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Bindu S, Bibi R, Pradeep R, Sarkar K. The evolving role of B cells in malignancies. Hum Immunol 2025; 86:111301. [PMID: 40132250 DOI: 10.1016/j.humimm.2025.111301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 03/07/2025] [Accepted: 03/19/2025] [Indexed: 03/27/2025]
Abstract
B cells play diverse roles in different pathological circumstances, such as neoplastic diseases, autoimmune disorders, and neurological maladies. B cells, which are essential elements of the adaptive immune system, demonstrate exceptional functional variety, including the generation of antibodies, the presentation of antigens, and the secretion of cytokines. Within the field of oncology, B cells display a multifaceted nature in the tumor microenvironment, simultaneously manifesting both tumor-promoting and tumor-suppressing characteristics. Studies have found that the existence of tertiary lymphoid structures, which consist of B cells, is linked to better survival rates in different types of cancers. This article examines the involvement of B cells in different types of malignancies, emphasizing their importance in the development of the diseases and their potential as biomarkers. Additionally, the review also examines the crucial role of B cells in autoimmune illnesses and their potential as targets for therapy. The article also analyses the role of B cells in immunization and exploring their potential uses in cancer immunotherapy. This analysis highlights the intricate and occasionally contradictory roles of B cells, underlining the necessity for additional research to clarify their varied actions in various illness scenarios.
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Affiliation(s)
- Soham Bindu
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu 603203, India
| | - Roshni Bibi
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu 603203, India
| | - R Pradeep
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu 603203, India
| | - Koustav Sarkar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu 603203, India.
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2
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Alonso-Marañón J, Solé L, Álvarez-Villanueva D, Maqueda M, Lobo-Jarne T, Montoto Á, Yélamos J, Borràs E, Uraga L, Hooper C, Sabidó E, Miyamoto S, Bigas A, Espinosa L. NEMO is essential for directing the kinases IKKα and ATM to the sites of DNA damage. Sci Signal 2025; 18:eadr0128. [PMID: 40067909 PMCID: PMC12070652 DOI: 10.1126/scisignal.adr0128] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 02/18/2025] [Indexed: 05/13/2025]
Abstract
The DNA damage repair kinase ATM is phosphorylated by the NF-κB pathway kinase IKKα, resulting in enhanced DNA damage repair through the nonhomologous end-joining pathway. Thus, inhibition of IKKα enhances the efficacy of cancer therapy based on inducing DNA damage. Here, we found a role for the IKK regulatory subunit NEMO in DNA damage repair mediated by ATM and IKKα. Exposure to damaging agents induced the interaction of NEMO with a preformed ATM-IKKα complex, which was required to target active ATM and IKKα to chromatin for efficient DNA damage repair but not for activating ATM. Recognition of damaged DNA by the IKKα-NEMO-ATM complex was facilitated by the interaction between NEMO and histones and depended on the ADP ribosylation of histones by the enzyme PARP1. NEMO-deficient cells showed increased activity of the kinase ATR, and inhibition of ATR potentiated the effect of chemotherapy in cells lacking NEMO or IKKα. Bioinformatic analysis of colorectal cancer datasets demonstrated that the expression of genes encoding IKKα, NEMO, and ATM correlated with poor patient prognosis, suggesting that the mechanism linking these three elements may be clinically relevant.
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Affiliation(s)
- Josune Alonso-Marañón
- Cancer Research Program, Hospital del Mar Research Institute, CIBERONC, Hospital del Mar, Doctor Aiguader 88, Barcelona 08003, Spain
| | - Laura Solé
- Cancer Research Program, Hospital del Mar Research Institute, CIBERONC, Hospital del Mar, Doctor Aiguader 88, Barcelona 08003, Spain
| | - Daniel Álvarez-Villanueva
