINS1 regulatory axis.
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Affiliation(s)
- Shanshan Chen
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yongchao Zhang
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoyan Ding
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Wei Li
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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38
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Xu Y, Yu X, Sun Z, He Y, Guo W. Roles of lncRNAs Mediating Wnt/β-Catenin Signaling in HCC. Front Oncol 2022; 12:831366. [PMID: 35356220 PMCID: PMC8959654 DOI: 10.3389/fonc.2022.831366] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 02/14/2022] [Indexed: 11/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is considered the second most deadly cancer worldwide. Due to the absence of early diagnostic markers and effective therapeutic approaches, distant metastasis and increasing recurrence rates are major difficulties in the clinical treatment of HCC. Further understanding of its pathogenesis has become an urgent goal in HCC research. Recently, abnormal expression of long noncoding RNAs (lncRNAs) was identified as a vital regulator involved in the initiation and development of HCC. Activation of the Wnt/β-catenin pathway has been reported to obviously impact cell proliferation, invasion, and migration of HCC. This article reviews specific interactions, significant mechanisms and molecules related to HCC initiation and progression to provide promising strategies for treatment.
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Affiliation(s)
- Yating Xu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation Medicine, Zhengzhou, China
| | - Xiao Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation Medicine, Zhengzhou, China
| | - Zongzong Sun
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuting He
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation Medicine, Zhengzhou, China
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation Medicine, Zhengzhou, China
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Ginckels P, Holvoet P. Oxidative Stress and Inflammation in Cardiovascular Diseases and Cancer: Role of Non-coding RNAs. THE YALE JOURNAL OF BIOLOGY AND MEDICINE 2022; 95:129-152. [PMID: 35370493 PMCID: PMC8961704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
High oxidative stress, Th1/Th17 immune response, M1 macrophage inflammation, and cell death are associated with cardiovascular diseases. Controlled oxidative stress, Th2/Treg anti-tumor immune response, M2 macrophage inflammation, and survival are associated with cancer. MiR-21 protects against cardiovascular diseases but may induce tumor growth by retaining the anti-inflammatory M2 macrophage and Treg phenotypes and inhibiting apoptosis. Down-regulation of let-7, miR-1, miR-9, miR-16, miR-20a, miR-22a, miR-23a, miR-24a, miR-26a, miR-29, miR-30a, miR-34a, miR-124, miR-128, miR-130a, miR-133, miR-140, miR-143-145, miR-150, miR-153, miR-181a, miR-378, and miR-383 may aid cancer cells to escape from stresses. Upregulation of miR-146 and miR-223 may reduce anti-tumor immune response together with miR-21 that also protects against apoptosis. MiR-155 and silencing of let-7e, miR-125, and miR-126 increase anti-tumor immune response. MiR expression depends on oxidative stress, cytokines, MYC, and TGF-β, and expression of silencing lncRNAs and circ-RNAs. However, one lncRNA or circ-RNA may have opposite effects by targeting several miRs. For example, PVT1 induces apoptosis by targeting miR-16a and miR-30a but inhibits apoptosis by silencing miR-17. In addition, levels of a non-coding RNA in a cell type depend not only on expression in that cell type but also on an exchange of microvesicles between cell types and tumors. Although we got more insight into the function of a growing number of individual non-coding RNAs, overall, we do not know enough how several of them interact in functional networks and how their expression changes at different stages of disease progression.
