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Zeng Z, Cai S, Ye C, Li T, Tian Y, Liu E, Cai J, Yuan X, Yang H, Liang Q, Li K, Peng C. Neural influences in colorectal cancer progression and therapeutic strategies. Int J Colorectal Dis 2025; 40:120. [PMID: 40379990 PMCID: PMC12084286 DOI: 10.1007/s00384-025-04887-w] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/05/2025] [Indexed: 05/19/2025]
Abstract
PURPOSE This review aims to elucidate the neural mechanisms driving colorectal cancer (CRC) growth, metastasis, and therapeutic resistance, summarizing the roles of neurotransmitters, neurotrophic factors, and neural signaling in carcinogenesis. It further explores therapeutic strategies targeting neural dependencies in CRC. METHODS A comprehensive PubMed search was conducted using the keywords colorectal cancer and tumor innervation, focusing on studies published between 2000 and 2024. The review synthesizes evidence across four domains: neurotransmitter-receptor interactions, gut-brain-microbiota axis dynamics, neuroimmune modulation, and neural regulation of cancer stem cells, discussing their collective impact on CRC pathophysiology. RESULTS Neural innervation significantly influences CRC progression. For instance, the neurotransmitter serotonin promotes tumor growth and metastasis via paracrine and autocrine stimulation, while neurotrophic mediators like nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) activate oncogenic signaling through receptor tyrosine kinases (RTKs). Downstream pathways, such as Wnt/β-catenin signaling, are modulated by neural inputs, underscoring CRC's neurodevelopmental dependency and highlighting their potential as therapeutic targets. CONCLUSION Neural mechanisms are pivotal in CRC progression, revealing novel therapeutic avenues. Strategies targeting neurotransmitter synthesis, neurotrophic signaling, or neuroimmune crosstalk may disrupt tumorigenic loops while preserving systemic nervous system integrity. Future research must prioritize translating these insights into clinical interventions to improve patient outcomes. Elucidating the intricate interplay between neural mediators and cancer pathogenesis, coupled with developing therapies specifically targeting the neurogenic basis of CRC aggressiveness, represents a critical frontier in oncology.
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Affiliation(s)
- Zhibin Zeng
- Division of Gastroenterology, Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China
| | - Shirong Cai
- Division of Gastroenterology, Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China
| | - Chenle Ye
- Division of Gastroenterology, Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China
| | - Tongduan Li
- Division of Gastroenterology, Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China
| | - Yan Tian
- Division of Gastroenterology, Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China
| | - Enyuan Liu
- Division of Gastroenterology, Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China
| | - Junbin Cai
- Division of Gastroenterology, Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China
| | - Xiaojun Yuan
- Division of Gastroenterology, Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China
| | - Heng Yang
- Division of Gastroenterology, Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China
| | - Quanqi Liang
- Division of Gastroenterology, Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China
| | - Kaishu Li
- Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China.
| | - Cui Peng
- Department of Gynaecology and Obstetrics, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China.
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Tiwari RK, Rawat SG, Rai S, Kumar A. Stress regulatory hormones and cancer: the contribution of epinephrine and cancer therapeutic value of beta blockers. Endocrine 2025; 88:359-386. [PMID: 39869294 DOI: 10.1007/s12020-025-04161-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 01/08/2025] [Indexed: 01/28/2025]
Abstract
The word "cancer" evokes myriad emotions, ranging from fear and despair to hope and determination. Cancer is aptly defined as a complex and multifaceted group of diseases that has unapologetically led to the loss of countless lives and affected innumerable families across the globe. The battle with cancer is not only a physical battle, but also an emotional, as well as a psychological skirmish for patients and for their loved ones. Cancer has been a part of our history, stories, and lives for centuries and has challenged the ingenuity of health and medical science, and the resilience of the human spirit. From the early days of surgery and radiation therapy to cutting-edge developments in chemotherapeutic agents, immunotherapy, and targeted treatments, the medical field continues to make significant headway in the fight against cancer. However, even after all these advancements, cancer is still among the leading cause of death globally. This urges us to understand the central hallmarks of neoplastic cells to identify novel molecular targets for the development of promising therapeutic approaches. Growing research suggests that stress mediators, including epinephrine, play a critical role in the development and progression of cancer by inducing neoplastic features through activating adrenergic receptors, particularly β-adrenoreceptors. Further, our experimental data has also shown that epinephrine mediates the growth of T-cell lymphoma by inducing proliferation, glycolysis, and apoptosis evasion via altering the expression levels of key regulators of these vital cellular processes. The beauty of receptor-based therapy lies in its precision and higher therapeutic value. Interestingly, the enhanced expression of β-adrenergic receptors (ADRBs), namely ADRB2 (β2-adrenoreceptor) and ADRB3 (β3-adrenoreceptor) has been noted in many cancers, such as breast, colon, gastric, pancreatic, and prostate and has been reported to play a pivotal role in facilitating cancer growth mainly by promoting proliferation, evasion of apoptosis, angiogenesis, invasion and metastasis, and chemoresistance. The present review article is an attempt to summarize the available findings which indicate a distinct relationship between stress hormones and cancer, with a special emphasis on epinephrine, considered as a key stress regulatory molecule. This article also discusses the possibility of using beta-blockers for cancer therapy.
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Affiliation(s)
- Rajan Kumar Tiwari
- Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
- School of Medicine and Health Sciences, The George Washington University, Washington DC, USA
| | - Shiv Govind Rawat
- Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
- MD Anderson Cancer Center, The University of Texas, Texas, USA
| | - Siddharth Rai
- Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Ajay Kumar
- Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
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Hussen BM, Sulaiman SHA, Abdullah SR, Hidayat HJ, Khudhur ZO, Eslami S, Samsami M, Taheri M. MiRNA-155: A double-edged sword in colorectal cancer progression and drug resistance mechanisms. Int J Biol Macromol 2025; 299:140134. [PMID: 39842591 DOI: 10.1016/j.ijbiomac.2025.140134] [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: 12/19/2024] [Revised: 01/15/2025] [Accepted: 01/19/2025] [Indexed: 01/24/2025]
Abstract
Colorectal cancer (CRC) is a leading cause of death worldwide due to its aggressive nature and drug resistance, which limit traditional treatment effectiveness. Recent studies highlight the role of microRNAs (miRNAs) in tumorigenesis, metastasis, and chemotherapy resistance, with miRNA-155 emerging as a key player in CRC. miRNA-155 exerts dual effects, inducing drug resistance while serving as a potential therapeutic target. It regulates a wide array of mRNA transcripts associated with apoptosis, cell cycle regulation, and DNA repair, impacting various cellular pathways. Overexpression of miRNA-155 is linked to resistance against multiple chemotherapeutic drugs, promoting tumor cell survival, proliferation, and the epithelial-mesenchymal transition (EMT) process by repressing tumor suppressors and activating oncogenes. Additionally, miRNA-155 holds promise as a diagnostic and prognostic marker due to its association with CRC patient survival rates. However, its regulatory mechanisms across CRC subtypes remain unclear. This study provides insights into miRNA-155's role in CRC, focusing on its involvement in therapeutic resistance and potential as a therapeutic target. We also explore its significance as a prognostic biomarker and emphasize its therapeutic applications based on evidence from human, in vivo, in vitro, and clinical studies.
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Affiliation(s)
- Bashdar Mahmud Hussen
- Department of Biomedical Sciences, College of Science, Cihan University-Erbil, Kurdistan Region, Iraq; Department of Clinical Analysis, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq
| | - Seerwan Hamad Ameen Sulaiman
- Department of Medical Laboratory Science, College of Health Sciences, Lebanese French University, Kurdistan Region, Erbil, Iraq
| | - Snur Rasool Abdullah
- Department of Medical Laboratory Science, College of Health Sciences, Lebanese French University, Kurdistan Region, Erbil, Iraq
| | - Hazha Jamal Hidayat
- Department of Biology, College of Education, Salahaddin University-, Erbil, Kurdistan Region, Iraq
| | | | - Solat Eslami
- Department of Medical Biotechnology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Majid Samsami
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospital, Jena, Germany; Urology and Nephrology Research Center, Research Institute for Urology and Nephrology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Xu C, Jiang C, Tian Y, Liu Y, Zhang H, Xiang Z, Xue H, Gu L, Xu Q. Nervous system in colorectal cancer. Cancer Lett 2024; 611:217431. [PMID: 39725147 DOI: 10.1016/j.canlet.2024.217431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 11/28/2024] [Accepted: 12/24/2024] [Indexed: 12/28/2024]
Abstract
A malignant tumor is a complex systemic disease involving the nervous system, which regulates nerve signals. Cancer neuroscience is a field that explores the interactions between tumors and the nervous system. The gastrointestinal tract is a typical peripheral organ with abundant neuroregulation and is regulated by the peripheral, enteric, and central nervous systems (PNS, ENS, and CNS, respectively). The physiological functions of the gastrointestinal tract are maintained via complex neuromodulation. Neuroregulatory imbalance is the primary cause of gastrointestinal diseases, including colorectal cancer (CRC). In CRC, there is a direct interaction between the nervous system and tumor cells. Moreover, this tumor-nerve interaction can indirectly regulate the tumor microenvironment, including the microbiota, immunity, and metabolism. In addition to the lower nerve centers, the stress response, emotion, and cognition represented by the higher nerve centers also participate in the occurrence and progression of CRC. Herein, we review some basic knowledge regarding cancer neuroscience and elucidate the mechanism underlying tumor-nerve interactions in CRC.
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Affiliation(s)
- Chunjie Xu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, China
| | - Chunhui Jiang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, China
| | - Yuan Tian
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, China
| | - Ye Liu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, China
| | - Hao Zhang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, China
| | - Zeyu Xiang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, China
| | - Hanbing Xue
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China.
| | - Lei Gu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, China.
| | - Qing Xu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, China.
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Dogra P, Shinglot V, Ruiz-Ramírez J, Cave J, Butner JD, Schiavone C, Duda DG, Kaseb AO, Chung C, Koay EJ, Cristini V, Ozpolat B, Calin GA, Wang Z. Translational modeling-based evidence for enhanced efficacy of standard-of-care drugs in combination with anti-microRNA-155 in non-small-cell lung cancer. Mol Cancer 2024; 23:156. [PMID: 39095771 PMCID: PMC11295620 DOI: 10.1186/s12943-024-02060-5] [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: 04/04/2024] [Accepted: 07/04/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects. METHODS We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs. RESULTS Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg administered once every three weeks has substantial anti-cancer activity. It led to a median progression-free survival (PFS) of 6.7 months, which compared favorably to cisplatin and immune checkpoint inhibitors. Further, we explored the combinations of anti-miR-155 with standard-of-care drugs, and found strongly synergistic two- and three-drug combinations. A three-drug combination of anti-miR-155, cisplatin, and pembrolizumab resulted in a median PFS of 13.1 months, while a two-drug combination of anti-miR-155 and cisplatin resulted in a median PFS of 11.3 months, which emerged as a more practical option due to its simple design and cost-effectiveness. Our analyses also provided valuable insights into unfavorable dose ratios for drug combinations, highlighting the need for optimizing dose regimens to prevent antagonistic effects. CONCLUSIONS This work bridges the gap between preclinical development and clinical translation of anti-miR-155 and unravels the potential of anti-miR-155 combination therapies in NSCLC.