- Cancer Research Program, Hospital del Mar Research Institute, CIBERONC, Hospital del Mar, Doctor Aiguader 88, Barcelona 08003, Spain
- Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - María Maqueda
- Cancer Research Program, Hospital del Mar Research Institute, CIBERONC, Hospital del Mar, Doctor Aiguader 88, Barcelona 08003, Spain
| | - Teresa Lobo-Jarne
- Cancer Research Program, Hospital del Mar Research Institute, CIBERONC, Hospital del Mar, Doctor Aiguader 88, Barcelona 08003, Spain
| | - Ángela Montoto
- Cancer Research Program, Hospital del Mar Research Institute, CIBERONC, Hospital del Mar, Doctor Aiguader 88, Barcelona 08003, Spain
| | - Jose Yélamos
- Cancer Research Program, Hospital del Mar Research Institute, CIBERONC, Hospital del Mar, Doctor Aiguader 88, Barcelona 08003, Spain
- Immunology Unit, Department of Pathology, Hospital del Mar, 08003 Barcelona, Spain
| | - Eva Borràs
- Proteomics Unit, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona 08003, Spain
- Proteomics Unit, Universitat Pompeu Fabra, Barcelona 08003, Spain
| | - Leire Uraga
- Cancer Research Program, Hospital del Mar Research Institute, CIBERONC, Hospital del Mar, Doctor Aiguader 88, Barcelona 08003, Spain
| | - Christopher Hooper
- McArdle Laboratory for Cancer Research, University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Wisconsin Institutes for Medical Research, Madison, WI 53705, USA
| | - Eduard Sabidó
- Proteomics Unit, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona 08003, Spain
- Proteomics Unit, Universitat Pompeu Fabra, Barcelona 08003, Spain
| | - Shigeki Miyamoto
- McArdle Laboratory for Cancer Research, University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Wisconsin Institutes for Medical Research, Madison, WI 53705, USA
| | - Anna Bigas
- Cancer Research Program, Hospital del Mar Research Institute, CIBERONC, Hospital del Mar, Doctor Aiguader 88, Barcelona 08003, Spain
- Josep Carreras Leukemia Research Institute, Barcelona 08916, Spain
| | - Lluís Espinosa
- Cancer Research Program, Hospital del Mar Research Institute, CIBERONC, Hospital del Mar, Doctor Aiguader 88, Barcelona 08003, Spain
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Morel KL, Germán B, Hamid AA, Nanda JS, Linder S, Bergman AM, van der Poel H, Hofland I, Bekers EM, Trostel SY, Burkhart DL, Wilkinson S, Ku AT, Kim M, Kim J, Ma D, Plummer JT, You S, Su XA, Zwart W, Sowalsky AG, Sweeney CJ, Ellis L. Low tristetraprolin expression activates phenotypic plasticity and primes transition to lethal prostate cancer in mice. J Clin Invest 2024; 135:e175680. [PMID: 39560993 PMCID: PMC11735106 DOI: 10.1172/jci175680] [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: 09/29/2023] [Accepted: 11/15/2024] [Indexed: 11/20/2024] Open
Abstract
Phenotypic plasticity is a hallmark of cancer and is increasingly realized as a mechanism of resistance to androgen receptor-targeted (AR-targeted) therapy. Now that many prostate cancer (PCa) patients are treated upfront with AR-targeted agents, it is critical to identify actionable mechanisms that drive phenotypic plasticity, to prevent the emergence of resistance. We showed that loss of tristetraprolin (TTP; gene ZFP36) increased NF-κB activation, and was associated with higher rates of aggressive disease and early recurrence in primary PCa. We also examined the clinical and biological impact of ZFP36 loss with co-loss of PTEN, a known driver of PCa. Analysis of multiple independent primary PCa cohorts demonstrated that PTEN and ZFP36 co-loss was associated with increased recurrence risk. Engineering prostate-specific Zfp36 deletion in vivo induced prostatic intraepithelial neoplasia, and, with Pten codeletion, resulted in rapid progression to castration-resistant adenocarcinoma. Zfp36 loss altered the cell state driven by Pten loss, as demonstrated by enrichment of epithelial-mesenchymal transition (EMT), inflammation, TNF-α/NF-κB, and IL-6-JAK/STAT3 gene sets. Additionally, our work revealed that ZFP36 loss also induced enrichment of multiple gene sets involved in mononuclear cell migration, chemotaxis, and proliferation. Use of the NF-κB inhibitor dimethylaminoparthenolide (DMAPT) induced marked therapeutic responses in tumors with PTEN and ZFP36 co-loss and reversed castration resistance.
