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Mamun M, Zheng YC, Wang N, Wang B, Zhang Y, Pang JR, Shen DD, Liu HM, Gao Y. Decoding CLU (Clusterin): Conquering cancer treatment resistance and immunological barriers. Int Immunopharmacol 2024; 137:112355. [PMID: 38851158 DOI: 10.1016/j.intimp.2024.112355] [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: 04/25/2024] [Revised: 05/22/2024] [Accepted: 05/24/2024] [Indexed: 06/10/2024]
Abstract
One major obstacle in the treatment of cancer is the presence of proteins resistant to cancer therapy, which can impede the effectiveness of traditional approaches such as radiation and chemotherapy. This resistance can lead to disease progression and cause treatment failure. Extensive research is currently focused on studying these proteins to create tailored treatments that can circumvent resistance mechanisms. CLU (Clusterin), a chaperone protein, has gained notoriety for its role in promoting resistance to a wide range of cancer treatments, including chemotherapy, radiation therapy, and targeted therapy. The protein has also been discovered to have a role in regulating the immunosuppressive environment within tumors. Its ability to influence oncogenic signaling and inhibit cell death bolster cancer cells resistant against treatments, which poses a significant challenge in the field of oncology. Researchers are actively investigating to the mechanisms by which CLU exerts its resistance-promoting effects, with the ultimate goal of developing strategies to circumvent its impact and enhance the effectiveness of cancer therapies. By exploring CLU's impact on cancer, resistance mechanisms, tumor microenvironment (TME), and therapeutic strategies, this review aims to contribute to the ongoing efforts to improve cancer treatment outcomes.
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Affiliation(s)
- Maa Mamun
- State Key Laboratory of Esophageal Cancer Prevention & Treatment Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
| | - Yi-Chao Zheng
- State Key Laboratory of Esophageal Cancer Prevention & Treatment Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
| | - Ning Wang
- The School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Bo Wang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
| | - Yu Zhang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
| | - Jing-Ru Pang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
| | - Dan-Dan Shen
- Key Laboratory of Endometrial Disease Prevention and Treatment, Zhengzhou China, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Hong-Min Liu
- State Key Laboratory of Esophageal Cancer Prevention & Treatment Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
| | - Ya Gao
- State Key Laboratory of Esophageal Cancer Prevention & Treatment Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
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Hlavca S, Chan WH, Engel RM, Abud HE. Clusterin: a marker and mediator of chemoresistance in colorectal cancer. Cancer Metastasis Rev 2024; 43:379-391. [PMID: 38319453 PMCID: PMC11015998 DOI: 10.1007/s10555-024-10173-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 01/24/2024] [Indexed: 02/07/2024]
Abstract
Intra-tumoural heterogeneity and cancer cell plasticity in colorectal cancer (CRC) have been key challenges to effective treatment for patients. It has been suggested that a subpopulation of LGR5-expressing cancer stem cells (CSCs) is responsible for driving tumour relapse and therapy resistance in CRC. However, studies have revealed that the LGR5+ve CSC population is highly sensitive to chemotherapy. It has been hypothesised that another subset of tumour cells can phenotypically revert to a stem-like state in response to chemotherapy treatment which replenishes the LGR5+ve CSC population and maintains tumour growth. Recently, a unique stem cell population marked by enriched clusterin (CLU) expression and termed the revival stem cell (RevSC) was identified in the regenerating murine intestine. This CLU-expressing cell population is quiescent during homeostasis but has the ability to survive and regenerate other stem cells upon injury. More recently, the CLU+ve signature has been implicated in several adverse outcomes in CRC, including chemotherapy resistance and poor patient survival; however, the mechanism behind this remains undetermined. In this review, we discuss recent insights on CLU in CRC and its roles in enhancing the plasticity of cells and further consider the implications of CLU as a prospective target for therapeutic intervention.
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Affiliation(s)
- Sara Hlavca
- Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, VIC, 3800, Australia
| | - Wing Hei Chan
- Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, VIC, 3800, Australia
| | - Rebekah M Engel
- Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, VIC, 3800, Australia
- Department of Surgery, Cabrini Monash University, Cabrini Hospital, Malvern, VIC, 3144, Australia
| | - Helen E Abud
- Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia.
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, VIC, 3800, Australia.
- Department of Surgery, Cabrini Monash University, Cabrini Hospital, Malvern, VIC, 3144, Australia.