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Affiliation(s)
- Pieterjan Ginckels
- Department of Architecture, Brussels and Gent, KU Leuven, Leuven, Belgium
| | - Paul Holvoet
- Experimental Cardiology, KU Leuven, Leuven, Belgium,To whom all correspondence should be addressed: Paul Holvoet, Experimental
Cardiology, KU Leuven, Belgium; ; ORCID iD:
https://orcid.org/0000-0001-9201-0772
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In Silico Analysis Identifies Upregulated lncRNA DLGAP1-AS1 Which Is Correlated to Poor Prognosis and Promotes Cell Proliferation in Glioblastoma. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:5038124. [PMID: 35341001 PMCID: PMC8941517 DOI: 10.1155/2022/5038124] [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: 10/07/2021] [Revised: 11/21/2021] [Accepted: 12/27/2021] [Indexed: 01/04/2023]
Abstract
Long noncoding RNAs have been reported to regulate the tumorigenesis, growth, and metastasis of glioblastomas. In this study, we identified 1623 differently expressed mRNAs and 38 lncRNAs utilizing the CGGA and TCGA databases. Among these mRNAs and lncRNAs, we focused on DLGAP1-AS1 in this study. The results demonstrated that DLGAP1-AS1 was higher in WHO IV glioma than in WHO II and WHO III gliomas, higher in WHO III glioma than in WHO II glioma samples, higher in IDH1 wildtype glioma than in IDH1-mutant glioma samples, and higher in 1p/19q noncodeletion glioma than in 1p/19q codeletion glioma samples. Moreover, we observed that higher expression levels of DLGAP1-AS1 were correlated to shorter OS time in both low-grade and high-grade gliomas. Next, we evaluated the function of DLGAP1-AS1 in GBM using in vivo experiments. The data revealed that DLGAP1-AS1 knockdown greatly hindered U87 cell and U251 cell proliferation. Using coexpression network analysis, we identified that ATG4A was a potential downstream target of DLGAP1-AS1. The further analysis showed that ATG4B was significantly upregulated and correlated to shorter OS time in gliomas using both the CGGA and TCGA databases. Finally, we showed that ablated ATG4B greatly hindered GBM cell proliferation. Our conclusion suggested that DLGAP1-AS1 may be a potential prognosis biomarker and facilitated the occurrence and development of glioma via ATG4A in GBM.
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Hu KQ, Ao XS. Long non-coding RNA DLGAP1 antisense RNA 1 accelerates glioma progression via the microRNA-628-5p/DEAD-box helicase 59 pathway. Clinics (Sao Paulo) 2022; 77:100002. [PMID: 35113786 PMCID: PMC8903805 DOI: 10.1016/j.clinsp.2021.100002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 10/15/2021] [Indexed: 12/03/2022] Open
Abstract
OBJECTIVES Abnormal expression of long non-coding RNAs (lncRNAs) plays a prominent role in glioma progression. However, the biological function and mechanism of lncRNA DLGAP1 antisense RNA 1 (DLGAP1-AS1) in gliomas are still unknown. METHODS The authors assessed DLGAP1-AS1 and miR-628-5p expression in glioma tissues and cell lines using quantitative real-time polymerase chain reaction (qRT-PCR) and evaluated their effects on glioma cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) using the cell counting kit-8 (CCK-8) assay, 5-Ethynyl-2'-deoxyuridine (EdU) assay, Transwell assay, and western blot, respectively. The expression of DEAD-box helicase 59 (DDX59) was quantified using western blotting, and a dual-luciferase reporter gene assay was performed to detect the interaction between DLGAP1-AS1 and miR-628-5p. RESULTS The authors observed increased DLGAP1-AS1 expression in glioma tissues and cell lines with higher WHO grades and shorter survival time. DLGAP1-AS1 promoted the proliferation, migration, invasion, and EMT of glioma cells, while miR-628-5p counteracted these effects. The authors identified DLGAP1-AS1 as a molecular sponge of miR-628-5p in glioma cells as the biological functions of DLGAP1-AS1 are partially mediated via miR-628-5p. In addition, DLGAP1-AS1 upregulated DDX59 expression by inhibiting miR-628-5p expression. CONCLUSION The DLGAP1-AS1/miR-628-5p/DDX59 axis regulates glioma progression.
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Affiliation(s)
- Ke-Qi Hu
- Department of Neurosurgery, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, China
| | - Xiang-Sheng Ao
- Department of Neurosurgery, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, China.