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Affiliation(s)
- Katherine L. Morel
- South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, South Australia, Australia
| | - Beatriz Germán
- Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
- Walter Reed National Military Medical Center, Bethesda, Maryland, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, Maryland, USA
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Anis A. Hamid
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
- Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia
| | - Jagpreet S. Nanda
- Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | | | | | | | | | - Elise M. Bekers
- Division of Pathology; Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Shana Y. Trostel
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Deborah L. Burkhart
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Scott Wilkinson
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Anson T. Ku
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Minhyung Kim
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Jina Kim
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Duanduan Ma
- David H. Koch Institute for Integrative Cancer Research, Bioinformatics and Computing Facility of Swanson Biotechnology Center, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Jasmine T. Plummer
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Sungyong You
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
- Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA
- Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, California, USA
| | - Xiaofeng A. Su
- Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
- Walter Reed National Military Medical Center, Bethesda, Maryland, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, Maryland, USA
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
- David H. Koch Institute for Integrative Cancer Research, Bioinformatics and Computing Facility of Swanson Biotechnology Center, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | | | - Adam G. Sowalsky
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Christopher J. Sweeney
- South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, South Australia, Australia
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Leigh Ellis
- Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
- Walter Reed National Military Medical Center, Bethesda, Maryland, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, Maryland, USA
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
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Żebrowska-Nawrocka M, Szmajda-Krygier D, Krygier A, Jeleń A, Balcerczak E. Bioinformatic Analysis of IKK Complex Genes Expression in Selected Gastrointestinal Cancers. Int J Mol Sci 2024; 25:9868. [PMID: 39337357 PMCID: PMC11432643 DOI: 10.3390/ijms25189868] [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: 07/12/2024] [Revised: 08/28/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
Gastrointestinal cancers account for over a quarter of all cancer cases and are associated with poor prognosis and high mortality rates. The IKK complex (the canonical I kappa B kinase), comprising the CHUK, IKBKB, and IKBKG genes, plays a crucial role in activating the NF-kB signaling pathway. This study aimed to analyze publicly available bioinformatics data to elucidate the oncogenic role of IKK genes in selected gastrointestinal cancers. Our findings reveal that IKBKB and IKBKG are significantly upregulated in all examined cancers, while CHUK is upregulated in esophageal carcinoma and stomach adenocarcinoma. Additionally, the expression of IKK genes varies with histological grade and nodal metastases. For instance, in stomach adenocarcinoma, CHUK and IKBKB are upregulated in higher histological grades and greater lymph node infiltration. Lower expression levels of CHUK, IKBKB, and IKBKG in stomach adenocarcinoma and IKBKB in esophageal squamous cell carcinoma correlate with shorter overall survival. Conversely, in esophageal adenocarcinoma, reduced IKBKG expression is linked to longer overall survival, while higher IKBKB expression in colon adenocarcinoma is associated with longer overall survival. Given the significant role of IKK genes in the development and progression of selected gastrointestinal cancers, they hold potential as prognostic markers and therapeutic targets, offering valuable insights for clinical practice.
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Affiliation(s)
- Marta Żebrowska-Nawrocka
- Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland
- Laboratory of Molecular Diagnostics, Brain Laboratories, Medical University of Lodz, Czechoslowacka 4, 92-216 Lodz, Poland
| | - Dagmara Szmajda-Krygier
- Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland
- Laboratory of Molecular Diagnostics, Brain Laboratories, Medical University of Lodz, Czechoslowacka 4, 92-216 Lodz, Poland
| | - Adrian Krygier
- Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland
| | - Agnieszka Jeleń
- Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland
- Laboratory of Molecular Diagnostics, Brain Laboratories, Medical University of Lodz, Czechoslowacka 4, 92-216 Lodz, Poland
| | - Ewa Balcerczak
- Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland
- Laboratory of Molecular Diagnostics, Brain Laboratories, Medical University of Lodz, Czechoslowacka 4, 92-216 Lodz, Poland
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5
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Riley C, Ammar U, Alsfouk A, Anthony NG, Baiget J, Berretta G, Breen D, Huggan J, Lawson C, McIntosh K, Plevin R, Suckling CJ, Young LC, Paul A, Mackay SP. Design and Synthesis of Novel Aminoindazole-pyrrolo[2,3- b]pyridine Inhibitors of IKKα That Selectively Perturb Cellular Non-Canonical NF-κB Signalling. Molecules 2024; 29:3515. [PMID: 39124921 PMCID: PMC11314561 DOI: 10.3390/molecules29153515] [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: 06/25/2024] [Revised: 07/11/2024] [Accepted: 07/18/2024] [Indexed: 08/12/2024] Open
Abstract
The inhibitory-kappaB kinases (IKKs) IKKα and IKKβ play central roles in regulating the non-canonical and canonical NF-κB signalling pathways. Whilst the proteins that transduce the signals of each pathway have been extensively characterised, the clear dissection of the functional roles of IKKα-mediated non-canonical NF-κB signalling versus IKKβ-driven canonical signalling remains to be fully elucidated. Progress has relied upon complementary molecular and pharmacological tools; however, the lack of highly potent and selective IKKα inhibitors has limited advances. Herein, we report the development of an aminoindazole-pyrrolo[2,3-b]pyridine scaffold into a novel series of IKKα inhibitors. We demonstrate high potency and selectivity against IKKα over IKKβ in vitro and explain the structure-activity relationships using structure-based molecular modelling. We show selective target engagement with IKKα in the non-canonical NF-κB pathway for both U2OS osteosarcoma and PC-3M prostate cancer cells by employing isoform-related pharmacodynamic markers from both pathways. Two compounds (SU1261 [IKKα Ki = 10 nM; IKKβ Ki = 680 nM] and SU1349 [IKKα Ki = 16 nM; IKKβ Ki = 3352 nM]) represent the first selective and potent pharmacological tools that can be used to interrogate the different signalling functions of IKKα and IKKβ in cells. Our understanding of the regulatory role of IKKα in various inflammatory-based conditions will be advanced using these pharmacological agents.