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Affiliation(s)
- Prashant Dogra
- Mathematics in Medicine Program, Department of Medicine, Houston Methodist Research Institute, Houston, TX, USA.
- Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA.
| | - Vrushaly Shinglot
- Mathematics in Medicine Program, Department of Medicine, Houston Methodist Research Institute, Houston, TX, USA
| | | | - Joseph Cave
- Mathematics in Medicine Program, Department of Medicine, Houston Methodist Research Institute, Houston, TX, USA
- Physiology, Biophysics, and Systems Biology Program, Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA
| | - Joseph D Butner
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Carmine Schiavone
- Mathematics in Medicine Program, Department of Medicine, Houston Methodist Research Institute, Houston, TX, USA
- Department of Chemical, Materials and Industrial Production Engineering, University of Naples Federico II, Naples, Italy
| | - Dan G Duda
- Edwin. L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Ahmed O Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Caroline Chung
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Eugene J Koay
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vittorio Cristini
- Mathematics in Medicine Program, Department of Medicine, Houston Methodist Research Institute, Houston, TX, USA
- Physiology, Biophysics, and Systems Biology Program, Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA
- Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA
- Department of Imaging Physics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Bulent Ozpolat
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA
| | - George A Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Zhihui Wang
- Mathematics in Medicine Program, Department of Medicine, Houston Methodist Research Institute, Houston, TX, USA.
- Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA.
- Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA.
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Li K, Wang J, Xie Y, Lu Z, Sun W, Wang K, Liang J, Chen X. Reactive oxygen species/glutathione dual sensitive nanoparticles with encapsulation of miR155 and curcumin for synergized cancer immunotherapy. J Nanobiotechnology 2024; 22:400. [PMID: 38972995 PMCID: PMC11229347 DOI: 10.1186/s12951-024-02575-5] [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: 04/28/2024] [Accepted: 05/20/2024] [Indexed: 07/09/2024] Open
Abstract
Considerable attention has been directed towards exploring the potential efficacy of miR-155 in the realm of cancer immunotherapy. Elevated levels of miR-155 in dendritic cells (DCs) have been shown to enhance their maturation, migration, cytokine secretion, and their ability to promote T cell activation. In addition, overexpression of mir155 in M2 macrophages boost the polarization towards the M1 phenotype. Conversely, miR-155 has the propensity to induce the accumulation of immunosuppressive cells like regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the tumor tissue. To account for this discrepancy, it is imperative to get help from a drug that could deal with immunosuppressive effect. Curcumin (CUR) exhibits the capacity to prompt Tregs converse into T helper 1 cells, fostering the polarization of M2 tumor-associated macrophage towards the M1 phenotype, and impeding the recruitment and aggregation of MDSCs within the tumor microenvironment. Nonetheless, CUR is known to exert an immunosuppressive impact on DCs by hindering the expression of maturation markers, cytokines, and chemokines, thereby prevent DCs response to immunostimulatory agents. Hence, a reactive oxygen species/glutathione dual responsive drug conveyance platform (CUR/miR155@DssD-Hb NPs) was devised to co-deliver CUR and miR155, with the aim of exploring their synergistic potential in bolstering a sustained and robust anti-tumor immune response. In vitro and in vivo results have suggested that CUR/miR155@DssD-Hb NPs can effectively inhibit the viability of 4T1 and B16F10 tumor cells, trigger the release of damage associated molecular patterns, stimulate DCs maturation, subsequent activation of CD8+ T cells, diminish immunosuppressive cell populations (MDSCs, Tregs, M2 TAMs and exhausted T cells), promote the formation of long-term immunity and lessen the formation of metastatic nodules in the lungs. In summary, the co-delivery system integrating CUR and miR155 (CUR/miR155@DssD-Hb NPs) demonstrates promise as a promising strategy for the immunotherapy of melanoma and triple negative breast cancer.
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Affiliation(s)
- Kangkang Li
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Juan Wang
- Pharmacy Department, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, China
| | - Yi Xie
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Ziyao Lu
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Wen Sun
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Kaixuan Wang
- Department of Neurosurgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jinxin Liang
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Xuehong Chen
- School of Basic Medicine, Qingdao University, Qingdao, China.
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Mohan S, Hakami MA, Dailah HG, Khalid A, Najmi A, Zoghebi K, Halawi MA, Alotaibi TM. From inflammation to metastasis: The central role of miR-155 in modulating NF-κB in cancer. Pathol Res Pract 2024; 253:154962. [PMID: 38006837 DOI: 10.1016/j.prp.2023.154962] [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: 10/24/2023] [Revised: 11/16/2023] [Accepted: 11/16/2023] [Indexed: 11/27/2023]
Abstract
Cancer is a multifaceted, complex disease characterized by unchecked cell growth, genetic mutations, and dysregulated signalling pathways. These factors eventually cause evasion of apoptosis, sustained angiogenesis, tissue invasion, and metastasis, which makes it difficult for targeted therapeutic interventions to be effective. MicroRNAs (miRNAs) are essential gene expression regulators linked to several biological processes, including cancer and inflammation. The NF-κB signalling pathway, a critical regulator of inflammatory reactions and oncogenesis, has identified miR-155 as a significant participant in its modulation. An intricate network of transcription factors known as the NF-κB pathway regulates the expression of genes related to inflammation, cell survival, and immunological responses. The NF-κB pathway's dysregulation contributes to many cancer types' development, progression, and therapeutic resistance. In numerous cancer models, the well-studied miRNA miR-155 has been identified as a crucial regulator of NF-κB signalling. The p65 subunit and regulatory molecules like IκB are among the primary targets that miR-155 directly targets to alter NF-κB activity. The molecular processes by which miR-155 affects the NF-κB pathway are discussed in this paper. It also emphasizes the miR-155's direct and indirect interactions with important NF-κB cascade elements to control the expression of NF-κB subunits. We also investigate how miR-155 affects NF-κB downstream effectors in cancer, including inflammatory cytokines and anti-apoptotic proteins.
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Affiliation(s)
- Syam Mohan
- Substance Abuse and Toxicology Research Centre, Jazan University, Jazan 45142, Saudi Arabia; School of Health Sciences, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India; Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India.
| | - Mohammed Ageeli Hakami
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Al, Quwayiyah, Shaqra University, Riyadh, Saudi Arabia.
| | - Hamad Ghaleb Dailah
- Research and Scientific Studies Unit, College of Nursing, Jazan University, Jazan 45142, Saudi Arabia
| | - Asaad Khalid
- Substance Abuse and Toxicology Research Centre, Jazan University, Jazan 45142, Saudi Arabia
| | - Asim Najmi
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Khalid Zoghebi
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Maryam A Halawi
- Department of Clinical Pharmacy, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
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Tiwari RK, Rawat SG, Gupta VK, Jaiswara PK, Sonker P, Kumar S, Gautam V, Mishra MK, Kumar A. Epinephrine facilitates the growth of T cell lymphoma by altering cell proliferation, apoptosis, and glucose metabolism. Chem Biol Interact 2023; 369:110278. [PMID: 36423730 DOI: 10.1016/j.cbi.2022.110278] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 11/05/2022] [Accepted: 11/18/2022] [Indexed: 11/23/2022]
Abstract
In recent years, studies have reported the role of stress-regulatory hormones, including epinephrine, in regulating the progression of a few cancers. However, the tumor-promoting action of epinephrine is not yet investigated in T cell malignancy, a rare and complicated neoplastic disorder. More so, very little is known regarding the implication of epinephrine in the glucose metabolic rewiring in tumor cells. The present investigation showed that epinephrine enhanced the proliferation of T lymphoma cells through up- and down-regulating the expression of PCNA, cyclin D, and p53, respectively. In addition, epinephrine inhibited apoptosis in T lymphoma cells possibly by increasing the level of BCL2 (an anti-apoptotic protein) and decreasing PARP level (a pro-apoptotic protein). Intriguingly, epinephrine is reported to stimulate glycolysis in T lymphoma cells by increasing the expression of crucial glycolysis regulatory molecules, namely HKII and PKM2, in a HIF-1α-dependent manner. Moreover, augmented production of ROS has been observed in T lymphoma cells, which might be a central player in epinephrine-mediated T cell lymphoma growth. Taken together, our study demonstrates that epinephrine might have a significant role in the progression of T cell lymphoma.
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Affiliation(s)
- Rajan Kumar Tiwari
- Tumor Biomarker and Therapeutics Lab, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India
| | - Shiv Govind Rawat
- Tumor Biomarker and Therapeutics Lab, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India
| | - Vishal Kumar Gupta
- Tumor Biomarker and Therapeutics Lab, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India
| | - Pradip Kumar Jaiswara
- Tumor Biomarker and Therapeutics Lab, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India
| | - Pratishtha Sonker
- Tumor Biomarker and Therapeutics Lab, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India
| | - Santosh Kumar
- Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, India
| | - Vibhav Gautam
- Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, 221005, Varanasi, India
| | - Manoj K Mishra
- Cancer Biology Research and Training, Department of Biological Sciences, Alabama State University, Montgomery, AL, USA
| | - Ajay Kumar
- Tumor Biomarker and Therapeutics Lab, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India.
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Kishani Farahani R, Soleimanpour S, Golmohammadi M, Soleimanpour-lichaei HR. PIWIL2 Regulates the Proliferation, Apoptosis and Colony Formation of Colorectal Cancer Cell Line. IRANIAN JOURNAL OF BIOTECHNOLOGY 2023; 21:e3176. [PMID: 36811102 PMCID: PMC9938935 DOI: 10.30498/ijb.2022.307054.3176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 07/06/2022] [Indexed: 02/24/2023]
Abstract
Background Tumor cells proliferation and apoptosis inhibition are the mechanisms through which the Colorectal Cancer (CRC) progression, metastasis and chemoresistance are promoted pathologically, offering clinical advantages for characterizing their molecular regulators. Objectives In this study, to unravel the role of PIWIL2 as a potential CRC oncogenic regulator, we examined the effect of its overexpression on proliferation, apoptosis and colony formation of SW480 colon cancer cell line. Material and Methods Established SW480-P (overexpression of PIWIL2) and SW480-control (SW480-empty vector) cell lines were cultured in DMEM containing 10% FBS with 1% penicillin-streptomycin. The total DNA and RNA was extracted for further experiments. Real-Time PCR and western blotting assay were performed to measure the differential expression of proliferation associated genes including the expression of cell cycle and anti-apoptotic genes as well as Ki-67 and PIWIL2 in both cell lines. Cell proliferation was determined using MTT assay, doubling time assay and the colony formation rate of transfected cells was measured with the 2D colony formation assay. Results At the molecular level, PIWIL2 overexpression was associated with significant up-regulation of cyclin D1, STAT3, BCL2-L1, BCL2-L2 and Ki-67 genes. MTT and doubling time assay showed that PIWIL2 expression induced time-related effects on proliferation rate of SW480 cells. Moreover, SW480-P cells had markedly greater capacity to form colonies. Conclusions PIWIL2 plays important roles to promote cancer cell proliferation and colonization via the cell cycle acceleration and inhibition of apoptosis, the mechanisms through which this gene seems to contribute to CRC development, metastasis and chemoresistance, hence potentially highlighting PIWIL2 targeted therapy as a valuable tool for CRC treatment.