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Khashkhashi Moghadam S, Bakhshinejad B, Khalafizadeh A, Mahmud Hussen B, Babashah S. Non-coding RNA-associated competitive endogenous RNA regulatory networks: Novel diagnostic and therapeutic opportunities for hepatocellular carcinoma. J Cell Mol Med 2021; 26:287-305. [PMID: 34907642 PMCID: PMC8743668 DOI: 10.1111/jcmm.17126] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 11/09/2021] [Accepted: 12/03/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC), as the most prevalent liver malignancy, is annually diagnosed in more than half a million people worldwide. HCC is strongly associated with hepatitis B and C viral infections as well as alcohol abuse. Obesity and nonalcoholic fatty liver disease (NAFLD) also significantly enhance the risk of liver cancer. Despite recent improvements in therapeutic approaches, patients diagnosed in advanced stages show poor prognosis. Accumulating evidence provides support for the regulatory role of non-coding RNAs (ncRNAs) in cancer. There are a variety of reports indicating the regulatory role of microRNAs (miRNAs) in different stages of HCC. Long non-coding RNAs (LncRNAs) exert their effects by sponging miRNAs and controlling the expression of miRNA-targeted genes. Circular RNAs (circRNAs) perform their biological functions by acting as transcriptional regulators, miRNA sponges and protein templates. Diverse studies have illustrated that dysregulation of competing endogenous RNA networks (ceRNETs) is remarkably correlated with HCC-causing diseases such as chronic viral infections, nonalcoholic steatohepatitis and liver fibrosis/cirrhosis. The aim of the current article was to provide an overview of the role and molecular mechanisms underlying the function of ceRNETs that modulate the characteristics of HCC such as uncontrolled cell proliferation, resistance to cell death, metabolic reprogramming, immune escape, angiogenesis and metastasis. The current knowledge highlights the potential of these regulatory RNA molecules as novel diagnostic biomarkers and therapeutic targets in HCC.
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Affiliation(s)
| | - Babak Bakhshinejad
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ali Khalafizadeh
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region, Iraq.,Center of Research and Strategic Studies, Lebanese French University, Erbil, Kurdistan Region, Iraq
| | - Sadegh Babashah
- Research and Development Center of Biotechnology, Tarbiat Modares University, Tehran, Iran.,Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
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Deldar Abad Paskeh M, Mirzaei S, Ashrafizadeh M, Zarrabi A, Sethi G. Wnt/β-Catenin Signaling as a Driver of Hepatocellular Carcinoma Progression: An Emphasis on Molecular Pathways. J Hepatocell Carcinoma 2021; 8:1415-1444. [PMID: 34858888 PMCID: PMC8630469 DOI: 10.2147/jhc.s336858] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 11/05/2021] [Indexed: 12/14/2022] Open
Abstract
Liver cancers cause a high rate of death worldwide and hepatocellular carcinoma (HCC) is considered as the most common primary liver cancer. HCC remains a challenging disease to treat. Wnt/β-catenin signaling pathway is considered a tumor-promoting factor in various cancers; hence, the present review focused on the role of Wnt signaling in HCC, and its association with progression and therapy response based on pre-clinical and clinical evidence. The nuclear translocation of β-catenin enhances expression level of genes such as c-Myc and MMPs in increasing cancer progression. The mutation of CTNNB1 gene encoding β-catenin and its overexpression can lead to HCC progression. β-catenin signaling enhances cancer stem cell features of HCC and promotes their growth rate. Furthermore, β-catenin prevents apoptosis in HCC cells and increases their migration via triggering EMT and upregulating MMP levels. It is suggested that β-catenin signaling participates in mediating drug resistance and immuno-resistance in HCC. Upstream mediators including ncRNAs can regulate β-catenin signaling in HCC. Anti-cancer agents inhibit β-catenin signaling and mediate its proteasomal degradation in HCC therapy. Furthermore, clinical studies have revealed the role of β-catenin and its gene mutation (CTNBB1) in HCC progression. Based on these subjects, future experiments can focus on developing novel therapeutics targeting Wnt/β-catenin signaling in HCC therapy.