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Affiliation(s)
- Christopher Riley
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
| | - Usama Ammar
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
| | - Aisha Alsfouk
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
| | - Nahoum G. Anthony
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
| | - Jessica Baiget
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
| | - Giacomo Berretta
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
| | - David Breen
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
| | - Judith Huggan
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
| | - Christopher Lawson
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
| | - Kathryn McIntosh
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
| | - Robin Plevin
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
| | - Colin J. Suckling
- Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, UK
| | - Louise C. Young
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
| | - Andrew Paul
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
| | - Simon P. Mackay
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
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Chen X, Wu W, Jeong JH, Rokavec M, Wei R, Feng S, Schroth W, Brauch H, Zhong S, Luo JL. Cytokines-activated nuclear IKKα-FAT10 pathway induces breast cancer tamoxifen-resistance. SCIENCE CHINA. LIFE SCIENCES 2024; 67:1413-1426. [PMID: 38565741 DOI: 10.1007/s11427-023-2460-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 09/26/2023] [Indexed: 04/04/2024]
Abstract
Endocrine therapy that blocks estrogen signaling is the most effective treatment for patients with estrogen receptor positive (ER+) breast cancer. However, the efficacy of agents such as tamoxifen (Tam) is often compromised by the development of resistance. Here we report that cytokines-activated nuclear IKKα confers Tam resistance to ER+ breast cancer by inducing the expression of FAT10, and that the expression of FAT10 and nuclear IKKα in primary ER+ human breast cancer was correlated with lymphotoxin β (LTB) expression and significantly associated with relapse and metastasis in patients treated with adjuvant mono-Tam. IKKα activation or enforced FAT10 expression promotes Tam-resistance while loss of IKKα or FAT10 augments Tam sensitivity. The induction of FAT10 by IKKα is mediated by the transcription factor Pax5, and coordinated via an IKKα-p53-miR-23a circuit in which activation of IKKα attenuates p53-directed repression of FAT10. Thus, our findings establish IKKα-to-FAT10 pathway as a new therapeutic target for the treatment of Tam-resistant ER+ breast cancer.
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Affiliation(s)
- Xueyan Chen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, 33458, USA
| | - Weilin Wu
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, 33458, USA
| | - Ji-Hak Jeong
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, 33458, USA
| | - Matjaz Rokavec
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, 33458, USA
| | - Rui Wei
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Shaolong Feng
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, 33458, USA
| | - Werner Schroth
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, 70376, Germany
- iFIT Cluster of Excellence, University of Tübingen, Tübingen, 72074, Germany
| | - Hiltrud Brauch
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, 70376, Germany
- iFIT Cluster of Excellence, University of Tübingen, Tübingen, 72074, Germany
| | - Shangwei Zhong
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, 33458, USA.
- The Cancer Research Institute and the Second Affiliated Hospital, Henyang Medical School, University of South China, Hengyang, 421001, China.
| | - Jun-Li Luo
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, 33458, USA.
- The Cancer Research Institute and the Second Affiliated Hospital, Henyang Medical School, University of South China, Hengyang, 421001, China.
- National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, 410008, China.
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7
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McKenzie M, Lian GY, Pennel KA, Quinn JA, Jamieson NB, Edwards J. NFκB signalling in colorectal cancer: Examining the central dogma of IKKα and IKKβ signalling. Heliyon 2024; 10:e32904. [PMID: 38975078 PMCID: PMC11226910 DOI: 10.1016/j.heliyon.2024.e32904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 05/20/2024] [Accepted: 06/11/2024] [Indexed: 07/09/2024] Open
Abstract
The NFκB pathway, known as the central regulator of inflammation, has a well-established role in colorectal cancer (CRC) initiation, progression, and therapy resistance. Due to the pathway's overarching roles in CRC, there have been efforts to characterise NFκB family members and target the pathway for therapeutic intervention. Initial research illustrated that the canonical NFκB pathway, driven by central kinase IKKβ, was a promising target for drug intervention. However, dose limiting toxicities and specificity concerns have resulted in failure of IKKβ inhibitors in clinical trials. The field has turned to look at targeting the less dominant kinase, IKKα, which along with NFκB inducing kinase (NIK), drives the lesser researched non-canonical NFκB pathway. However prognostic studies of the non-canonical pathway have produced conflicting results. There is emerging evidence that IKKα is involved in other signalling pathways, which lie outside of canonical and non-canonical NFκB signalling. Evidence suggests that some of these alternative pathways involve a truncated form of IKKα, and this may drive poor cancer-specific survival in CRC. This review aims to explore the multiple components of NFκB signalling, highlighting that NIK may be the central kinase for non-canonical NFκB signalling, and that IKKα is involved in novel pathways which promote CRC.