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Zhang Q, Teow JY, Kerishnan JP, Abd Halim AA, Chen Y. Clusterin and Its Isoforms in Oral Squamous Cell Carcinoma and Their Potential as Biomarkers: A Comprehensive Review. Biomedicines 2023; 11:biomedicines11051458. [PMID: 37239129 DOI: 10.3390/biomedicines11051458] [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: 03/14/2023] [Revised: 04/25/2023] [Accepted: 05/05/2023] [Indexed: 05/28/2023] Open
Abstract
Oral squamous cell carcinoma (OSCC) is a prevalent type of head and neck cancer, ranked as the sixth most common cancer worldwide, accounting for approximately 300,000 new cases and 145,000 deaths annually. Early detection using biomarkers significantly increases the 5-year survival rate of OSCC by up to 80-90%. Clusterin (CLU), also known as apolipoprotein J, is a sulfated chaperonic glycoprotein expressed in all tissues and human fluids and has been reported to be a potential biomarker of OSCC. CLU has been implicated as playing a vital role in many biological processes such as apoptosis, cell cycle, etc. Abnormal CLU expression has been linked with the development and progression of cancers. Despite the fact that there are many studies that have reported the involvement of CLU and its isoforms in OSCC, the exact roles of CLU and its isoforms in OSCC carcinogenesis have not been fully explored. This article aims to provide a comprehensive review of the current understanding of CLU structure and genetics and its correlation with OSCC tumorigenesis to better understand potential diagnostic and prognostic biomarker development. The relationship between CLU and chemotherapy resistance in cancer will also be discussed to explore the therapeutic application of CLU and its isoforms in OSCC.
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Affiliation(s)
- Qinyi Zhang
- Department of Biomedical Science, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Jun Yao Teow
- Department of Biomedical Science, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | | | - Adyani Azizah Abd Halim
- Department of Oral and Craniofacial Sciences, Faculty of Dentistry, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Yeng Chen
- Department of Oral and Craniofacial Sciences, Faculty of Dentistry, Universiti Malaya, Kuala Lumpur 50603, Malaysia
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Ciccone G, Ibba ML, Coppola G, Catuogno S, Esposito CL. The Small RNA Landscape in NSCLC: Current Therapeutic Applications and Progresses. Int J Mol Sci 2023; 24:ijms24076121. [PMID: 37047090 PMCID: PMC10093969 DOI: 10.3390/ijms24076121] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/17/2023] [Accepted: 03/22/2023] [Indexed: 04/14/2023] Open
Abstract
Non-small-cell lung cancer (NSCLC) is the second most diagnosed type of malignancy and the first cause of cancer death worldwide. Despite recent advances, the treatment of choice for NSCLC patients remains to be chemotherapy, often showing very limited effectiveness with the frequent occurrence of drug-resistant phenotype and the lack of selectivity for tumor cells. Therefore, new effective and targeted therapeutics are needed. In this context, short RNA-based therapeutics, including Antisense Oligonucleotides (ASOs), microRNAs (miRNAs), short interfering (siRNA) and aptamers, represent a promising class of molecules. ASOs, miRNAs and siRNAs act by targeting and inhibiting specific mRNAs, thus showing an improved specificity compared to traditional anti-cancer drugs. Nucleic acid aptamers target and inhibit specific cancer-associated proteins, such as "nucleic acid antibodies". Aptamers are also able of receptor-mediated cell internalization, and therefore, they can be used as carriers of secondary agents giving the possibility of producing very highly specific and effective therapeutics. This review provides an overview of the proposed applications of small RNAs for NSCLC treatment, highlighting their advantageous features and recent advancements in the field.
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Affiliation(s)
- Giuseppe Ciccone
- Institute of Experimental Endocrinology and Oncology "Gaetano Salvatore" (IEOS), National Research Council (CNR), 80145 Naples, Italy
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", 81100 Caserta, Italy
| | - Maria Luigia Ibba
- Institute of Experimental Endocrinology and Oncology "Gaetano Salvatore" (IEOS), National Research Council (CNR), 80145 Naples, Italy
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", 80138 Caserta, Italy
| | - Gabriele Coppola
- Institute of Experimental Endocrinology and Oncology "Gaetano Salvatore" (IEOS), National Research Council (CNR), 80145 Naples, Italy
| | - Silvia Catuogno
- Institute of Experimental Endocrinology and Oncology "Gaetano Salvatore" (IEOS), National Research Council (CNR), 80145 Naples, Italy
| | - Carla Lucia Esposito
- Institute of Experimental Endocrinology and Oncology "Gaetano Salvatore" (IEOS), National Research Council (CNR), 80145 Naples, Italy
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Abstract
Metastasis is a major contributor to cancer-associated deaths. It is characterized by a multistep process that occurs through the acquisition of molecular and phenotypic changes enabling cancer cells from a primary tumour to disseminate and colonize at distant organ sites. Over the past decade, the discovery and characterization of long noncoding RNAs (lncRNAs) have revealed the diversity of their regulatory roles, including key contributions throughout the metastatic cascade. Here, we review how lncRNAs promote metastasis by functioning in discrete pro-metastatic steps including the epithelial-mesenchymal transition, invasion and migration and organotrophic colonization, and by influencing the metastatic tumour microenvironment, often by interacting within ribonucleoprotein complexes or directly with other nucleic acid entities. We discuss well-characterized lncRNAs with in vivo phenotypes and highlight mechanistic commonalities such as convergence with the TGFβ-ZEB1/ZEB2 axis or the nuclear factor-κB pathway, in addition to lncRNAs with controversial mechanisms and the influence of methodologies on mechanistic interpretation. Furthermore, some lncRNAs can help identify tumours with increased metastatic risk and spur novel therapeutic strategies, with several lncRNAs having shown potential as novel targets for antisense oligonucleotide therapy in animal models. In addition to well-characterized examples of lncRNAs functioning in metastasis, we discuss controversies and ongoing challenges in lncRNA biology. Finally, we present areas for future study for this rapidly evolving field.