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Affiliation(s)
- Mahshid Deldar Abad Paskeh
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, Istanbul, Turkey
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul, Turkey
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul, Turkey
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Sariyer, Istanbul, 34396, Turkey
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Cancer Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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STK39 enhances the progression of Cholangiocarcinoma via PI3K/AKT pathway. iScience 2021; 24:103223. [PMID: 34746696 PMCID: PMC8551078 DOI: 10.1016/j.isci.2021.103223] [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: 07/30/2021] [Revised: 09/10/2021] [Accepted: 09/30/2021] [Indexed: 02/07/2023] Open
Abstract
Serine/threonine kinase 39 (STK39) is overexpressed in various tumor tissues and plays an essential role in tumor progression. In this study, we investigated the clinical value, as well as the potential functions and mechanisms of STK39 in cholangiocarcinoma (CCA). The results showed that STK39 was overexpressed in CCA and negatively associated with the prognosis of patients with CCA. Functionally, STK39 knockdown suppressed cell proliferation, migration, and invasion, while STK39 overexpression facilitated tumor aggressiveness. The tumor-promoting effects of STK39 in CCA were also validated by in vivo experiments. Mechanistically, RNA-seq analysis identified that STK39 enhanced the progression of CCA by activating PI3K/AKT signaling pathway. Furthermore, overexpression of STK39 could induce gemcitabine resistance in CCA cells. Moreover, the increased expression of STK39 may be mediated by the dysregulation of miR-26a-5p. In summary, STK39 could be served as a valuable prognostic candidate and a potential therapeutic target of CCA.
STK39 was overexpressed in CCA, negatively associated with the prognosis of patients with CCA STK39 knockdown suppressed cell proliferation and invasion. STK39 overexpression facilitated tumor aggressiveness STK39 mediates oncogenic effects on CCA cells by activating the PI3K/AKT signaling pathway STK39 reduces CCA sensitivity to gemcitabine. Increased expression of STK39 may be mediated by dysregulation of miR-26a-5p
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Zheng X, Gou Y, Jiang Z, Yang A, Yang Z, Qin S. Icaritin-Induced FAM99A Affects GLUT1-Mediated Glycolysis via Regulating the JAK2/STAT3 Pathway in Hepatocellular Carcinoma. Front Oncol 2021; 11:740557. [PMID: 34765550 PMCID: PMC8576446 DOI: 10.3389/fonc.2021.740557] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 09/29/2021] [Indexed: 11/19/2022] Open
Abstract
Icaritin is a potential treatment option for hepatocellular carcinoma (HCC) based on the results of its phase 2 stage trial. Glucose transporter 1 (GLUT1), a critical gene in regulating glycolysis, has been recognized as a promising target in HCC treatment. Previous studies have reported that FAM99A, a new long noncoding (lncRNA), is associated with HCC metastasis. It has also been demonstrated that the JAK2/STAT3 pathway is related to HCC and is the target of icaritin treatment. However, whether FAM99A participates in icaritin treatment and regulates GLUT1-mediated glycolysis via the JAK2/STAT3 pathway in HCC cells remains to be explored. Our study aimed to clarify the mechanisms underlying glycolysis and understand the regulating effects of the FAM99A and JAK2/STAT3 pathway in HCC cells in icaritin treatment. Molecular mechanism studies were conducted to verify whether FAM99A could bind to the JAK2/STAT3 pathway and to identify the regulatory mechanisms in the HCC cells. It was revealed that icaritin inhibited proliferation, GLUT1 level, and the glycolysis of the HCC cells. FAM99A in HCC cells was upregulated after a high concentration treatment of icaritin. FAM99A inhibited GLUT1 by blocking the JAK2/STAT3 pathway. Mechanically, FAM99A interacted with EIF4B to inhibit gp130 and gp80 translation, which then interacted with miR-299-5p to upregulate SOCS3, causing the JAK2 pathway to inhibit STAT3 phosphorylation, so that JAK2/STAT3 was blocked in HCC cells. Overall, our study proved that icaritin-induced FAM99A can inhibit HCC cell viability and GLUT1-mediated glycolysis via blocking the JAK2/STAT3 pathway.