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Affiliation(s)
- Molly McKenzie
- School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, G61 1BD, UK
| | - Guang-Yu Lian
- School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, G61 1BD, UK
| | - Kathryn A.F. Pennel
- School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, G61 1BD, UK
| | - Jean A. Quinn
- School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, G61 1BD, UK
| | - Nigel B. Jamieson
- School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, G61 1BD, UK
| | - Joanne Edwards
- School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, G61 1BD, UK
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8
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Ouyang J, Hu S, Zhu Q, Li C, Kang T, Xie W, Wang Y, Li Y, Lu Y, Qi J, Xia M, Chen J, Yang Y, Sun Y, Gao T, Ye L, Liang Q, Pan Y, Zhu C. RANKL/RANK signaling recruits Tregs via the CCL20-CCR6 pathway and promotes stemness and metastasis in colorectal cancer. Cell Death Dis 2024; 15:437. [PMID: 38902257 PMCID: PMC11190233 DOI: 10.1038/s41419-024-06806-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 05/24/2024] [Accepted: 06/03/2024] [Indexed: 06/22/2024]
Abstract
TNF receptor superfamily member 11a (TNFRSF11a, RANK) and its ligand TNF superfamily member 11 (TNFRSF11, RANKL) are overexpressed in many malignancies. However, the clinical importance of RANKL/RANK in colorectal cancer (CRC) is mainly unknown. We examined CRC samples and found that RANKL/RANK was elevated in CRC tissues compared with nearby normal tissues. A higher RANKL/RANK expression was associated with a worse survival rate. Furthermore, RANKL was mostly produced by regulatory T cells (Tregs), which were able to promote CRC advancement. Overexpression of RANK or addition of RANKL significantly increased the stemness and migration of CRC cells. Furthermore, RANKL/RANK signaling stimulated C-C motif chemokine ligand 20 (CCL20) production by CRC cells, leading to Treg recruitment and boosting tumor stemness and malignant progression. This recruitment process was accomplished by CCL20-CCR6 interaction, demonstrating a connection between CRC cells and immune cells. These findings suggest an important role of RANKL/RANK in CRC progression, offering a potential target for CRC prevention and therapy.
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Affiliation(s)
- Jing Ouyang
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Shuang Hu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Qingqing Zhu
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Chenxin Li
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Tingting Kang
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Wenlin Xie
- Pathological Diagnostic Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Yun Wang
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Yan Li
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Yingsi Lu
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Junhua Qi
- Department of Clinical Medical Laboratory, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Ming Xia
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Jinrun Chen
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Yingqian Yang
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Yazhou Sun
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
- Clinical Big Data Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Tianshun Gao
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
- Clinical Big Data Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Liping Ye
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China.
| | - Qian Liang
- Department of Spine Surgery, The First Affiliated Hospital of Shenzhen University, The Shenzhen Second People's Hospital, Shenzhen, China.
| | - Yihang Pan
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China.
| | - Chengming Zhu
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China.
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9
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Yarmolinsky J, Robinson JW, Mariosa D, Karhunen V, Huang J, Dimou N, Murphy N, Burrows K, Bouras E, Smith-Byrne K, Lewis SJ, Galesloot TE, Kiemeney LA, Vermeulen S, Martin P, Albanes D, Hou L, Newcomb PA, White E, Wolk A, Wu AH, Le Marchand L, Phipps AI, Buchanan DD, Zhao SS, Gill D, Chanock SJ, Purdue MP, Davey Smith G, Brennan P, Herzig KH, Järvelin MR, Amos CI, Hung RJ, Dehghan A, Johansson M, Gunter MJ, Tsilidis KK, Martin RM. Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis. EBioMedicine 2024; 100:104991. [PMID: 38301482 PMCID: PMC10844944 DOI: 10.1016/j.ebiom.2024.104991] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 01/15/2024] [Accepted: 01/17/2024] [Indexed: 02/03/2024] Open
Abstract
BACKGROUND Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. METHODS We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P < 5.0 × 10-8) cis-acting SNPs (i.e., in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r2 < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P-value ("q-value") <0.05 was used as a threshold to define "strong evidence" to support associations and 0.05 ≤ q-value < 0.20 to define "suggestive evidence". A colocalisation posterior probability (PPH4) >70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. FINDINGS We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10-1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20-1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53-0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88-0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48-4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. INTERPRETATION Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. FUNDING Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).