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Affiliation(s)
- S John Liu
- Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA
| | - Ha X Dang
- Department of Internal Medicine, Washington University in St Louis, St Louis, MO, USA
- Siteman Cancer Center, Washington University in St Louis, St Louis, MO, USA
- McDonnell Genome Institute, Washington University in St Louis, St Louis, MO, USA
| | - Daniel A Lim
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA
- San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA
| | - Felix Y Feng
- Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
- Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Department of Urology, University of California, San Francisco, San Francisco, CA, USA
| | - Christopher A Maher
- Department of Internal Medicine, Washington University in St Louis, St Louis, MO, USA.
- Siteman Cancer Center, Washington University in St Louis, St Louis, MO, USA.
- McDonnell Genome Institute, Washington University in St Louis, St Louis, MO, USA.
- Department of Biomedical Engineering, Washington University in St Louis, St Louis, MO, USA.
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Praharaj PP, Patra S, Panigrahi DP, Patra SK, Bhutia SK. Clusterin as modulator of carcinogenesis: A potential avenue for targeted cancer therapy. Biochim Biophys Acta Rev Cancer 2020; 1875:188500. [PMID: 33385484 DOI: 10.1016/j.bbcan.2020.188500] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 12/14/2020] [Accepted: 12/24/2020] [Indexed: 12/30/2022]
Abstract
Clusterin (CLU) is an evolutionary conserved molecular chaperone present in different human tissues and fluids and established to be a significant cancer regulator. It controls several cancer-associated cellular events, including cancer cell proliferation, stemness, survival, metastasis, epithelial-mesenchymal transition, therapy resistance, and inhibition of programmed cell death to support cancer growth and recurrence. This multifunctional role of CLU makes it an ideal target for cancer control. More importantly, genetic and antisense-mediated (OGX-011) inhibition of CLU enhances the anticancer potential of different FDA-approved chemotherapeutic drugs at the clinical level, improving patient's survival. In this review, we have discussed the detailed mechanism of CLU-mediated modulation of different cancer-associated signaling pathways. We have also provided updated information on the current preclinical and clinical findings that drive trials in various cancer types for potential targeted cancer therapy.
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Affiliation(s)
- Prakash Priyadarshi Praharaj
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Srimanta Patra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Debasna Pritimanjari Panigrahi
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Samir Kumar Patra
- Epigenetics and Cancer Research Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Sujit Kumar Bhutia
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India.
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Nguyen TM, Alchalabi S, Oluwatoyosi A, Ropri AS, Herschkowitz JI, Rosen JM. New twists on long noncoding RNAs: from mobile elements to motile cancer cells. RNA Biol 2020; 17:1535-1549. [PMID: 32522127 DOI: 10.1080/15476286.2020.1760535] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The purpose of this review is to highlight several areas of lncRNA biology and cancer that we hope will provide some new insights for future research. These include the relationship of lncRNAs and the epithelial to mesenchymal transition (EMT) with a focus on transcriptional and alternative splicing mechanisms and mRNA stability through miRNAs. In addition, we highlight the potential role of enhancer e-lncRNAs, the importance of transposable elements in lncRNA biology, and finally the emerging area of using antisense oligonucleotides (ASOs) and small molecules to target lncRNAs and their therapeutic implications.