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Affiliation(s)
- Xia Zheng
- Nanjing University of Chinese Medicine, Nanjing, China.,Oncology Department, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Yudong Gou
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Ziyu Jiang
- Nanjing University of Chinese Medicine, Nanjing, China.,Oncology Department, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Aizhen Yang
- Laboratory Department, Nanjing Jinling Hospital, Nanjing, China
| | - Zhihui Yang
- Pathology Department, Nanjing Jinling Hospital, Nanjing, China
| | - Shukui Qin
- Nanjing University of Chinese Medicine, Nanjing, China.,Oncology Department, Nanjing Jinling Hospital, Nanjing, China
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Shi Y, Liu JB, Deng J, Zou DZ, Wu JJ, Cao YH, Yin J, Ma YS, Da F, Li W. The role of ceRNA-mediated diagnosis and therapy in hepatocellular carcinoma. Hereditas 2021; 158:44. [PMID: 34758879 PMCID: PMC8582193 DOI: 10.1186/s41065-021-00208-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/12/2021] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide due to its high degree of malignancy, high incidence, and low survival rate. However, the underlying mechanisms of hepatocarcinogenesis remain unclear. Long non coding RNA (lncRNA) has been shown as a novel type of RNA. lncRNA by acting as ceRNA can participate in various biological processes of HCC cells, such as tumor cell proliferation, migration, invasion, apoptosis and drug resistance by regulating downstream target gene expression and cancer-related signaling pathways. Meanwhile, lncRNA can predict the efficacy of treatment strategies for HCC and serve as a potential target for the diagnosis and treatment of HCC. Therefore, lncRNA serving as ceRNA may become a vital candidate biomarker for clinical diagnosis and treatment. In this review, the epidemiology of HCC, including morbidity, mortality, regional distribution, risk factors, and current treatment advances, was briefly discussed, and some biological functions of lncRNA in HCC were summarized with emphasis on the molecular mechanism and clinical application of lncRNA-mediated ceRNA regulatory network in HCC. This paper can contribute to the better understanding of the mechanism of the influence of lncRNA-mediated ceRNA networks (ceRNETs) on HCC and provide directions and strategies for future studies.
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Affiliation(s)
- Yi Shi
- College of Life Sciences and Chemistry, Hunan University of Technology, Zhuzhou, 412007, Hunan, China.,Cancer Institute, Affiliated Tumor Hospital of Nantong University, Nantong, 226631, China.,National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, 410004, Hunan, China
| | - Ji-Bin Liu
- Cancer Institute, Affiliated Tumor Hospital of Nantong University, Nantong, 226631, China
| | - Jing Deng
- National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, 410004, Hunan, China
| | - Da-Zhi Zou
- Department of Spine Surgery, Longhui County People's Hospital, Longhui, 422200, Hunan, China
| | - Jian-Jun Wu
- Nantong Haimen Yuelai Health Centre, Haimen, 226100, China
| | - Ya-Hong Cao
- Department of Respiratory, Nantong Traditional Chinese Medicine Hospital, Nantong, 226019, Jiangsu Province, China
| | - Jie Yin
- Department of General Surgery, Haian people's Hospital, Haian, 226600, Jiangsu, China
| | - Yu-Shui Ma
- Cancer Institute, Affiliated Tumor Hospital of Nantong University, Nantong, 226631, China.
| | - Fu Da
- Cancer Institute, Affiliated Tumor Hospital of Nantong University, Nantong, 226631, China. .,National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, 410004, Hunan, China.
| | - Wen Li
- College of Life Sciences and Chemistry, Hunan University of Technology, Zhuzhou, 412007, Hunan, China. .,National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, 410004, Hunan, China.