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Affiliation(s)
- Roya Kishani Farahani
- Department of Stem Cells and Regenerative Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | | | | | - Hamid Reza Soleimanpour-lichaei
- Department of Stem Cells and Regenerative Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
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10
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Moayedi F, Shojaei-Ghahrizjani F, Yaghoobi H. Inhibition of miR-155-5p in non-small cell lung cancer, a potential target for induction of autophagy. Meta Gene 2021. [DOI: 10.1016/j.mgene.2021.100855] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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11
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Sartorius K, An P, Winkler C, Chuturgoon A, Li X, Makarova J, Kramvis A. The Epigenetic Modulation of Cancer and Immune Pathways in Hepatitis B Virus-Associated Hepatocellular Carcinoma: The Influence of HBx and miRNA Dysregulation. Front Immunol 2021; 12:661204. [PMID: 33995383 PMCID: PMC8117219 DOI: 10.3389/fimmu.2021.661204] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/15/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) pathogenesis is fueled by persistent HBV infection that stealthily maintains a delicate balance between viral replication and evasion of the host immune system. HBV is remarkably adept at using a combination of both its own, as well as host machinery to ensure its own replication and survival. A key tool in its arsenal, is the HBx protein which can manipulate the epigenetic landscape to decrease its own viral load and enhance persistence, as well as manage host genome epigenetic responses to the presence of viral infection. The HBx protein can initiate epigenetic modifications to dysregulate miRNA expression which, in turn, can regulate downstream epigenetic changes in HBV-HCC pathogenesis. We attempt to link the HBx and miRNA induced epigenetic modulations that influence both the HBV and host genome expression in HBV-HCC pathogenesis. In particular, the review investigates the interplay between CHB infection, the silencing role of miRNA, epigenetic change, immune system expression and HBV-HCC pathogenesis. The review demonstrates exactly how HBx-dysregulated miRNA in HBV-HCC pathogenesis influence and are influenced by epigenetic changes to modulate both viral and host genome expression. In particular, the review identifies a specific subset of HBx induced epigenetic miRNA pathways in HBV-HCC pathogenesis demonstrating the complex interplay between HBV infection, epigenetic change, disease and immune response. The wide-ranging influence of epigenetic change and miRNA modulation offers considerable potential as a therapeutic option in HBV-HCC.
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Affiliation(s)
- Kurt Sartorius
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa.,Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban, South Africa.,Department of Surgery, University of KwaZulu-Natal Gastrointestinal Cancer Research Centre, Durban, South Africa
| | - Ping An
- Basic Research Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Cheryl Winkler
- Basic Research Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Anil Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, Durban, South Africa
| | - Xiaodong Li
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
| | - Julia Makarova
- Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Moscow, Russia.,Higher School of Economics University, Moscow, Russia
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
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12
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M2 macrophage-derived exosomal microRNA-155-5p promotes the immune escape of colon cancer by downregulating ZC3H12B. MOLECULAR THERAPY-ONCOLYTICS 2021; 20:484-498. [PMID: 33718596 PMCID: PMC7932913 DOI: 10.1016/j.omto.2021.02.005] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 02/02/2021] [Indexed: 12/30/2022]
Abstract
Previous evidence has highlighted M2 macrophage regulation of cancer cells via exosome shuttling of microRNAs (miRNAs or miRs). The current study set out to explore the possible role of M2 macrophage-derived exosomal miR-155-5p in regard to immune escape of colon cancer cells. Experimental data from quantitative reverse-transcriptase PCR (qRT-PCR) and western blot analysis revealed highly expressed miR-155-5p and interleukin (IL)-6 and poorly expressed ZC3H12B in M2 macrophage-derived exosomes. Additionally, miR-155-5p could be transferred by M2 macrophage-isolated exosomes to colon cancer cells, which targeted ZC3H12B by binding to the 3¢ UTR, as identified by dual luciferase reporter gene. Meanwhile, gain- and loss-of function experimentation on miR-155-5p and ZC3H12B in SW48 and HT29 cells cocultured with M2 macrophage-secreted exosomes demonstrated that miR-155-5p overexpression or ZC3H12B silencing promoted the proliferation and antiapoptosis ability of SW48 and HT29 cells, as well as augmenting the CD3+ T cell proliferation and the proportion of interferon (IFN)-γ+ T cells. Xenograft models confirmed that M2 macrophage-derived exosomal miR-155-5p reduced the ZC3H12B expression to upregulate IL-6, which consequently induced immune escape and tumor formation. Collectively, our findings indicated that M2 macrophage-derived exosomal miR-155-5p can potentially promote the immune escape of colon cancer by impairing ZC3H12B-mediated IL-6 stability reduction, thereby promoting the occurrence and development of colon cancer.
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13
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Massaro C, Safadeh E, Sgueglia G, Stunnenberg HG, Altucci L, Dell’Aversana C. MicroRNA-Assisted Hormone Cell Signaling in Colorectal Cancer Resistance. Cells 2020; 10:cells10010039. [PMID: 33396628 PMCID: PMC7823834 DOI: 10.3390/cells10010039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 12/26/2020] [Accepted: 12/28/2020] [Indexed: 12/17/2022] Open
Abstract
Despite substantial progress in cancer therapy, colorectal cancer (CRC) is still the third leading cause of cancer death worldwide, mainly due to the acquisition of resistance and disease recurrence in patients. Growing evidence indicates that deregulation of hormone signaling pathways and their cross-talk with other signaling cascades inside CRC cells may have an impact on therapy resistance. MicroRNAs (miRNAs) are small conserved non-coding RNAs thatfunction as negative regulators in many gene expression processes. Key studies have identified miRNA alterations in cancer progression and drug resistance. In this review, we provide a comprehensive overview and assessment of miRNAs role in hormone signaling pathways in CRC drug resistance and their potential as future targets for overcoming resistance to treatment.
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Affiliation(s)
- Crescenzo Massaro
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via De Crecchio, 7, 80138 Naples, Italy; (C.M.); (E.S.); (G.S.)
| | - Elham Safadeh
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via De Crecchio, 7, 80138 Naples, Italy; (C.M.); (E.S.); (G.S.)
| | - Giulia Sgueglia
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via De Crecchio, 7, 80138 Naples, Italy; (C.M.); (E.S.); (G.S.)
| | | | - Lucia Altucci
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via De Crecchio, 7, 80138 Naples, Italy; (C.M.); (E.S.); (G.S.)
- Correspondence: (L.A.); (C.D.); Tel.: +39-081-566-7564 (L.A.); +39-081-566-7566 (C.D.)
| | - Carmela Dell’Aversana
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via De Crecchio, 7, 80138 Naples, Italy; (C.M.); (E.S.); (G.S.)
- Institute of Experimental Endocrinology and Oncology “Gaetano Salvatore” (IEOS)-National Research Council (CNR), Via Sergio Pansini 5, 80131 Naples, Italy
- Correspondence: (L.A.); (C.D.); Tel.: +39-081-566-7564 (L.A.); +39-081-566-7566 (C.D.)
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14
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Sartorius K, Swadling L, An P, Makarova J, Winkler C, Chuturgoon A, Kramvis A. The Multiple Roles of Hepatitis B Virus X Protein (HBx) Dysregulated MicroRNA in Hepatitis B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) and Immune Pathways. Viruses 2020; 12:v12070746. [PMID: 32664401 PMCID: PMC7412373 DOI: 10.3390/v12070746] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 12/11/2022] Open
Abstract
Currently, the treatment of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) [HBV-HCC] relies on blunt tools that are unable to offer effective therapy for later stage pathogenesis. The potential of miRNA to treat HBV-HCC offer a more targeted approach to managing this lethal carcinoma; however, the complexity of miRNA as an ancillary regulator of the immune system remains poorly understood. This review examines the overlapping roles of HBx-dysregulated miRNA in HBV-HCC and immune pathways and seeks to demonstrate that specific miRNA response in immune cells is not independent of their expression in hepatocytes. This interplay between the two pathways may provide us with the possibility of using candidate miRNA to manipulate this interaction as a potential therapeutic option.
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Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg 2050, South Africa
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
- UKZN Gastrointestinal Cancer Research Centre, Durban 4041, South Africa
- Correspondence:
| | - Leo Swadling
- Division of Infection and Immunity, University College London, London WC1E6BT, UK;
| | - Ping An
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Julia Makarova
- National Research University Higher School of Economics, Faculty of Biology and Biotechnology, 10100 Moscow, Russia;
| | - Cheryl Winkler
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Anil Chuturgoon
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2050, South Africa;
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15
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Assessment of adrenaline-induced DNA damage in whole blood cells with the comet assay. Arh Hig Rada Toksikol 2019; 69:304-308. [PMID: 30864376 DOI: 10.2478/aiht-2018-69-3154] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 11/01/2018] [Indexed: 02/04/2023] Open
Abstract
Harmful effects of elevated levels of catecholamines are mediated by various mechanisms, including gene transcription and formation of oxidation products. The aim of this study was to see whether the molecular mechanisms underlying the damaging action of adrenaline on DNA are mediated by reactive oxygen species (ROS). To do that, we exposed human whole blood cells to 10 μmol L-1adrenaline or 50 μmol L-1H2O2(used as positive control) that were separately pre-treated or post-treated with 500 μmol L-1of quercetin, a scavenger of free radicals. Quercetin significantly reduced DNA damage in both pre- and post-treatment protocols, which suggests that adrenaline mainly acts via the production of ROS. This mechanism is also supported by gradual lowering of adrenaline and H2O2-induced DNA damage 15, 30, 45, and 60 min after treatment. Our results clearly show that DNA repair mechanisms are rather effective against ROS-mediated DNA damage induced by adrenaline.