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Affiliation(s)
- Tuan M Nguyen
- Harvard Medical School Initiative for RNA Medicine, Harvard Medical School , Boston, MA, USA.,Cancer Research Institute, Beth Israel Deaconess Medical Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA, USA
| | - Sumayya Alchalabi
- Department of Biomedical Sciences, Cancer Research Center, University at Albany, SUNY , Rensselaer, NY, USA
| | - Adewunmi Oluwatoyosi
- Department of Molecular & Cellular Biology, Baylor College of Medicine , Houston, TX, USA
| | - Ali S Ropri
- Department of Biomedical Sciences, Cancer Research Center, University at Albany, SUNY , Rensselaer, NY, USA
| | - Jason I Herschkowitz
- Department of Biomedical Sciences, Cancer Research Center, University at Albany, SUNY , Rensselaer, NY, USA
| | - Jeffrey M Rosen
- Department of Molecular & Cellular Biology, Baylor College of Medicine , Houston, TX, USA
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Hoter A, Rizk S, Naim HY. The Multiple Roles and Therapeutic Potential of Molecular Chaperones in Prostate Cancer. Cancers (Basel) 2019; 11:cancers11081194. [PMID: 31426412 PMCID: PMC6721600 DOI: 10.3390/cancers11081194] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 08/14/2019] [Accepted: 08/15/2019] [Indexed: 12/19/2022] Open
Abstract
Prostate cancer (PCa) is one of the most common cancer types in men worldwide. Heat shock proteins (HSPs) are molecular chaperones that are widely implicated in the pathogenesis, diagnosis, prognosis, and treatment of many cancers. The role of HSPs in PCa is complex and their expression has been linked to the progression and aggressiveness of the tumor. Prominent chaperones, including HSP90 and HSP70, are involved in the folding and trafficking of critical cancer-related proteins. Other members of HSPs, including HSP27 and HSP60, have been considered as promising biomarkers, similar to prostate-specific membrane antigen (PSMA), for PCa screening in order to evaluate and monitor the progression or recurrence of the disease. Moreover, expression level of chaperones like clusterin has been shown to correlate directly with the prostate tumor grade. Hence, targeting HSPs in PCa has been suggested as a promising strategy for cancer therapy. In the current review, we discuss the functions as well as the role of HSPs in PCa progression and further evaluate the approach of inhibiting HSPs as a cancer treatment strategy.
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Affiliation(s)
- Abdullah Hoter
- Department of Biochemistry and Chemistry of Nutrition, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt
- Department of Physiological Chemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany
| | - Sandra Rizk
- School of Arts and Sciences, Lebanese American University, Beirut 1102 2801, Lebanon
| | - Hassan Y Naim
- Department of Physiological Chemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
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Foster EM, Dangla-Valls A, Lovestone S, Ribe EM, Buckley NJ. Clusterin in Alzheimer's Disease: Mechanisms, Genetics, and Lessons From Other Pathologies. Front Neurosci 2019; 13:164. [PMID: 30872998 PMCID: PMC6403191 DOI: 10.3389/fnins.2019.00164] [Citation(s) in RCA: 233] [Impact Index Per Article: 38.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 02/12/2019] [Indexed: 01/10/2023] Open
Abstract
Clusterin (CLU) or APOJ is a multifunctional glycoprotein that has been implicated in several physiological and pathological states, including Alzheimer's disease (AD). With a prominent extracellular chaperone function, additional roles have been discussed for clusterin, including lipid transport and immune modulation, and it is involved in pathways common to several diseases such as cell death and survival, oxidative stress, and proteotoxic stress. Although clusterin is normally a secreted protein, it has also been found intracellularly under certain stress conditions. Multiple hypotheses have been proposed regarding the origin of intracellular clusterin, including specific biogenic processes leading to alternative transcripts and protein isoforms, but these lines of research are incomplete and contradictory. Current consensus is that intracellular clusterin is most likely to have exited the secretory pathway at some point or to have re-entered the cell after secretion. Clusterin's relationship with amyloid beta (Aβ) has been of great interest to the AD field, including clusterin's apparent role in altering Aβ aggregation and/or clearance. Additionally, clusterin has been more recently identified as a mediator of Aβ toxicity, as evidenced by the neuroprotective effect of CLU knockdown and knockout in rodent and human iPSC-derived neurons. CLU is also the third most significant genetic risk factor for late onset AD and several variants have been identified in CLU. Although the exact contribution of these variants to altered AD risk is unclear, some have been linked to altered CLU expression at both mRNA and protein levels, altered cognitive and memory function, and altered brain structure. The apparent complexity of clusterin's biogenesis, the lack of clarity over the origin of the intracellular clusterin species, and the number of pathophysiological functions attributed to clusterin have all contributed to the challenge of understanding the role of clusterin in AD pathophysiology. Here, we highlight clusterin's relevance to AD by discussing the evidence linking clusterin to AD, as well as drawing parallels on how the role of clusterin in other diseases and pathways may help us understand its biological function(s) in association with AD.