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Lv W, Tan Y, Zhao C, Wang Y, Wu M, Wu Y, Ren Y, Zhang Q. Identification of pyroptosis-related lncRNAs for constructing a prognostic model and their correlation with immune infiltration in breast cancer. J Cell Mol Med 2021; 25:10403-10417. [PMID: 34632690 PMCID: PMC8581320 DOI: 10.1111/jcmm.16969] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 08/28/2021] [Accepted: 09/19/2021] [Indexed: 12/19/2022] Open
Abstract
The inflammasome-dependent cell death, which is denoted as pyroptosis, might be abnormally regulated during oncogenesis and tumour progression. Long non-coding RNAs (LncRNAs) are pivotal orchestrators in breast cancer (BC), which have the potential to be a biomarker for BC diagnosis and therapy. The present study aims to explore the correlation between pyroptosis-related lncRNAs and BC prognosis. In this study, a profile of 8 differentially expressed lncRNAs was screened in the TCGA database and used to construct a prognostic model. The BC patients were divided into high- and low-risk groups dependent on the median cutoff of the risk score in the model. Interestingly, the risk model significantly distinguished the clinical characteristics of BC patients between high- and low-risk groups. Then, the risk score of the model was identified to be an excellent independent prognostic factor. Notably, the GO, KEGG, GSEA and ssGSEA analyses revealed the different immune statuses between the high- and low-risk groups. Particularly, the 8 lncRNAs expressed differentially in BC tissues between two risk subgroups in vitro validation. Collectively, this constructed well-validated model is of high effectiveness to predict the prognosis of BC, which will provide novel means that is applicable for BC prognosis recognition.
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Affiliation(s)
- Wenchang Lv
- Department of Plastic and Cosmetic SurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Yufang Tan
- Department of Plastic and Cosmetic SurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Chongru Zhao
- Department of Plastic and Cosmetic SurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Yichen Wang
- Department of Plastic and Cosmetic SurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Min Wu
- Department of Plastic and Cosmetic SurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Yiping Wu
- Department of Plastic and Cosmetic SurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Yuping Ren
- Department of Plastic and Cosmetic SurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Qi Zhang
- Department of Plastic and Cosmetic SurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
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Zhu C, Zhang H, Wei D, Sun Z. Silencing lncRNA GAS5 alleviates apoptosis and fibrosis in diabetic cardiomyopathy by targeting miR-26a/b-5p. Acta Diabetol 2021; 58:1491-1501. [PMID: 34091757 DOI: 10.1007/s00592-021-01745-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 05/11/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND LncRNA GAS5 is associated with high glucose-induced cardiomyocyte injury, but its role in diabetic cardiomyopathy (DCM) remains unclear. METHODS Mice were administered with streptozotocin to construct the diabetic model (DM). Primary mouse cardiomyocytes were isolated and treated with 30 mmol/L high glucose to mimic the diabetic condition in vitro. GAS5 expression was detected by quantitative reverse transcription polymerase chain reaction. The relationship between GAS5 and miR-26a/b-5p was determined by bioinformatic prediction, luciferase reporter assay and RNA immunoprecipitation assay. The cardiac function of diabetic mice was evaluated by two-dimensional echocardiography. RESULTS GAS5 was significantly upregulated in diabetic cardiomyopathy both in vitro and in vivo. GAS5 knockdown and miR-26a/b-5p overexpression not only effectively attenuated myocardial fibrosis of diabetic mice in vivo but also inhibited high glucose-induced cardiomyocyte injury in vitro. miR-26a/b-5p was identified as a target of GAS5. GAS5 knockdown efficiently attenuated myocardial fibrosis and high glucose-induced cardiomyocyte injury through negatively regulating miR-26a/b-p. CONCLUSION Our study showed that GAS5 promotes DCM progression by regulating miR-26a/b-5p, suggesting that GAS5 might be a potential therapeutic target for DCM.
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Affiliation(s)
- Chunping Zhu
- Department of Cardiac Function, The First Hospital of Qiqihar & Affiliated Qiqihar Hospital, Southern Medical University, Qiqihar, 161005, Heilongjiang, People's Republic of China
| | - Haijun Zhang
- The Second Department of Endocrinology, The First Hospital of Qiqihar & Affiliated Qiqihar Hospital, Southern Medical University, No. 30 Park Road, Longsha, Qiqihar, 161005, Heilongjiang, People's Republic of China.