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16
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Huang C, Liu J, Xu L, Hu W, Wang J, Wang M, Yao X. MicroRNA-17 promotes cell proliferation and migration in human colorectal cancer by downregulating SIK1. Cancer Manag Res 2019; 11:3521-3534. [PMID: 31118777 PMCID: PMC6497923 DOI: 10.2147/cmar.s191087] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 03/05/2019] [Indexed: 01/13/2023] Open
Abstract
Purpose: There is mounting evidence to indicate that microRNA-17 (miR-17) is expressed and functionally involved in human cancers. However, the molecular mechanism underlying the role of miR-17 in colorectal cancer (CRC) remains largely unclear. This study aims to reveal the biological function of miR-17 in colorectal cancer. Materials and methods: The expression of miR-17 in CRC cells and tissues was examined using qRT-PCR. Cell proliferation and migration assays were performed after transfection with an miR-17 mimic and inhibitors. The potential gene targets of miR-17 were predicted by bioinformatics analysis and further validated by PCR, Western blot and dual luciferase reporter assays. Results: The expression of miR-17 was significantly upregulated in CRC cell lines and tissues and may imply poor prognosis. miR-17 upregulation promoted cell invasion and migration in CRC cell lines in vitro, while downregulation of miR-17 inhibited tumor progression. SIK1 was identified as a potential direct target of miR-17 by dual luciferase reporter assay, and its downregulation in CRC may suggest poor prognosis. Conclusions: Our study indicated that upregulated miR-17 may promote the progression of CRC and may exert its function as a tumor suppressor miRNA by targeting SIK1.
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Affiliation(s)
- Chengzhi Huang
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, People's Republic of China.,Medical College, Shantou University, Shantou, Guangdong, People's Republic of China
| | - Jianhua Liu
- Department of Gastroenterology Oncology, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, People's Republic of China
| | - Lishu Xu
- Department of Gastroenterology, Guangdong Provincial Geriatrics Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, People's Republic of China
| | - Weixian Hu
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, People's Republic of China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, People's Republic of China
| | - Junjiang Wang
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, People's Republic of China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, People's Republic of China
| | - Muqing Wang
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, People's Republic of China.,School of Medicine, South China University of Technology, Guangzhou, Guangdong, People's Republic of China
| | - Xueqing Yao
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, People's Republic of China.,Medical College, Shantou University, Shantou, Guangdong, People's Republic of China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, People's Republic of China.,School of Medicine, South China University of Technology, Guangzhou, Guangdong, People's Republic of China
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17
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Bayraktar R, Van Roosbroeck K. miR-155 in cancer drug resistance and as target for miRNA-based therapeutics. Cancer Metastasis Rev 2019; 37:33-44. [PMID: 29282605 DOI: 10.1007/s10555-017-9724-7] [Citation(s) in RCA: 165] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Small non-coding microRNAs (miRNAs) are instrumental in physiological processes, such as proliferation, cell cycle, apoptosis, and differentiation, processes which are often disrupted in diseases like cancer. miR-155 is one of the best conserved and multifunctional miRNAs, which is mainly characterized by overexpression in multiple diseases including malignant tumors. Altered expression of miR-155 is found to be associated with various physiological and pathological processes, including hematopoietic lineage differentiation, immune response, inflammation, and tumorigenesis. Furthermore, miR-155 drives therapy resistance mechanisms in various tumor types. Therefore, miR-155-mediated signaling pathways became a potential target for the molecular treatment of cancer. In this review, we summarize the current findings of miR-155 in hematopoietic lineage differentiation, the immune response, inflammation, and cancer therapy resistance. Furthermore, we discuss the potential of miR-155-based therapeutic approaches for the treatment of cancer.
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Affiliation(s)
- Recep Bayraktar
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1881 Holcombe Boulevard, Unit 1950, Houston, TX, 77054, USA
| | - Katrien Van Roosbroeck
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1881 Holcombe Boulevard, Unit 1950, Houston, TX, 77054, USA.
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18
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Farhan M, Ullah MF, Faisal M, Farooqi AA, Sabitaliyevich UY, Biersack B, Ahmad A. Differential Methylation and Acetylation as the Epigenetic Basis of Resveratrol's Anticancer Activity. MEDICINES 2019; 6:medicines6010024. [PMID: 30781847 PMCID: PMC6473688 DOI: 10.3390/medicines6010024] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 02/10/2019] [Accepted: 02/11/2019] [Indexed: 01/15/2023]
Abstract
Numerous studies support the potent anticancer activity of resveratrol and its regulation of key oncogenic signaling pathways. Additionally, the activation of sirtuin 1, a deacetylase, by resveratrol has been known for many years, making resveratrol perhaps one of the earliest nutraceuticals with associated epigenetic activity. Such epigenetic regulation by resveratrol, and the mechanism thereof, has attracted much attention in the past decade. Focusing on methylation and acetylation, the two classical epigenetic regulations, we showcase the potential of resveratrol as an effective anticancer agent by virtue of its ability to induce differential epigenetic changes. We discuss the de-repression of tumor suppressors such as BRCA-1, nuclear factor erythroid 2-related factor 2 (NRF2) and Ras Associated Domain family-1α (RASSF-1α) by methylation, PAX1 by acetylation and the phosphatase and tensin homologue (PTEN) by both methylation and acetylation, in addition to the epigenetic regulation of oncogenic NF-κB and STAT3 signaling by resveratrol. Further, we evaluate the literature supporting the potentiation of HDAC inhibitors and the inhibition of DNMTs by resveratrol in different human cancers. This discussion underlines a robust epigenetic activity of resveratrol that warrants further evaluation, particularly in clinical settings.
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Affiliation(s)
- Mohd Farhan
- College of Basic Sciences, King Faisal University, Hofuf 400-Al Ahsa-31982, Saudi Arabia.
| | - Mohammad Fahad Ullah
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, P.O. Box 741, Tabuk 71491, Saudi Arabia.
| | - Mohd Faisal
- Department of Psychiatry, University Hospital Limerick, Limerick V94 T9PX, Ireland.
| | - Ammad Ahmad Farooqi
- Institute of Biomedical and Genetic Engineering (IBGE), Islamabad 44000, Pakistan.
| | | | - Bernhard Biersack
- Organic Chemistry Laboratory, Department of Chemistry, University of Bayreuth, Universitaetsstrasse 30, 95447 Bayreuth, Germany.
| | - Aamir Ahmad
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
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19
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Zhang Z, Wang Y, Li Q. Mechanisms underlying the effects of stress on tumorigenesis and metastasis (Review). Int J Oncol 2018; 53:2332-2342. [PMID: 30272293 DOI: 10.3892/ijo.2018.4570] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 07/18/2018] [Indexed: 11/06/2022] Open
Abstract
Stress is one of the fundamental survival mechanisms in nature. Although chronic or long-lasting stress can be detrimental to health, acute or short-term stress can have health benefits. The aim of the present review was to address the complexity and significance of stress in tumorigenesis. The review covers an evaluation of previously used and reported experimental animal models of stress, as well as the effects of stress on the neuroendocrine system, immune function, gut microbiota, and inflammation and multidrug resistance, all of which are closely associated with cancer occurrence, progression and treatment. The review concludes that understanding the efficacy of stress management (prevention and rehabilitation) is crucial to the development of comprehensive and individualized strategies for cancer prevention and treatment.
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Affiliation(s)
- Zhaozhou Zhang
- Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Yan Wang
- Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Qi Li
- Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
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20
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Guo X, Ma Z, Du B, Li T, Li W, Xu L, He J, Kang L. Dop1 enhances conspecific olfactory attraction by inhibiting miR-9a maturation in locusts. Nat Commun 2018; 9:1193. [PMID: 29567955 PMCID: PMC5864846 DOI: 10.1038/s41467-018-03437-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Accepted: 02/09/2018] [Indexed: 12/21/2022] Open
Abstract
Dopamine receptor 1 (Dop1) mediates locust attraction behaviors, however, the mechanism by which Dop1 modulates this process remains unknown to date. Here, we identify differentially expressed small RNAs associated with locust olfactory attraction after activating and inhibiting Dop1. Small RNA transcriptome analysis and qPCR validation reveal that Dop1 activation and inhibition downregulates and upregulates microRNA-9a (miR-9a) expression, respectively. miR-9a knockdown in solitarious locusts increases their attraction to gregarious volatiles, whereas miR-9a overexpression in gregarious locusts reduces olfactory attraction. Moreover, miR-9a directly targets adenylyl cyclase 2 (ac2), causing its downregulation at the mRNA and protein levels. ac2 responds to Dop1 and mediates locust olfactory attraction. Mechanistically, Dop1 inhibits miR-9a expression through inducing the dissociation of La protein from pre-miR-9a and resulting in miR-9a maturation inhibition. Our results reveal a Dop1–miR-9a–AC2 circuit that modulates locust olfactory attraction underlying aggregation. This study suggests that miRNAs act as key messengers in the GPCR signaling. Migratory locusts shift between aggregating together during gregarious phases and living individually during solitary phases. Here, the authors find that the D1-like dopamine receptor regulates the olfactory attraction underlying this behavioral switch via microRNA-9a and adenylyl cyclase.
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Affiliation(s)
- Xiaojiao Guo
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,Beijing Institutes of Life Sciences, Chinese Academy of Sciences, Beijing, 100101, China
| | - Zongyuan Ma
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,Beijing Institutes of Life Sciences, Chinese Academy of Sciences, Beijing, 100101, China
| | - Baozhen Du
- Beijing Institutes of Life Sciences, Chinese Academy of Sciences, Beijing, 100101, China
| | - Ting Li
- Beijing Institutes of Life Sciences, Chinese Academy of Sciences, Beijing, 100101, China
| | - Wudi Li
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Lingling Xu
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Jing He
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Le Kang
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. .,Beijing Institutes of Life Sciences, Chinese Academy of Sciences, Beijing, 100101, China.
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21
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Li Y, Duo Y, Bi J, Zeng X, Mei L, Bao S, He L, Shan A, Zhang Y, Yu X. Targeted delivery of anti-miR-155 by functionalized mesoporous silica nanoparticles for colorectal cancer therapy. Int J Nanomedicine 2018; 13:1241-1256. [PMID: 29535520 PMCID: PMC5841950 DOI: 10.2147/ijn.s158290] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION MicroRNA-155 (miR-155) is an oncogenic microRNA, which is upregulated in many human cancers including colorectal cancer (CRC). Overexpression of miR-155 has been found to regulate several cancer-related pathways, and therefore, targeting miR-155 may be an effective strategy for cancer therapy. However, effective and safe delivery of anti-miR-155 to tumors remains challenging for the clinical applications of anti-miR-155-based therapeutics. METHODS In this study, we explored the expression of miR-155 and the transcription factor nuclear factor kappa B (NF-κB) in CRC tissues and cell lines, and the possible relationship between miR-155 and NF-κB. We further report on anti-miR-155-loaded mesoporous silica nanoparticles (MSNs) modified with polymerized dopamine (PDA) and AS1411 aptamer (MSNs-anti-miR-155@PDA-Apt) for the targeted treatment of CRC. RESULTS Results showed that miR-155 is overexpressed in CRC tissues and cell lines, and there is a positive feedback loop between NF-κB and miR-155. Compared to the control groups, MSNs-anti-miR-155@PDA-Apt could efficiently downregulate miR-155 expression in SW480 cells and achieve significantly high targeting efficiency and enhanced therapeutic effects in both in vivo and in vitro experiments. Furthermore, inhibition of miR-155 by MSNs-anti-miR-155@PDA-Apt can enhance the sensitivity of SW480 to 5-fluorouracil chemotherapy. CONCLUSION Thus, our results suggested that MSNs-anti-miR-155@PDA-Apt is a promising nanoformulation for CRC treatment.