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Affiliation(s)
| | | | | | | | - Noel J. Buckley
- Department of Psychiatry, University of Oxford, Oxford, United Kingdom
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10
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Chen J, Tang Y, Liu Y, Dou Y. Nucleic Acid-Based Therapeutics for Pulmonary Diseases. AAPS PharmSciTech 2018; 19:3670-3680. [PMID: 30338490 PMCID: PMC7101845 DOI: 10.1208/s12249-018-1183-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 09/07/2018] [Indexed: 12/12/2022] Open
Abstract
Nucleic acid-based therapeutics present huge potential in the treatment
of pulmonary diseases ranging from lung cancer to asthma and chronic pulmonary
diseases, which are often fatal and widely prevalent. The susceptibility of nucleic
acids to degradation and the complex structure of lungs retard the effective
pulmonary delivery of nucleic acid drug. To overcome these barriers, different
strategies have been exploited to increase the delivery efficiency using chemically
synthesized nucleic acids, vector encapsulation, proper formulation, and
administration route. However, several limitations regarding off-target effects and
immune stimulation of nucleic acid drugs hamper their translation into the clinical
practice. Therefore, their successful clinical application will ultimately rely on
well-developed carriers and methods to ensure safety and efficacy. In this review,
we provide a comprehensive overview of the nucleic acid application for pulmonary
diseases, covering action mechanism of the nucleic acid drugs, the novel delivery
systems, and the current formulation for the administration to lungs. The latest
advances of nucleic acid drugs under clinical evaluation to treat pulmonary
disorders will also be detailed.
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Ming X, Bao C, Hong T, Yang Y, Chen X, Jung YS, Qian Y. Clusterin, a Novel DEC1 Target, Modulates DNA Damage-Mediated Cell Death. Mol Cancer Res 2018; 16:1641-1651. [PMID: 30002194 DOI: 10.1158/1541-7786.mcr-18-0070] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 04/28/2018] [Accepted: 06/20/2018] [Indexed: 11/16/2022]
Abstract
Differentiated embryonic chondrocyte expressed gene 1 (DEC1, also known as Sharp2/Stra13/BHLHE40) is a basic helix-loop-helix transcription factor that plays an important role in circadian rhythms, cell proliferation, apoptosis, cellular senescence, hypoxia response, and epithelial-to-mesenchymal transition of tumor cells. Secretory clusterin (sCLU) is a cytoprotective protein that guards against genotoxic stresses. Here, clusterin (CLU) was identified as a novel target gene of DEC1 and suppresses DNA damage-induced cell death in tumor cells. Mechanistically, based on chromatin immunoprecipitation and luciferase assays, DEC1 binds to and activates the promoter of the CLU gene. DEC1 and DNA-damaging agents induce sCLU expression, whereas DEC1 knockdown decreases the expression of sCLU upon DNA damage. Moreover, the data demonstrate that DEC1 inhibits, whereas sCLU knockdown enhances, DNA damage-induced cell death in MCF7 breast cancer cells. Given that DEC1 and sCLU are frequently overexpressed in breast cancers, these data provide mechanistic insight into DEC1 as a prosurvival factor by upregulating sCLU to reduce the DNA damage-induced apoptotic response. Together, this study reveals sCLU as a novel target of DEC1 which modulates the sensitivity of the DNA damage response.Implications: DEC1 and sCLU are frequently overexpressed in breast cancer, and targeting the sCLU-mediated cytoprotective signaling pathway may be a novel therapeutic approach. Mol Cancer Res; 16(11); 1641-51. ©2018 AACR.
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Affiliation(s)
- Xin Ming
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, China
| | - Chenyi Bao
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, China
| | - Tao Hong
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, China
| | - Ying Yang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, China
| | - Xinbin Chen
- The Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California at Davis, Davis, California
| | - Yong-Sam Jung
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, China
| | - Yingjuan Qian
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, China.
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Personalized therapy: CNS HGNET-BCOR responsiveness to arsenic trioxide combined with radiotherapy. Oncotarget 2017; 8:114210-114225. [PMID: 29371980 PMCID: PMC5768397 DOI: 10.18632/oncotarget.23174] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 11/16/2017] [Indexed: 01/08/2023] Open
Abstract
High-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) is a rare, highly malignant tumor. At the time of this publication, no standard protocol exists to treat this tumor entity. In this work, we tested the responsiveness of the primary culture PhKh1 derived from tumor tissue from a pediatric HGNET-BCOR patient (P1) to inhibitors of the Sonic hedgehog pathway combined with radiation. The SMO inhibitors vismodegib and itraconazole had low effect on the proliferation of the PhKh1 cells. However, the GLI inhibitor arsenic trioxide reduced the expression of GLI target genes in the PhKh1 cells and in combination with radiotherapy significantly decreased their clonogenic potential. PhKh1 cells resistant to arsenic trioxide were characterized by the overexpression of molecular chaperones. We combined arsenic trioxide and radiation in the relapse therapy protocol of P1, achieving complete remission after seven weeks. Clinical remission lasted for six months, when P1 developed systemic metastases. Meanwhile, an increase in the concentration of circulating tumor DNA carrying a BCOR internal tandem duplication was observed. Molecular characterization of a second patient (P2) was also performed. In P2, we detected a larger tandem duplication and greater activation of the Sonic hedgehog pathway than in P1. These findings suggest that combining arsenic trioxide with radiotherapy may represent a new therapeutic approach. Moreover, peripheral blood analysis for circulating tumor DNA could help in the early detection of systemic metastases.