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Affiliation(s)
- James Yarmolinsky
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK.
| | - Jamie W Robinson
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Daniela Mariosa
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Ville Karhunen
- Research Unit of Population Health, Faculty of Medicine, University of Oulu, Oulu, Finland; Research Unit of Mathematical Sciences, University of Oulu, Oulu, Finland
| | - Jian Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK; Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Niki Dimou
- Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Kimberley Burrows
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Emmanouil Bouras
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Karl Smith-Byrne
- The Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Sarah J Lewis
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | | | | | - Sita Vermeulen
- Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Paul Martin
- School of Biochemistry, Biomedical Sciences Building, University of Bristol, University Walk, Bristol, UK
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Lifang Hou
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; School of Public Health, University of Washington, Seattle, WA, USA
| | - Emily White
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA
| | - Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Anna H Wu
- University of Southern California, Preventative Medicine, Los Angeles, CA, USA
| | - Loïc Le Marchand
- Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA
| | - Amanda I Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA
| | - Daniel D Buchanan
- Colorectal Oncogenomic Group, Department of Clinical Pathology, University of Melbourne, Parkville, Victoria, Australia; Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, Victoria, Australia; Genetic Medicine and Family Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Sizheng Steven Zhao
- Centre for Epidemiology Versus Arthritis, Faculty of Biological Medicine and Health, University of Manchester, Manchester, UK
| | - Dipender Gill
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK
| | - Stephen J Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - Mark P Purdue
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - George Davey Smith
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Paul Brennan
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Karl-Heinz Herzig
- Institute of Biomedicine, Medical Research Center and Oulu University Hospital, University of Oulu, Oulu, Finland; Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Marjo-Riitta Järvelin
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France; Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK; Unit of Primary Health Care, Oulu University Hospital, OYS, Oulu, Finland; Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, UK
| | - Chris I Amos
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
| | - Rayjean J Hung
- Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
| | - Abbas Dehghan
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK; Dementia Research Institute, Imperial College London, London, UK
| | - Mattias Johansson
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Marc J Gunter
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK; Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Kostas K Tsilidis
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Richard M Martin
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; University Hospitals Bristol and Weston NHS Foundation Trust, National Institute for Health Research Bristol Biomedical Research Centre, University of Bristol, Bristol, UK
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Wu K, Sun Q, Liu D, Lu J, Wen D, Zang X, Gao L. Genetically predicted circulating levels of cytokines and the risk of oral cavity and pharyngeal cancer: a bidirectional mendelian-randomization study. Front Genet 2024; 14:1321484. [PMID: 38274108 PMCID: PMC10808506 DOI: 10.3389/fgene.2023.1321484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Accepted: 12/26/2023] [Indexed: 01/27/2024] Open
Abstract
Background: Epidemiological research has established associations between various inflammatory cytokines and the occurrence of oral cancer and oropharyngeal cancer (OCPC). We performed a Mendelian randomization (MR) analysis to systematically investigate the causal relationship between inflammatory cytokines and OCPC. Methods: We performed a bidirectional two-sample MR analysis using OCPC from 12 studies (6,034 cases and 6,585 controls) and genome-wide association study (GWAS) results for 41 serum cytokines from 8,293 Finns, respectively. Inverse variance weighting was used as the primary MR method and four additional MR methods (MR Egger, Weighted median, Simple mode, Weighted mode) were used to examine genetic associations between inflammatory traits and OCPC, and Cochran's Q test, MR-Egger intercept, leave-one-out analysis, funnel plot, and multivariate MR (MVMR) analysis were used to assess the MR results. Results: The results suggested a potential association between high gene expression of Macrophage inflammatory protein-1α (MIP1α/CCL3) and an increased risk of OCPC (Odds Ratio (OR): 1.71, 95% Confidence Interval (CI): 1.09-2.68, p = 0.019). Increasing the expression levels of the interleukin-7 (IL-7) gene by 1 standard deviation reduced the risk of OCPC (OR: 0.64, 95%CI: 0.48-0.86, p = 0.003). In addition, multivariate Mendelian randomization analysis also showed the same results (MIP1α/CCL3, OR: 1.002, 95% CI: 0.919-1.092, p = 0.044; IL-7, OR: 0.997, 95% CI: 0.994-0.999, p = 0.011). Conversely, there was a positive correlation between genetic susceptibility to OCPC and an increase in Interleukin-4 (IL-4) (OR: 1.04, 95%CI: 1.00-1.08, p = 0.027). Conclusion: Our study systematically assessed the association between inflammatory cytokines and the risk of OCPC. We identified two upstream regulatory factors (IL-7 and CCL3) and one downstream effector factor (IL-4) that were associated with OCPC, offering potential avenues for the development of novel treatments.