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Affiliation(s)
- Yang Li
- Department of Hepatobiliary and Pancreas Surgery, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen 518020, China
- Department of Emergency, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen 518020, China
| | - Yanhong Duo
- Department of Hepatobiliary and Pancreas Surgery, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen 518020, China
- Key Laboratory of Plant Cell Activities and Stress Adaptation, Ministry of Education, School of Life Sciences, Lanzhou University, Lanzhou 730000, China
| | - Jiangang Bi
- Department of Hepatobiliary and Pancreas Surgery, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen 518020, China
| | - Xiaowei Zeng
- Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518020, China
| | - Lin Mei
- Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518020, China
| | - Shiyun Bao
- Department of Hepatobiliary and Pancreas Surgery, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen 518020, China
| | - Lisheng He
- Department of Pathology, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen 518020, China
| | - Aijun Shan
- Department of Emergency, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen 518020, China
| | - Yue Zhang
- Department of Hepatobiliary and Pancreas Surgery, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen 518020, China
| | - Xiaofang Yu
- Department of Hepatobiliary and Pancreas Surgery, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen 518020, China
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Liu Y, Yu X, Zhuang J. Epinephrine Stimulates Cell Proliferation and Induces Chemoresistance in Myeloma Cells through the β-Adrenoreceptor in vitro. Acta Haematol 2017; 138:103-110. [PMID: 28848082 DOI: 10.1159/000478517] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 06/06/2017] [Indexed: 01/07/2023]
Abstract
OBJECTIVES To explore the effect of the β-adrenoreceptor signaling pathway on myeloma cells. METHODS The myeloma U266 cell line was treated with epinephrine and propranolol. Cell proliferation was analyzed by MTS assay. Apoptosis was detected by flow cytometry. The β-receptor subtype and the key enzyme of epinephrine were identified by reverse transcription polymerase chain reaction (RT-PCR). RESULTS Epinephrine (5-50 μM) promoted U266 cell growth in a dose-dependent manner and neutralized the inhibition effect of bortezomib (25 and 50 ng/mL) in vitro. Cell proliferation was inhibited by a β-receptor antagonist, propranolol, at a concentration of 50-200 μM. The proportions of early and late apoptotic cells were enhanced after treatment with propranolol. The expression of caspase 3/7, 8, and 9 was elevated in propranolol-treated myeloma cells. Both β1- and β2-adrenoceptor mRNAs were expressed in the U266 cell line. Key enzymes dopamine hydroxylase and tyrosinehydroxylase were identified in myeloma cells. CONCLUSIONS Our results reveal that epinephrine stimulates myeloma cell growth in vitro while the β-blocker propranolol has an antiproliferative effect, indicating that stress hormones may trigger the progression of myeloma.
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Affiliation(s)
- Yang Liu
- Department of Hematology, Peking Union Medical College Hospital, Beijing, China
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23
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Non-coding RNAs Enabling Prognostic Stratification and Prediction of Therapeutic Response in Colorectal Cancer Patients. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 937:183-204. [PMID: 27573901 DOI: 10.1007/978-3-319-42059-2_10] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Colorectal cancer (CRC) is a heterogeneous disease and current treatment options for patients are associated with a wide range of outcomes and tumor responses. Although the traditional TNM staging system continues to serve as a crucial tool for estimating CRC prognosis and for stratification of treatment choices and long-term survival, it remains limited as it relies on macroscopic features and cases of surgical resection, fails to incorporate new molecular data and information, and cannot perfectly predict the variety of outcomes and responses to treatment associated with tumors of the same stage. Although additional histopathologic features have recently been applied in order to better classify individual tumors, the future might incorporate the use of novel molecular and genetic markers in order to maximize therapeutic outcome and to provide accurate prognosis. Such novel biomarkers, in addition to individual patient tumor phenotyping and other validated genetic markers, could facilitate the prediction of risk of progression in CRC patients and help assess overall survival. Recent findings point to the emerging role of non-protein-coding regions of the genome in their contribution to the progression of cancer and tumor formation. Two major subclasses of non-coding RNAs (ncRNAs), microRNAs and long non-coding RNAs, are often dysregulated in CRC and have demonstrated their diagnostic and prognostic potential as biomarkers. These ncRNAs are promising molecular classifiers and could assist in the stratification of patients into appropriate risk groups to guide therapeutic decisions and their expression patterns could help determine prognosis and predict therapeutic options in CRC.
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24
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Ciurea RN, Rogoveanu I, Pirici D, Târtea GC, Streba CT, Florescu C, Cătălin B, Puiu I, Târtea EA, Vere CC. B2 adrenergic receptors and morphological changes of the enteric nervous system in colorectal adenocarcinoma. World J Gastroenterol 2017; 23:1250-1261. [PMID: 28275305 PMCID: PMC5323450 DOI: 10.3748/wjg.v23.i7.1250] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 12/26/2016] [Accepted: 01/11/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To study the morphology of the enteric nervous system and the expression of beta-2 adrenergic (B2A) receptors in primary colorectal cancer. METHODS In this study, we included forty-eight patients with primary colorectal cancer and nine patients for control tissue from the excision of a colonic segment for benign conditions. We determined the clinicopathological features and evaluated the immunohistochemical expression pattern of B2A receptors as well as the morphological changes of the enteric nervous system (ENS). In order to assess statistical differences, we used the student t-test for comparing the means of two groups and one-way analysis of variance with Bonferroni's post hoc analysis for comparing the means of more than two groups. Correlations were assessed using the Pearson's correlation coefficient. RESULTS B2A receptors were significantly associated with tumor grading, tumor size, tumor invasion, lymph node metastasis (P < 0.05), while there were no statistically significant associations with gender, CRC location and gross appearance (P > 0.05). We observed, on one hand, a decrease of the relative area for both Auerbach and Meissner plexuses with the increase of the tumor grading, and on the other hand, an increase of the relative area of other nervous elements not in the Meissner plexus or in the Auerbach plexus with the tumor grading. For G1 tumors we found that epithelial B2A area showed an inverse correlation with the Auerbach plexus areas [r(14) = -0.531, P < 0.05], while for G2 tumors, epithelial B2A areas showed an indirect variation with both the Auerbach plexus areas [r(14) = -0.453, P < 0.05] and the Meissner areas [r(14) = -0.825, P < 0.01]. For G3 tumors, the inverse dependence increased for both Auerbach [r(14) = -0.587, P < 0.05] and Meissner [r(14) = -0.934, P < 0.05] plexuses. CONCLUSION B2A receptors play an important role in colorectal carcinogenesis and can be utilized as prognostic factors. Furthermore, study of the ENS in colorectal cancer may lead to targeted molecular therapies.
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25
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Van Roosbroeck K, Fanini F, Setoyama T, Ivan C, Rodriguez-Aguayo C, Fuentes-Mattei E, Xiao L, Vannini I, Redis RS, D'Abundo L, Zhang X, Nicoloso MS, Rossi S, Gonzalez-Villasana V, Rupaimoole R, Ferracin M, Morabito F, Neri A, Ruvolo PP, Ruvolo VR, Pecot CV, Amadori D, Abruzzo L, Calin S, Wang X, You MJ, Ferrajoli A, Orlowski R, Plunkett W, Lichtenberg TM, Davuluri RV, Berindan-Neagoe I, Negrini M, Wistuba II, Kantarjian HM, Sood AK, Lopez-Berestein G, Keating MJ, Fabbri M, Calin GA. Combining Anti-Mir-155 with Chemotherapy for the Treatment of Lung Cancers. Clin Cancer Res 2016; 23:2891-2904. [PMID: 27903673 DOI: 10.1158/1078-0432.ccr-16-1025] [Citation(s) in RCA: 121] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Revised: 10/19/2016] [Accepted: 11/08/2016] [Indexed: 12/31/2022]
Abstract
Purpose: The oncogenic miR-155 is upregulated in many human cancers, and its expression is increased in more aggressive and therapy-resistant tumors, but the molecular mechanisms underlying miR-155-induced therapy resistance are not fully understood. The main objectives of this study were to determine the role of miR-155 in resistance to chemotherapy and to evaluate anti-miR-155 treatment to chemosensitize tumors.Experimental Design: We performed in vitro studies on cell lines to investigate the role of miR-155 in therapy resistance. To assess the effects of miR-155 inhibition on chemoresistance, we used an in vivo orthotopic lung cancer model of athymic nude mice, which we treated with anti-miR-155 alone or in combination with chemotherapy. To analyze the association of miR-155 expression and the combination of miR-155 and TP53 expression with cancer survival, we studied 956 patients with lung cancer, chronic lymphocytic leukemia, and acute lymphoblastic leukemia.Results: We demonstrate that miR-155 induces resistance to multiple chemotherapeutic agents in vitro, and that downregulation of miR-155 successfully resensitizes tumors to chemotherapy in vivo We show that anti-miR-155-DOPC can be considered non-toxic in vivo We further demonstrate that miR-155 and TP53 are linked in a negative feedback mechanism and that a combination of high expression of miR-155 and low expression of TP53 is significantly associated with shorter survival in lung cancer.Conclusions: Our findings support the existence of an miR-155/TP53 feedback loop, which is involved in resistance to chemotherapy and which can be specifically targeted to overcome drug resistance, an important cause of cancer-related death. Clin Cancer Res; 23(11); 2891-904. ©2016 AACR.