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13
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Clusterin inhibition mediates sensitivity to chemotherapy and radiotherapy in human cancer. Anticancer Drugs 2017; 28:702-716. [PMID: 28471806 DOI: 10.1097/cad.0000000000000507] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Since its discovery in 1983, the protein clusterin (CLU) has been isolated from almost all human tissues and fluids and linked to the development of different physiopathological processes, including carcinogenesis and tumor progression. During the last few years, several studies have shown the cytoprotective role of secretory CLU in tumor cells, inhibiting their apoptosis and enhancing their resistance to conventional treatments including hormone depletion, chemotherapy, and radiotherapy. In an effort to determine the therapeutic potential that the inhibition of this protein could have on the development of new strategies for cancer treatment, numerous studies have been carried out in this field, with results, in most cases, satisfactory but sometimes contradictory. In this document, we summarize for the first time the current knowledge of the effects that CLU inhibition has on sensitizing tumor cells to conventional cancer treatments and discuss its importance in the development of new strategies against cancer.
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Tat-Tagged and Folate-Modified N-Succinyl-chitosan (Tat-Suc-FA) Self-assembly Nanoparticle for Therapeutic Delivery OGX-011 to A549 Cells. Mol Pharm 2017; 14:1898-1905. [PMID: 28464609 DOI: 10.1021/acs.molpharmaceut.6b01167] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The objective of this study was to develop a novel type of an antisense oligonucleotide (OGX-011) loaded Tat-tagged and folate-modified N-succinyl-chitosan (Tat-Suc-FA) nanoparticles (NPs) for improving tumor targetability. In this study, Tat-Suc-FA/OGX-011NPs were prepared and its physicochemical characterizations were also evaluated. The nanoparticles showed an average diameter of 73 ± 16.6 nm, the zeta potential of +23.6 ± 0.3 mV, and a high entrapment efficiency of 89.6 ± 6.6%. Transmission electron microscopy analysis showed the nanoparticles were mostly spherical and well dispersed. The delivery efficiency of this system was investigated both in vitro and in vivo. In comparison with nontargeted Lipofectamin2000/OGX-011 and free OGX-011, Tat-Suc-FA/GOX-011 showed the highest apoptosis rate of 14.2% ± 1.8% and significant uptake in A549 cells. Tat-Suc-FA NPs loaded with GOX-011 induced significant down-regulation of s-CLU mRNA and protein levels in A549 cells. In A549 tumor-bearing mice model, Tat-Suc-FA/GOX-011 produced a more efficient down-regulation of s-CLU compared to Lipofectamin2000/OGX-011. Furthermore, the combined use of Tat-Suc-FA/OGX-011 with DDP chemotherapy showed a most significant inhibition of tumor growth and greatly enhanced the survival rate of A549 tumor-bearing mice. These findings suggested successful application of Tat-Suc-FA NPs for the high efficiency and specificity in therapeutic delivery of OGX-011 to A549 cells.
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Crawford ED, Petrylak D, Sartor O. Navigating the evolving therapeutic landscape in advanced prostate cancer. Urol Oncol 2017; 35S:S1-S13. [PMID: 28283376 DOI: 10.1016/j.urolonc.2017.01.020] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Revised: 01/13/2017] [Accepted: 01/26/2017] [Indexed: 01/01/2023]
Abstract
Prostate cancer is the most common cause of cancer in men, with 137.9 new cases per 100,000 men per year. The overall 5-year survival rate for prostate cancer is very high. Up to 20% of men who undergo state-of-the art treatment for prostate cancer will develop castration-resistant prostate cancer (CRPC) within 5 years, with median survival for those with metastatic CRPC ranging from approximately 15 to 36 months in recent studies. With the advent of several new drugs in the past 5 years to treat CRPC, the challenge facing clinicians is how to best sequence or combine therapies or both to optimize outcomes. A better understanding of the disease process and the role of the androgen receptor as a target for both therapy and resistance have led to the consideration of biomarkers as an approach to aid in selecting the appropriate agent for a given patient as patients respond to or tolerate different drugs differently. Research to identify new prognostic biomarkers, which are associated with outcome measures, as well as predictive biomarkers, which predict response or resistance to therapy is ongoing. The treatment of advanced prostate cancer and the research related to biomarkers are discussed.
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Affiliation(s)
- E David Crawford
- Department of Surgery, Section of Urologic Oncology, School of Medicine, University of Colorado Denver, Aurora, CO
| | - Daniel Petrylak
- Department of Medicine (Medical Oncology), Yale (Smilow) Cancer Center, New Haven, CT; Department of Urology, Yale (Smilow) Cancer Center, New Haven, CT
| | - Oliver Sartor
- Department of Medicine, Tulane Cancer Center, New Orleans, LA; Department of Urology, Tulane Cancer Center, New Orleans, LA.