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Affiliation(s)
- Kehan Wu
- Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Qianhui Sun
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Dongxu Liu
- Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Jiayi Lu
- Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Deyu Wen
- Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Xiyan Zang
- Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Li Gao
- Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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Ertay A, Ewing RM, Wang Y. Synthetic lethal approaches to target cancers with loss of PTEN function. Genes Dis 2023; 10:2511-2527. [PMID: 37533462 PMCID: PMC7614861 DOI: 10.1016/j.gendis.2022.12.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 12/26/2022] [Accepted: 12/27/2022] [Indexed: 02/05/2023] Open
Abstract
Phosphatase and tensin homolog (PTEN) is a tumour suppressor gene and has a role in inhibiting the oncogenic AKT signalling pathway by dephosphorylating phosphatidylinositol 3,4,5-triphosphate (PIP3) into phosphatidylinositol 4,5-bisphosphate (PIP2). The function of PTEN is regulated by different mechanisms and inactive PTEN results in aggressive tumour phenotype and tumorigenesis. Identifying targeted therapies for inactive tumour suppressor genes such as PTEN has been challenging as it is difficult to restore the tumour suppressor functions. Therefore, focusing on the downstream signalling pathways to discover a targeted therapy for inactive tumour suppressor genes has highlighted the importance of synthetic lethality studies. This review focuses on the potential synthetic lethality genes discovered in PTEN-inactive cancer types. These discovered genes could be potential targeted therapies for PTEN-inactive cancer types and may improve the treatment response rates for aggressive types of cancer.
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Affiliation(s)
- Ayse Ertay
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
| | - Rob M. Ewing
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
- Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
| | - Yihua Wang
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
- Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
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12
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Yarmolinsky J, Robinson JW, Mariosa D, Karhunen V, Huang J, Dimou N, Murphy N, Burrows K, Bouras E, Smith-Byrne K, Lewis SJ, Galesloot TE, Kiemeney LA, Vermeulen S, Martin P, Albanes D, Hou L, Newcomb PA, White E, Wolk A, Wu AH, Marchand LL, Phipps AI, Buchanan DD, Zhao SS, Gill D, Chanock SJ, Purdue MP, Smith GD, Brennan P, Herzig KH, Jarvelin MR, Dehghan A, Johansson M, Gunter MJ, Tsilidis KK, Martin RM. Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.05.04.23289196. [PMID: 37205426 PMCID: PMC10187459 DOI: 10.1101/2023.05.04.23289196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Background Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. Methods We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,162 cancer cases and up to 824,556 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P < 5.0 x 10-8) cis-acting SNPs (i.e. in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r2 < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P-value ("q-value") < 0.05 was used as a threshold to define "strong evidence" to support associations and 0.05 ≤ q-value < 0.20 to define "suggestive evidence". A colocalisation posterior probability (PPH4) > 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Results We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR 1.19, 95% CI 1.10-1.29, q-value=0.033, PPH4=84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR 1.42, 95% CI 1.20-1.69, q-value=0.055, PPH4=73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR 0.66, 95% CI 0.53-0.81, q-value=0.067, PPH4=81.8%), macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR 1.14, 95% CI 1.05-1.23, q-value=0.072, PPH4=76.1%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR 0.92, 95% CI 0.88-0.97, q-value=0.15), PPH4=85.6%). For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥ 0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. Conclusion Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 5 circulating inflammatory markers in risk of 5 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated.
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Affiliation(s)
- James Yarmolinsky
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Jamie W Robinson
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Daniela Mariosa
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Ville Karhunen
- Research Unit of Population Health, Faculty of Medicine, University of Oulu, Oulu, Finland
- Research Unit of Mathematical Sciences, University of Oulu, Oulu, Finland
| | - Jian Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary’s Campus, London
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Niki Dimou
- Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Kimberley Burrows
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Emmanouil Bouras
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Karl Smith-Byrne
- The Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Sarah J Lewis
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | | | | | - Sita Vermeulen
- Department for Health Evidence, Radboudumc, Nijmegen, The Netherlands
| | - Paul Martin
- School of Biochemistry, Biomedical Sciences Building, University of Bristol, University Walk, Bristol, UK
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Lifang Hou
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- School of Public Health, University of Washington, Seattle, Washington, USA
| | - Emily White
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA
| | - Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Anna H Wu
- University of Southern California, Preventative Medicine, Los Angeles, California, USA
| | - Loïc Le Marchand
- Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA 22
| | - Amanda I Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA
| | - Daniel D Buchanan
- Colorectal Oncogenomic Group, Department of Clinical Pathology, University of Melbourne, Parkville, Victoria, Australia
- Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, Victoria, Australia
- Genetic Medicine and Family Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | | | - Sizheng Steven Zhao
- Centre for Epidemiology Versus Arthritis, Faculty of Biological Medicine and Health, University of Manchester, Manchester, UK
| | - Dipender Gill
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary’s Campus, London
| | - Stephen J Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - Mark P Purdue