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Affiliation(s)
- Katrien Van Roosbroeck
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Francesca Fanini
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) S.r.l. IRCCS, Unit of Gene Therapy, Meldola (FC) 47014, Italy
| | - Tetsuro Setoyama
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Cristina Ivan
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Cristian Rodriguez-Aguayo
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Enrique Fuentes-Mattei
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Lianchun Xiao
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ivan Vannini
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) S.r.l. IRCCS, Unit of Gene Therapy, Meldola (FC) 47014, Italy
| | - Roxana S Redis
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Lucilla D'Abundo
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara 44121, Italy
| | - Xinna Zhang
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Milena S Nicoloso
- Division of Experimental Oncology 2, CRO, National Cancer Institute, Aviano 33081, Italy
| | - Simona Rossi
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Vianey Gonzalez-Villasana
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,Departamento de Biologia Celular y Genetica, Universidad Autonoma de Nuevo Leon, 66450 San Nicolas de los Garza, Nuevo Leon, Mexico
| | - Rajesha Rupaimoole
- Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Manuela Ferracin
- Department of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, Bologna 40126, Italy
| | | | - Antonino Neri
- Department of Clinical Sciences and Community Health, University of Milano and Hematology, Ospedale Policlinico, Milano 20122, Italy
| | - Peter P Ruvolo
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Vivian R Ruvolo
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Chad V Pecot
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Dino Amadori
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) S.r.l. IRCCS, Unit of Gene Therapy, Meldola (FC) 47014, Italy
| | - Lynne Abruzzo
- Department of Pathology, The Ohio State University, Columbus, OH 43210, USA
| | - Steliana Calin
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Xuemei Wang
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - M James You
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Alessandra Ferrajoli
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Robert Orlowski
- Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - William Plunkett
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Tara M Lichtenberg
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ramana V Davuluri
- Department of Preventive Medicine - Division of Health and Biomedical Informatics, Northwestern University - Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Ioana Berindan-Neagoe
- Department of Functional Genomics, The Oncology Institute, 400015 Cluj-Napoca, Romania.,Research Center for Functional Genomics, Biomedicine and Translational Medicine, University of Medicine and Pharmacy Iuliu Hatieganu, 400012 Cluj-Napoca, Romania
| | - Massimo Negrini
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara 44121, Italy
| | - Ignacio I Wistuba
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX77030, USA
| | - Hagop M Kantarjian
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Anil K Sood
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Gabriel Lopez-Berestein
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Michael J Keating
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Muller Fabbri
- Departments of Pediatrics and Molecular Microbiology & Immunology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Saban
| | - George A Calin
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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26
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Ragusa M, Barbagallo C, Statello L, Condorelli AG, Battaglia R, Tamburello L, Barbagallo D, Di Pietro C, Purrello M. Non-coding landscapes of colorectal cancer. World J Gastroenterol 2015; 21:11709-11739. [PMID: 26556998 PMCID: PMC4631972 DOI: 10.3748/wjg.v21.i41.11709] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 07/28/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
For two decades Vogelstein’s model has been the paradigm for describing the sequence of molecular changes within protein-coding genes that would lead to overt colorectal cancer (CRC). This model is now too simplistic in the light of recent studies, which have shown that our genome is pervasively transcribed in RNAs other than mRNAs, denominated non-coding RNAs (ncRNAs). The discovery that mutations in genes encoding these RNAs [i.e., microRNAs (miRNAs), long non-coding RNAs, and circular RNAs] are causally involved in cancer phenotypes has profoundly modified our vision of tumour molecular genetics and pathobiology. By exploiting a wide range of different mechanisms, ncRNAs control fundamental cellular processes, such as proliferation, differentiation, migration, angiogenesis and apoptosis: these data have also confirmed their role as oncogenes or tumor suppressors in cancer development and progression. The existence of a sophisticated RNA-based regulatory system, which dictates the correct functioning of protein-coding networks, has relevant biological and biomedical consequences. Different miRNAs involved in neoplastic and degenerative diseases exhibit potential predictive and prognostic properties. Furthermore, the key roles of ncRNAs make them very attractive targets for innovative therapeutic approaches. Several recent reports have shown that ncRNAs can be secreted by cells into the extracellular environment (i.e., blood and other body fluids): this suggests the existence of extracellular signalling mechanisms, which may be exploited by cells in physiology and pathology. In this review, we will summarize the most relevant issues on the involvement of cellular and extracellular ncRNAs in disease. We will then specifically describe their involvement in CRC pathobiology and their translational applications to CRC diagnosis, prognosis and therapy.
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27
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Nagaraju GP, Madanraj AS, Aliya S, Rajitha B, Alese OB, Kariali E, Alam A, El-Rayes BF. MicroRNAs as biomarkers and prospective therapeutic targets in colon and pancreatic cancers. Tumour Biol 2015; 37:97-104. [PMID: 26537581 DOI: 10.1007/s13277-015-4346-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2015] [Accepted: 10/28/2015] [Indexed: 12/15/2022] Open
Abstract
Colon and pancreatic cancers have high mortality rates due to early metastasis prior to the onset of symptoms. Screening tests for colorectal cancer are invasive and expensive. No effective screening is available for pancreatic cancer. Identification of biomarkers for early detection in both of these cancers is being extensively researched. MicroRNAs (miRNA) are small non-coding molecule biomarkers that regulate cancers. Measurement of miRNAs in pancreatic fluid or blood could be a preferred non-invasive screening method. The regulation of colon and pancreatic cancers by miRNA is complex. miRNA play a central role in inflammation, invasiveness, and tumor progression in these two cancers, as well as regulation of the NF-κB pathway. miRNA's evolving role in screening is also reviewed.
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Affiliation(s)
- Ganji Purnachandra Nagaraju
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365 Clifton RD NE, Office 3025, Atlanta, GA, 30322, USA.
| | - Appiya Santharam Madanraj
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK, 12 LE1 9HN
| | - Sheik Aliya
- Department of Biotechnology, Jawaharlal Nehru Technological University, Hyderabad, Andhra Pradesh, 500085, India
| | - Balney Rajitha
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365 Clifton RD NE, Office 3025, Atlanta, GA, 30322, USA.,Department of Microbiology, Banasthali University, Banasthali, Rajasthan, 304022, India
| | - Olatunji Boladale Alese
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365 Clifton RD NE, Office 3025, Atlanta, GA, 30322, USA
| | - Ekamber Kariali
- School of Life Sciences, Department of Biotechnology, Sambalpur University, Jyoti Vihar, Sambalpur, Odisha, 768019, India
| | - Afroz Alam
- Department of Microbiology, Banasthali University, Banasthali, Rajasthan, 304022, India
| | - Bassel F El-Rayes
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365 Clifton RD NE, Office 3025, Atlanta, GA, 30322, USA
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Abstract
Preclinical Research MicroRNA (miR)-155 and cyclooxygenase (COX)-2 are both elevated in numerous cancers including colorectal cancer. MiR-155 enhances COX-2 expression and is an established regulator of epithelial-mesenchymal transition and inflammation. Inhibition of miR-155 or COX-2 exhibit similar negative effects on tumorigenicity. Thus, it is hypothesized that miR-155 may be a promising target for antagonizing COX-2 expression in colorectal and other cancers.
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Affiliation(s)
- Brian S Comer
- Department of Cellular and Integrative Physiology, Indiana University, Indianapolis, IN, USA
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29
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Li Z, Yu X, Shen J, Chan MTV, Wu WKK. MicroRNA in intervertebral disc degeneration. Cell Prolif 2015; 48:278-83. [PMID: 25736871 DOI: 10.1111/cpr.12180] [Citation(s) in RCA: 148] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 11/22/2014] [Indexed: 12/17/2022] Open
Abstract
Aetiology of intervertebral disc degeneration (IDD) is complex, with genetic, developmental, biochemical and biomechanical factors contributing to the disease process. It is becoming obvious that epigenetic processes influence evolution of IDD as strongly as the genetic background. Deregulated phenotypes of nucleus pulposus cells, including differentiation, migration, proliferation and apoptosis, are involved in all stages of progression of human IDD. Non-coding RNAs, including microRNAs, have recently been recognized as important regulators of gene expression. Research into roles of microRNAs in IDD has been very active over the past 5 years. Our review summarizes current research enlightenment towards understanding roles of microRNAs in regulating nucleus pulposus cell functions in IDD. These exciting findings support the notion that specific modulation of microRNAs may represent an attractive approach for management of IDD.
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Affiliation(s)
- Zheng Li
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, 100007, China
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30
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Djelić N, Radaković M, Spremo-Potparević B, Živković L, Bajić V, Stevanović J, Stanimirović Z. Evaluation of cytogenetic and DNA damage in human lymphocytes treated with adrenaline in vitro. Toxicol In Vitro 2015; 29:27-33. [DOI: 10.1016/j.tiv.2014.08.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 05/09/2014] [Accepted: 08/10/2014] [Indexed: 10/24/2022]
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Tong L, Yuan Y, Wu S. Therapeutic microRNAs targeting the NF-kappa B signaling circuits of cancers. Adv Drug Deliv Rev 2015; 81:1-15. [PMID: 25220353 DOI: 10.1016/j.addr.2014.09.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Revised: 08/27/2014] [Accepted: 09/03/2014] [Indexed: 02/06/2023]
Abstract
MicroRNAs (miRNAs) not only directly regulate NF-κB expression, but also up- or down-regulate NF-κB activity via upstream and downstream signaling pathways of NF-κB. In many cancer cells, miRNA expressions are altered accompanied with an elevation of NF-κB activity, which often plays a role in promoting cancer development and progression as well as hindering the effectiveness of chemo and radiation therapies. Thus NF-κB-targeting miRNAs have been identified and characterized as potential therapeutics for cancer treatment and sensitizers of chemo and radiotherapies. However, due to cross-targeting and instability of miRNAs, some limitations of using miRNA as cancer therapeutics still exist. In this review, the mechanisms for miRNA-mediated alteration of NF-κB expression and activation in different types of cancers will be discussed. The results of therapeutic use of NF-κB-targeting miRNA for cancer treatment will be examined. Some limitations, challenges and potential strategies in future development of miRNA as cancer therapeutics are also assessed.
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Abstract
Theory and empirical evidence suggest that psychological stress and other adverse psychosocial experiences can contribute to cancer progression. Research has begun to explore the potential role of epigenetic changes in these pathways. In basic, animal and human models, exposure to stressors or to the products of the physiological stress response (e.g., cortisol) has been associated with epigenetic changes, such as DNA methylation and microRNA (miR) expression, which may influence tumor growth, progression, metastasis, or chemoresistance. However, the specific biological pathways linking stress, epigenetic changes, and cancer outcomes remain unclear. Numerous opportunities exist to extend the preliminary evidence for the role of epigenetic mechanisms in the biopsychosocial pathways contributing to cancer progression. Such work will improve our understanding of how the psychosocial environment influences cancer risk and survival, potentially leading to improved prevention and treatment strategies.