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Abstract
Recent studies have led to a greater appreciation of the diverse roles RNAs play in maintaining normal cellular function and how they contribute to disease pathology, broadening the number of potential therapeutic targets. Antisense oligonucleotides are the most direct means to target RNA in a selective manner and have become an established platform technology for drug discovery. There are multiple molecular mechanisms by which antisense oligonucleotides can be used to modulate RNAs in cells, including promoting the degradation of the targeted RNA or modulating RNA function without degradation. Antisense drugs utilizing various antisense mechanisms are demonstrating therapeutic potential for the treatment of a broad variety of diseases. This review focuses on some of the advances that have taken place in translating antisense technology from the bench to the clinic.
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Affiliation(s)
| | | | - Nguyen Pham
- Ionis Pharmaceuticals, Carlsbad, California 92010;
| | - Eric Swayze
- Ionis Pharmaceuticals, Carlsbad, California 92010;
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Fini ME, Bauskar A, Jeong S, Wilson MR. Clusterin in the eye: An old dog with new tricks at the ocular surface. Exp Eye Res 2016; 147:57-71. [PMID: 27131907 DOI: 10.1016/j.exer.2016.04.019] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 04/22/2016] [Accepted: 04/23/2016] [Indexed: 12/30/2022]
Abstract
The multifunctional protein clusterin (CLU) was first described in 1983 as a secreted glycoprotein present in ram rete testis fluid that enhanced aggregation ('clustering') of a variety of cells in vitro. It was also independently discovered in a number of other systems. By the early 1990s, CLU was known under many names and its expression had been demonstrated throughout the body, including in the eye. Its homeostatic activities in proteostasis, cytoprotection, and anti-inflammation have been well documented, however its roles in health and disease are still not well understood. CLU is prominent at fluid-tissue interfaces, and in 1996 it was demonstrated to be the most highly expressed transcript in the human cornea, the protein product being localized to the apical layers of the mucosal epithelia of the cornea and conjunctiva. CLU protein is also present in human tears. Using a preclinical mouse model for desiccating stress that mimics human dry eye disease, the authors recently demonstrated that CLU prevents and ameliorates ocular surface barrier disruption by a remarkable sealing mechanism dependent on attainment of a critical all-or-none concentration in the tears. When the CLU level drops below the critical all-or-none threshold, the barrier becomes vulnerable to desiccating stress. CLU binds selectively to the ocular surface subjected to desiccating stress in vivo, and in vitro to LGALS3 (galectin-3), a key barrier component. Positioned in this way, CLU not only physically seals the ocular surface barrier, but it also protects the barrier cells and prevents further damage to barrier structure. CLU depletion from the ocular surface epithelia is seen in a variety of inflammatory conditions in humans and mice that lead to squamous metaplasia and a keratinized epithelium. This suggests that CLU might have a specific role in maintaining mucosal epithelial differentiation, an idea that can now be tested using the mouse model for desiccating stress. Most excitingly, the new findings suggest that CLU could serve as a novel biotherapeutic for dry eye disease.
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Affiliation(s)
- M Elizabeth Fini
- USC Institute for Genetic Medicine and Departments of Cell & Neurobiology and Ophthalmology, Keck School of Medicine of USC, University of Southern California, 2250 Alcatraz St., Suite 240, Los Angeles, CA 90089-9037, USA.
| | - Aditi Bauskar
- USC Institute for Genetic Medicine and Graduate Program in Medical Biology, Keck School of Medicine of USC, University of Southern California, 2250 Alcatraz St., Suite 240, Los Angeles, CA 90089-9037, USA.
| | - Shinwu Jeong
- USC Institute for Genetic Medicine and Department of Ophthalmology, Keck School of Medicine of USC, University of Southern California, 2250 Alcatraz St., Suite 240, Los Angeles, CA 90089-9037, USA.
| | - Mark R Wilson
- Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Northfields Avenue, Wollongong, New South Wales, 2522 Australia.