| | - Dongmei Wei
- Department of Traditional Chinese Medicine Geriatrics, The First Hospital of Qiqihar & Affiliated Qiqihar Hospital, Southern Medical University, Qiqihar, 161005, Heilongjiang, People's Republic of China
| | - Zhe Sun
- The Second Department of Endocrinology, The First Hospital of Qiqihar & Affiliated Qiqihar Hospital, Southern Medical University, No. 30 Park Road, Longsha, Qiqihar, 161005, Heilongjiang, People's Republic of China
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Jeong W, Jho EH. Regulation of the Low-Density Lipoprotein Receptor-Related Protein LRP6 and Its Association With Disease: Wnt/β-Catenin Signaling and Beyond. Front Cell Dev Biol 2021; 9:714330. [PMID: 34589484 PMCID: PMC8473786 DOI: 10.3389/fcell.2021.714330] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/25/2021] [Indexed: 11/13/2022] Open
Abstract
Wnt signaling plays crucial roles in development and tissue homeostasis, and its dysregulation leads to various diseases, notably cancer. Wnt/β-catenin signaling is initiated when the glycoprotein Wnt binds to and forms a ternary complex with the Frizzled and low-density lipoprotein receptor-related protein 5/6 (LRP5/6). Despite being identified as a Wnt co-receptor over 20 years ago, the molecular mechanisms governing how LRP6 senses Wnt and transduces downstream signaling cascades are still being deciphered. Due to its role as one of the main Wnt signaling components, the dysregulation or mutation of LRP6 is implicated in several diseases such as cancer, neurodegeneration, metabolic syndrome and skeletal disease. Herein, we will review how LRP6 is activated by Wnt stimulation and explore the various regulatory mechanisms involved. The participation of LRP6 in other signaling pathways will also be discussed. Finally, the relationship between LRP6 dysregulation and disease will be examined in detail.
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Affiliation(s)
- Wonyoung Jeong
- Department of Life Science, University of Seoul, Seoul, South Korea
| | - Eek-Hoon Jho
- Department of Life Science, University of Seoul, Seoul, South Korea
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Wang Z, Han Y, Li Q, Wang B, Ma J. LncRNA DLGAP1-AS1 accelerates glioblastoma cell proliferation through targeting miR-515-5p/ROCK1/NFE2L1 axis and activating Wnt signaling pathway. Brain Behav 2021; 11:e2321. [PMID: 34536977 PMCID: PMC8553332 DOI: 10.1002/brb3.2321] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 07/06/2021] [Accepted: 07/22/2021] [Indexed: 12/28/2022] Open
Abstract
INTRODUCTION Glioblastoma (GBM), the primary malignant tumor in the central nervous system, features high aggressiveness and mortality. Long noncoding RNAs (lncRNAs) can exert the crucial function in regulating various human diseases, including GBM. However, the function and mechanism of lncRNA DLGAP1 antisense RNA 1 (DLGAP1-AS1) in GBM remain still unknown. METHODS DLGAP1-AS1 expression in GBM cells was detected by RT-qPCR. Functional assays were conducted to determine GBM cell proliferation and apoptosis. RIP, RNA pull down, and luciferase reporter assay were applied for measuring the interplay of DLGAP1-AS1 with other RNAs. RESULTS DLGAP1-AS1 was distinctly upregulated in GBM cells. DLGAP1-AS1 depletion inhibited cell proliferation, but induced apoptosis. MiR-515-5p could be sponged by DLGAP1-AS1 in GBM cells and to repress cell proliferation in GBM. Further, Rho-associated coiled-coil containing protein kinase 1 (ROCK1) and Nuclear factor erythroid-2 like 1 (NFE2L1) were confirmed as the target gene of miR-515-5p. Wnt signaling pathway could be activated by DLGAP1-AS1 via regulating ROCK1 and NFE2L1 expression. Rescue assays proved that overexpression of both ROCK1 and NFE2L1 could totally reverse the inhibitory effect of silencing DLGAP1-AS1 on GBM cell proliferation. CONCLUSION LncRNA DLGAP1-AS1 accelerated cell proliferation in GBM via targeting miR-515-5p/ROCK1/NFE2L1 axis and activating Wnt signaling pathway.
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Affiliation(s)
- Zixuan Wang
- Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yipeng Han
- Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qifeng Li
- Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Baocheng Wang
- Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jie Ma
- Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
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