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33
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Abstract
Nuclear Factor kappa B (NF-κB) plays important roles in regulation of countless cellular functions, including cell cycle and apoptosis. As a versatile transcription factor, NF-κB is a target of a large amount of miRNAs. Abnormal NF-κB activity is frequently associated with an abnormal level of miRNAs, which is found to play critical roles in disease progression including cancer. While the expression and activity of NF-κB can be directly or indirectly up-regulated or downregulated by various miRNAs, NF-κB can also regulate the expression of many miRNAs. Intriguingly, reciprocal regulation between miRNAs and NF-κB, which exists in the form of positive and negative feedback loops, is often observed in various cancers. In this chapter, the mechanisms and roles of miRNA-regulated NF-κB and NF-κB-regulated miRNAs in a variety of cancers will be discussed. The potential therapeutic use of miRNAs that are up- and down-stream of NF-κB signaling pathways as targets for cancer treatment will also be accessed.
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Farooqi AA, Qureshi MZ, Coskunpinar E, Naqvi SKUH, Yaylim I, Ismail M. MiR-421, miR-155 and miR-650: emerging trends of regulation of cancer and apoptosis. Asian Pac J Cancer Prev 2014; 15:1909-12. [PMID: 24716910 DOI: 10.7314/apjcp.2014.15.5.1909] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
It is becoming progressively more understandable that between transcription and translation there lies another versatile regulator that quantitatively controls the expression of mRNAs. Identification of miRNAs as key regulators of wide ranging signaling cascades and modulators of different cell-type and context dependent activities attracted basic and clinical scientists to study modes and mechanisms in details. In line with this approach overwhelmingly increasing in vivo and in vitro studies are deepening our understanding regarding miR-421, mir-155 and miR-650 mediated regulation of cellular activities. We also attempt to provide an overview of long non coding RNAs.
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Affiliation(s)
- Ammad Ahmad Farooqi
- Laboratory for Translational Oncology and Personalized Medicine, Rashid Latif Medical College, Lahore, Pakistan E-mail :
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35
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Zhao L, Xu JH. Role of adrenergic receptor signaling pathway in colorectal cancer. Shijie Huaren Xiaohua Zazhi 2014; 22:5285-5290. [DOI: 10.11569/wcjd.v22.i34.5285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is one of the most common malignancies. During the past decades, studies have continued to shed light on the role of adrenergic receptor signaling in cancer. Preclinical studies have shown that adrenergic receptor signaling is involved in colon cancer progression and metastasis and have implicated that stress hormones or behavioral changes are highly associated with tumor formation and progression. Therefore, further understanding of the role of the adrenergic receptor (AR) signaling pathway in colorectal cancer progression and metastasis will be of great value in developing therapeutic strategies for this malignancy.
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Billeter AT, Hellmann J, Roberts H, Druen D, Gardner SA, Sarojini H, Galandiuk S, Chien S, Bhatnagar A, Spite M, Polk HC. MicroRNA-155 potentiates the inflammatory response in hypothermia by suppressing IL-10 production. FASEB J 2014; 28:5322-36. [PMID: 25231976 DOI: 10.1096/fj.14-258335] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Therapeutic hypothermia is commonly used to improve neurological outcomes in patients after cardiac arrest. However, therapeutic hypothermia increases sepsis risk and unintentional hypothermia in surgical patients increases infectious complications. Nonetheless, the molecular mechanisms by which hypothermia dysregulates innate immunity are incompletely understood. We found that exposure of human monocytes to cold (32°C) potentiated LPS-induced production of TNF and IL-6, while blunting IL-10 production. This dysregulation was associated with increased expression of microRNA-155 (miR-155), which potentiates Toll-like receptor (TLR) signaling by negatively regulating Ship1 and Socs1. Indeed, Ship1 and Socs1 were suppressed at 32°C and miR-155 antagomirs increased Ship1 and Socs1 and reversed the alterations in cytokine production in cold-exposed monocytes. In contrast, miR-155 mimics phenocopied the effects of cold exposure, reducing Ship1 and Socs1 and altering TNF and IL-10 production. In a murine model of LPS-induced peritonitis, cold exposure potentiated hypothermia and decreased survival (10 vs. 50%; P < 0.05), effects that were associated with increased miR-155, suppression of Ship1 and Socs1, and alterations in TNF and IL-10. Importantly, miR-155-deficiency reduced hypothermia and improved survival (78 vs. 32%, P < 0.05), which was associated with increased Ship1, Socs1, and IL-10. These results establish a causal role of miR-155 in the dysregulation of the inflammatory response to hypothermia.
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Affiliation(s)
- Adrian T Billeter
- Price Institute of Surgical Research, Hiram C. Polk, Jr., M.D. Department of Surgery, and
| | - Jason Hellmann
- Diabetes and Obesity Center, Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Henry Roberts
- Price Institute of Surgical Research, Hiram C. Polk, Jr., M.D. Department of Surgery, and
| | - Devin Druen
- Price Institute of Surgical Research, Hiram C. Polk, Jr., M.D. Department of Surgery, and
| | - Sarah A Gardner
- Price Institute of Surgical Research, Hiram C. Polk, Jr., M.D. Department of Surgery, and
| | - Harshini Sarojini
- Price Institute of Surgical Research, Hiram C. Polk, Jr., M.D. Department of Surgery, and
| | - Susan Galandiuk
- Price Institute of Surgical Research, Hiram C. Polk, Jr., M.D. Department of Surgery, and
| | - Sufan Chien
- Price Institute of Surgical Research, Hiram C. Polk, Jr., M.D. Department of Surgery, and
| | - Aruni Bhatnagar
- Diabetes and Obesity Center, Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Matthew Spite
- Diabetes and Obesity Center, Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Hiram C Polk
- Price Institute of Surgical Research, Hiram C. Polk, Jr., M.D. Department of Surgery, and
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Sun S, Sun P, Wang C, Sun T. Downregulation of microRNA-155 accelerates cell growth and invasion by targeting c-myc in human gastric carcinoma cells. Oncol Rep 2014; 32:951-6. [PMID: 24969405 DOI: 10.3892/or.2014.3288] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Accepted: 05/06/2014] [Indexed: 11/06/2022] Open
Abstract
MicroRNAs (miRNAs) are a recently discovered class of small non-coding RNAs that regulate gene expression. miRNAs can contribute to cancer development and progression and are differentially expressed in normal tissue and cancer. In the present study, our aim was to investigate the expression of miR-155 in gastric cancer and to explore the mechanisms by which it influences gastric cancer cells. The level of miR-155 in 52 gastric carcinoma and corresponding non-tumor tissues was quantified by real-time reverse transcriptase-polymerase chain reaction. We used the data from EdU, CASY and cell adhesion assays to show how the expression of miR-155 affects viability and proliferation in SGC-7901 cancer cells. We also performed functional assays using the 3'-untranslated region (3'-UTR) of the c-myc gene as a miR-155 target in a luciferase reporter assay system. Our results indicated that miR-155 is downregulated in both human gastric carcinoma tissues and SGC-7901 cells. The high expression level of miR-155 may significantly downregulate cancer cell viability, proliferation and attachment. The level of miR-155 could influence endogenous c-myc expression in SGC-7901 cells, and may decrease its expression by binding to 3'-UTR of c-myc. In conclusion, our results suggest that miR-155 is extensively involved in the cancer pathogenesis of gastric carcinoma and support its function as recessive cancer genes. c-myc is an important miR-155 target gene.
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Affiliation(s)
- Shibo Sun
- Department of General Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Peng Sun
- Department of General Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Chunmei Wang
- Department of Animal Biology, Northeast Agricultural University, Harbin, Heilongjiang 150001, P.R. China
| | - Tiewei Sun
- Department of General Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
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Ouyang M, Li Y, Ye S, Ma J, Lu L, Lv W, Chang G, Li X, Li Q, Wang S, Wang W. MicroRNA profiling implies new markers of chemoresistance of triple-negative breast cancer. PLoS One 2014; 9:e96228. [PMID: 24788655 PMCID: PMC4008525 DOI: 10.1371/journal.pone.0096228] [Citation(s) in RCA: 158] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Accepted: 04/04/2014] [Indexed: 02/06/2023] Open
Abstract
Objective Triple-negative breast cancer (TNBC) patients with truly chemosensitive disease still represent a minority among all TNBC patients. The aim of the present study is to identify microRNAs (miRNAs) that correlate with TNBC chemoresistance. Methods In this study, we conducted miRNAs profile comparison between triple-negative breast cancer (TNBCs) and normal breast tissues by microRNA array. Quantitative real-time PCR (qRT-PCR) was utilized to confirm the specific deregulated miRNAs change trend. We used starBase 2.1 and GOrilla to predict the potential targets of the specific miRNAs. Cells viability and apoptosis assays were employed to determine the effect of alteration of the specific miRNAs in TNBC cells on the chemosensitivity. Results We identified 11 specific deregulated miRNAs, including 5 up-regulated miRNAs (miR-155-5p, miR-21-3p, miR-181a-5p, miR-181b-5p, and miR-183-5p) and 6 down-regulated miRNAs (miR-10b-5p, miR-451a, miR-125b-5p, miR-31-5p, miR-195-5p and miR-130a-3p). Thereafter, this result was confirmed by qRT-PCR. We predicted the potential targets of the candidate miRNAs and found that they are involved in cancer-associated pathways. For the first time, we found that miR-130a-3p and miR-451a were down-regulated in TNBC. 9 of the 11 specific deregulated miRNAs were found to be associated with chemoresistance. In vitro assays, we found that up-regulation of either miR-130a-3p or miR-451a in MDA-MB-231 cells significantly changed the cells sensitivity to doxorubicin. The results suggest that TNBC chemotherapy might be affected by a cluster of miRNAs. Conclusion The abnormal expression miRNAs in TNBC are mainly chemoresistance related. This might be part of reason that TNBC likely to evade from chemotherapy resulting in early relapse and high risk of death. To alter their expression status might be a potential therapeutic strategy to improve the outcome of chemotherapy for TNBC patients.