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Wang C, Zhang Y, Guo K, Wang N, Jin H, Liu Y, Qin W. Heat shock proteins in hepatocellular carcinoma: Molecular mechanism and therapeutic potential. Int J Cancer 2015; 138:1824-34. [PMID: 26853533 DOI: 10.1002/ijc.29723] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Revised: 07/06/2015] [Accepted: 08/03/2015] [Indexed: 12/30/2022]
Abstract
Heat shock proteins (HSPs) are highly conserved proteins, which are expressed at low levels under normal conditions, but significantly induced in response to cellular stresses. As molecular chaperones, HSPs play crucial roles in protein homeostasis, apoptosis, invasion and cellular signaling transduction. The induction of HSPs is an important part of heat shock response, which could help cancer cells to adapt to stress conditions. Because of the constant stress condition in tumor microenvironment, HSPs overexpression is widely reported in many human cancers. In light of the significance of HSPs for cancer cells to survive and obtain invasive phenotype under stress condition, HSPs are often associated with poor prognosis and treatment resistance in many types of human cancers. It has been described that upregulation of HSPs may serve as diagnostic and prognostic markers in hepatocellular carcinoma (HCC). Targeting HSPs with specific inhibitor alone or in combination with chemotherapy regimens holds promise for the improvement of outcomes for HCC patients. In this review, we summarize the expression profiles, functions and molecular mechanisms of HSPs (HSP27, HSP70 and HSP90) as well as a HSP-like protein (clusterin) in HCC. In addition, we address progression and challenges in targeting these HSPs as novel therapeutic strategies in HCC.
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Affiliation(s)
- Cun Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yurong Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kun Guo
- Liver Cancer Institute, Zhongshan Hospital and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
| | - Ning Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haojie Jin
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yinkun Liu
- Liver Cancer Institute, Zhongshan Hospital and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
- Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Wenxin Qin
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Xiu P, Dong XF, Li XP, Li J. Clusterin: Review of research progress and looking ahead to direction in hepatocellular carcinoma. World J Gastroenterol 2015; 21:8262-8270. [PMID: 26217078 PMCID: PMC4507096 DOI: 10.3748/wjg.v21.i27.8262] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Revised: 04/01/2015] [Accepted: 05/21/2015] [Indexed: 02/06/2023] Open
Abstract
Liver cancer, a large proportion of which is hepatocellular carcinoma (HCC), is diagnosed in more than 700000 people each year worldwide. Liver cancer is particularly prevalent in Asia, Sub-Saharan Africa and the South Pacific, where hepatitis B and hepatitis C infection rates are very high. However, due to resistance to chemotherapy, patients with intermediate and advanced-stage disease cannot benefit from this treatment. Clusterin, which is overexpressed in many different cancers, is a stress-induced cytoprotective protein that confers treatment resistance. Custirsen (OGX-011) is a novel 2’-methoxyethyl modified phosphorothioate antisense oligonucleotide that targets secretory clusterin protein expression and is currently in clinical trials for patients with different cancers. In recent years, a number of different clinical trials have been performed, and two phase III clinical trials of custirsen evaluating combinations with chemotherapy in patients with metastatic castration-resistant prostate cancer and metastatic non-small cell lung cancer are currently in progress. The aims of this review are to summarize the current state of research on clusterin, predict future research directions and analyze the potential of the clinical application of custirsen in HCC.
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Crea F, Clermont PL, Parolia A, Wang Y, Helgason CD. The non-coding transcriptome as a dynamic regulator of cancer metastasis. Cancer Metastasis Rev 2015; 33:1-16. [PMID: 24346158 PMCID: PMC3988524 DOI: 10.1007/s10555-013-9455-3] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Since the discovery of microRNAs, non-coding RNAs (NC-RNAs) have increasingly attracted the attention of cancer investigators. Two classes of NC-RNAs are emerging as putative metastasis-related genes: long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs). LncRNAs orchestrate metastatic progression through several mechanisms, including the interaction with epigenetic effectors, splicing control and generation of microRNA-like molecules. In contrast, snoRNAs have been long considered “housekeeping” genes with no relevant function in cancer. However, recent evidence challenges this assumption, indicating that some snoRNAs are deregulated in cancer cells and may play a specific role in metastasis. Interestingly, snoRNAs and lncRNAs share several mechanisms of action, and might synergize with protein-coding genes to generate a specific cellular phenotype. This evidence suggests that the current paradigm of metastatic progression is incomplete. We propose that NC-RNAs are organized in complex interactive networks which orchestrate cellular phenotypic plasticity. Since plasticity is critical for cancer cell metastasis, we suggest that a molecular interactome composed by both NC-RNAs and proteins orchestrates cancer metastasis. Interestingly, expression of lncRNAs and snoRNAs can be detected in biological fluids, making them potentially useful biomarkers. NC-RNA expression profiles in human neoplasms have been associated with patients’ prognosis. SnoRNA and lncRNA silencing in pre-clinical models leads to cancer cell death and/or metastasis prevention, suggesting they can be investigated as novel therapeutic targets. Based on the literature to date, we critically discuss how the NC-RNA interactome can be explored and manipulated to generate more effective diagnostic, prognostic, and therapeutic strategies for metastatic neoplasms.
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Affiliation(s)
- Francesco Crea
- Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC, Canada,
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Azad AA, Zoubeidi A, Gleave ME, Chi KN. Targeting heat shock proteins in metastatic castration-resistant prostate cancer. Nat Rev Urol 2014; 12:26-36. [DOI: 10.1038/nrurol.2014.320] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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