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Affiliation(s)
- Mao Ouyang
- Laboratory of Department of Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
- Center for Cellular and Structural Biology, Guangzhou, Guangdong, People's Republic of China
- Department of Clinical Laboratory, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Yongxin Li
- Laboratory of Department of Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Sheng Ye
- Department of Medical Oncology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Jieyi Ma
- Laboratory of Department of Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Liming Lu
- Department of Medical Statistics and Epidemiology, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Weiming Lv
- Department of Vascular, Thyroid and Breast Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Guangqi Chang
- Department of Vascular, Thyroid and Breast Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Xiaoxi Li
- Department of Vascular, Thyroid and Breast Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Qing Li
- Center for Cellular and Structural Biology, Guangzhou, Guangdong, People's Republic of China
- * E-mail: (WW); (SW); (QL)
| | - Shenming Wang
- Department of Vascular, Thyroid and Breast Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
- * E-mail: (WW); (SW); (QL)
| | - Wenjian Wang
- Laboratory of Department of Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
- * E-mail: (WW); (SW); (QL)
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Ye JJ, Cao J. MicroRNAs in colorectal cancer as markers and targets: Recent advances. World J Gastroenterol 2014; 20:4288-4299. [PMID: 24764666 PMCID: PMC3989964 DOI: 10.3748/wjg.v20.i15.4288] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 01/02/2014] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs are evolutionarily conserved small non-coding RNA molecules encoded by eukaryotic genomic DNA, and function in post-transcriptional regulation of gene expression via base-pairing with complementary sequences in target mRNAs, resulting in translational repression or degradation of target mRNAs. They represent one of the major types of epigenetic modification and play important roles in all aspects of cellular activities. Altered expression of microRNAs has been found in various human diseases including cancer. Many efforts have been made to discover the characteristic microRNA expression profiles, to understand the roles of aberrantly expressed microRNAs and underlying mechanisms in different cancers. With the application of DNA microarray, real-time quantitative polymerase chain reaction and other molecular biology techniques, increasing evidence has been accumulated which reveal that aberrant microRNAs can be detected not only intracellularly within the cancer cells, but also extracellularly in plasma of patients, postulating the potential of aberrant microRNAs as promising diagnostic/prognostic markers and attracting therapeutic targets. This review is intended to provide the most recent advances in microRNA studies in one of the most common cancers, colorectal cancer, especially the identification of those specifically altered microRNAs in colorectal cancer, validation for their relevance to clinical pathological parameters of patients, functional analyses and potential applications of these microRNAs.
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Hong L, Han Y, Yang J, Zhang H, Zhao Q, Wu K, Fan D. MicroRNAs in gastrointestinal cancer: prognostic significance and potential role in chemoresistance. Expert Opin Biol Ther 2014; 14:1103-11. [PMID: 24707835 DOI: 10.1517/14712598.2014.907787] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Although chemotherapy is an important therapeutic strategy for gastrointestinal cancer, its clinical effect remains unsatisfied due to drug resistance. Drug resistance is a complex multistep process resulting from deregulated expression of many molecules, including tumor suppressor genes, oncogenes and microRNAs (miRNAs). A better understanding of drug resistance-related miRNAs may eventually lead to optimized therapeutic strategies for cancer patients. AREAS COVERED This review summarizes the recent advances of drug resistance-related miRNAs in esophageal, gastric and colorectal cancer. Furthermore, this study envisages future developments toward the clinical applications of these miRNAs to cancer therapy. EXPERT OPINION Drug resistance-related miRNAs may be potentially predicting biomarkers that help guide individualized chemotherapy. Specific miRNAs and their target genes can be used as therapeutic targets by reversing drug resistance. More investigations should be performed to promote the translational bridging of the latest research into clinical application.
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Affiliation(s)
- Liu Hong
- Fourth Military Medical University, Xijing Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Cancer Biology , Xi'an, 710032, Shaanxi Province , China +86 29 84773974 ; +86 29 82539041 ;
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41
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Chen Z, Ma T, Huang C, Hu T, Li J. The pivotal role of microRNA-155 in the control of cancer. J Cell Physiol 2014; 229:545-50. [PMID: 24122356 DOI: 10.1002/jcp.24492] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2013] [Accepted: 10/09/2013] [Indexed: 12/11/2022]
Abstract
microRNAs (miRNAs) are emerging as important gene expression regulators linked to various biological processes at a posttranscriptional level. miRNAs have been known to play important roles in cell proliferation, cell differentiation, and apoptosis. Recently, accumulate studies indicate that up-regulation of miR-155 has been described in several types of human tumors. miR-155 has been considered to act as an oncogene or a tumor suppressor, depending on tumor system. Silencing oncomiRs or gene therapy approaches could be an effective therapeutic approach against tumor. Here we review the current knowledge on the functional role of miR-155 in the control of various cancers.
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Affiliation(s)
- Zhaolin Chen
- Anhui Key Laboratory of Bioactivity of Natural Products, Institute for Liver Diseases of Anhui Medical University (AMU), School of Pharmacy, Anhui Medical University, Hefei, China
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Hutchison J, Cohen Z, Onyeaguchi BC, Funk J, Nelson MA. How microRNAs influence both hereditary and inflammatory-mediated colon cancers. Cancer Genet 2013; 206:309-16. [PMID: 24042167 PMCID: PMC3893936 DOI: 10.1016/j.cancergen.2013.06.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 06/03/2013] [Accepted: 06/24/2013] [Indexed: 01/08/2023]
Abstract
MicroRNAs have emerged as important post-translational regulators of gene expression and are involved in several physiological and pathological states including the pathogenesis of human colon cancers. In regards to tumor development, microRNAs can act as oncogenes or tumor suppressors. Two hereditary predispositions (i.e., Lynch syndrome and familial adenomatous polyposis) contribute to the development of colon cancer. In addition, individuals who suffer from inflammatory bowel diseases such as Crohn's disease or ulcerative colitis have a higher risk of developing colon cancer. Here, we discuss the occurrence of the deregulated expression of microRNAs in colon cancer that arise as a result of hereditary predisposition and inflammatory bowel disease.
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Affiliation(s)
| | - Zoe Cohen
- Department of Physiology, University of Arizona
| | | | - Janet Funk
- Department of Medicine, Arizona Cancer Center, University of Arizona
| | - Mark A. Nelson
- Department of Pathology, Arizona Cancer Center, University of Arizona
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Kang H, Kim C, Lee H, Kim W, Lee EK. Post-transcriptional controls by ribonucleoprotein complexes in the acquisition of drug resistance. Int J Mol Sci 2013; 14:17204-20. [PMID: 23965981 PMCID: PMC3759960 DOI: 10.3390/ijms140817204] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Revised: 07/31/2013] [Accepted: 08/09/2013] [Indexed: 01/03/2023] Open
Abstract
Acquisition of drug resistance leads to failure of anti-cancer treatments and therapies. Although several successive chemotherapies are available, along with efforts towards clinical applications of new anti-cancer drugs, it is generally realized that there is a long way to go to treat cancers. Resistance to anti-cancer drugs results from various factors, including genetic as well as epigenetic differences in tumors. Determining the molecular and cellular mechanisms responsible for the acquisition of drug resistance may be a helpful approach for the development of new therapeutic strategies to overcome treatment failure. Several studies have shown that the acquisition of drug resistance is tightly regulated by post-transcriptional regulators such as RNA binding proteins (RBPs) and microRNAs (miRNAs), which change the stability and translation of mRNAs encoding factors involved in cell survival, proliferation, epithelial-mesenchymal transition, and drug metabolism. Here, we review our current understanding of ribonucleoprotein complexes, including RBPs and miRNAs, which play critical roles in the acquisition of drug resistance and have potential clinical implications for cancer.
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Affiliation(s)
- Hoin Kang
- Department of Biochemistry, College of Medicine, Catholic University of Korea, Seoul 137-701, Korea; E-Mails: (H.K.); (C.K.); (H.L.)
| | - Chongtae Kim
- Department of Biochemistry, College of Medicine, Catholic University of Korea, Seoul 137-701, Korea; E-Mails: (H.K.); (C.K.); (H.L.)
| | - Heejin Lee
- Department of Biochemistry, College of Medicine, Catholic University of Korea, Seoul 137-701, Korea; E-Mails: (H.K.); (C.K.); (H.L.)
| | - Wook Kim
- Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea
- Authors to whom correspondence should be addressed; E-Mails: (W.K.); (E.K.L.); Tel.: +82-31-219-2513 (W.K.); +82-2-2258-7295 (E.K.L.); Fax: +82-31-219-1610 (W.K.); +82-2-596-4435 (E.K.L.)
| | - Eun Kyung Lee
- Department of Biochemistry, College of Medicine, Catholic University of Korea, Seoul 137-701, Korea; E-Mails: (H.K.); (C.K.); (H.L.)
- Authors to whom correspondence should be addressed; E-Mails: (W.K.); (E.K.L.); Tel.: +82-31-219-2513 (W.K.); +82-2-2258-7295 (E.K.L.); Fax: +82-31-219-1610 (W.K.); +82-2-596-4435 (E.K.L.)
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The influence of R substituents in triphenylphosphinegold(I) carbonimidothioates, Ph3PAu[SC(OR)=NPh] (R=Me, Et and iPr), upon in vitro cytotoxicity against the HT-29 colon cancer cell line and upon apoptotic pathways. J Inorg Biochem 2013; 127:24-38. [PMID: 23850666 DOI: 10.1016/j.jinorgbio.2013.05.011] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Revised: 05/23/2013] [Accepted: 05/23/2013] [Indexed: 11/20/2022]
Abstract
The Ph3PAu[SC(OR)=NPh], R=Me (1), Et (2) and iPr (3), compounds are significantly cytotoxic to the HT-29 cancer cell line with 1 being the most active. Based on human apoptosis PCR-array analysis, caspase activities, DNA fragmentation, cell apoptotic assays, intracellular reactive oxygen species (ROS) measurements and human topoisomerase I inhibition, induction of apoptosis is demonstrated and both the extrinsic and intrinsic pathways of apoptosis have been shown to occur. Compound 1 activates the p73 gene, whereas each of 2 and 3 activates the p53 gene. An additional apoptotic mechanism is exhibited by 2, that is, via the JNK/MAP pathway.
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S100P/RAGE signaling regulates microRNA-155 expression via AP-1 activation in colon cancer. Exp Cell Res 2013; 319:2081-2090. [PMID: 23693020 DOI: 10.1016/j.yexcr.2013.05.009] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2013] [Revised: 05/08/2013] [Accepted: 05/13/2013] [Indexed: 01/08/2023]
Abstract
Accumulating evidence indicates that elevated S100P promotes the pathogenesis of cancers, including colon cancer. S100P exerts its effects by binding to and activating the Receptor for Advance Glycation End-products (RAGE). The effects of up-regulated S100P/RAGE signaling on cell functions are well documented. Despite these observations, little is known about the downstream targets of S100P/RAGE signaling. In the present study, we demonstrated for the first time that activation of RAGE by S100P regulates oncogenic microRNA-155 (miR-155) expression through Activator Protein-1 (AP-1) stimulation in colon cancer cells. Ectopic S100P up-regulated miR-155 levels in human colon cancer cells. Conversely, knockdown of S100P resulted in a decrease in miR-155 levels. Exogenous S100P induced miR-155 expression, but blockage of the RAGE with anti-RAGE antibody suppressed the induction of miR-155 by exogenous S100P. Attenuation of AP-1 activation through pharmacological inhibition of MEK activation or genetic inhibition of c-Jun activation using dominant negative c-Jun (TAM67) suppressed miR-155 induction by exogenous S100P. Also, S100P treatment stimulated the enrichment of c-Fos, an AP-1 family member, at the miR-155 host gene promoter site. Finally, a functional study demonstrated that miR-155 knockdown decreases colon cancer cell growth, motility, and invasion. Altogether, these data demonstrate that the expression of miR-155 is regulated by S100P and is dependent on RAGE activation and stimulation of AP-1.
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