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - George Davey Smith
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Paul Brennan
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Karl-Heinz Herzig
- Institute of Biomedicine, Medical Research Center and Oulu University Hospital, University of Oulu, Finland
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Marjo-Riitta Jarvelin
- Research Unit of Population Health, Faculty of Medicine, University of Oulu, Oulu, Finland
- MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
- Unit of Primary Health Care, Oulu University Hospital, OYS, Oulu, Finland
- Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, United Kingdom
| | - Abbas Dehghan
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary’s Campus, London
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland
- Dementia Research Institute, Imperial College London, London, UK
| | - Mattias Johansson
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Marc J Gunter
- Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Kostas K Tsilidis
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary’s Campus, London
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Richard M Martin
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- University Hospitals Bristol and Weston NHS Foundation Trust, National Institute for Health Research Bristol Biomedical Research Centre, University of Bristol, Bristol, UK
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Alam SK, Wang L, Zhu Z, Hoeppner LH. IKKα promotes lung adenocarcinoma growth through ERK signaling activation via DARPP-32-mediated inhibition of PP1 activity. NPJ Precis Oncol 2023; 7:33. [PMID: 36966223 PMCID: PMC10039943 DOI: 10.1038/s41698-023-00370-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 03/08/2023] [Indexed: 03/27/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) accounts for 80-85% cases of lung cancer cases. Diagnosis at advanced stages is common, after which therapy-refractory disease progression frequently occurs. Therefore, a better understanding of the molecular mechanisms that control NSCLC progression is necessary to develop new therapies. Overexpression of IκB kinase α (IKKα) in NSCLC correlates with poor patient survival. IKKα is an NF-κB-activating kinase that is important in cell survival and differentiation, but its regulation of oncogenic signaling is not well understood. We recently demonstrated that IKKα promotes NSCLC cell migration by physically interacting with dopamine- and cyclic AMP-regulated phosphoprotein, Mr 32000 (DARPP-32), and its truncated splice variant, t-DARPP. Here, we show that IKKα phosphorylates DARPP-32 at threonine 34, resulting in DARPP-32-mediated inhibition of protein phosphatase 1 (PP1), subsequent inhibition of PP1-mediated dephosphorylation of ERK, and activation of ERK signaling to promote lung oncogenesis. Correspondingly, IKKα ablation in human lung adenocarcinoma cells reduced their anchorage-independent growth in soft agar. Mice challenged with IKKα-ablated HCC827 cells exhibited less lung tumor growth than mice orthotopically administered control HCC827 cells. Our findings suggest that IKKα drives NSCLC growth through the activation of ERK signaling via DARPP-32-mediated inhibition of PP1 activity.
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Affiliation(s)
- Sk Kayum Alam
- The Hormel Institute, University of Minnesota, Austin, MN, USA.
| | - Li Wang
- The Hormel Institute, University of Minnesota, Austin, MN, USA
| | - Zhu Zhu
- The Hormel Institute, University of Minnesota, Austin, MN, USA
| | - Luke H Hoeppner
- The Hormel Institute, University of Minnesota, Austin, MN, USA.
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
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14
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Design of Nanoparticles in Cancer Therapy Based on Tumor Microenvironment Properties. Pharmaceutics 2022; 14:pharmaceutics14122708. [PMID: 36559202 PMCID: PMC9785496 DOI: 10.3390/pharmaceutics14122708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/23/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022] Open
Abstract
Cancer is one of the leading causes of death worldwide, and battling cancer has always been a challenging subject in medical sciences. All over the world, scientists from different fields of study try to gain a deeper knowledge about the biology and roots of cancer and, consequently, provide better strategies to fight against it. During the past few decades, nanoparticles (NPs) have attracted much attention for the delivery of therapeutic and diagnostic agents with high efficiency and reduced side effects in cancer treatment. Targeted and stimuli-sensitive nanoparticles have been widely studied for cancer therapy in recent years, and many more studies are ongoing. This review aims to provide a broad view of different nanoparticle systems with characteristics that allow them to target diverse properties of the tumor microenvironment (TME) from nanoparticles that can be activated and release their cargo due to the specific characteristics of the TME (such as low pH, redox, and hypoxia) to nanoparticles that can target different cellular and molecular targets of the present cell and molecules in the TME.
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15
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Tsai PJ, Lai YH, Manne RK, Tsai YS, Sarbassov D, Lin HK. Akt: a key transducer in cancer. J Biomed Sci 2022; 29:76. [PMID: 36180910 PMCID: PMC9526305 DOI: 10.1186/s12929-022-00860-9] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 09/21/2022] [Indexed: 01/27/2023] Open
Abstract
Growth factor signaling plays a pivotal role in diverse biological functions, such as cell growth, apoptosis, senescence, and migration and its deregulation has been linked to various human diseases. Akt kinase is a central player transmitting extracellular clues to various cellular compartments, in turn executing these biological processes. Since the discovery of Akt three decades ago, the tremendous progress towards identifying its upstream regulators and downstream effectors and its roles in cancer has been made, offering novel paradigms and therapeutic strategies for targeting human diseases and cancers with deregulated Akt activation. Unraveling the molecular mechanisms for Akt signaling networks paves the way for developing selective inhibitors targeting Akt and its signaling regulation for the management of human diseases including cancer.
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Affiliation(s)
- Pei-Jane Tsai
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Hsin Lai
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Rajesh Kumar Manne
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Yau-Sheng Tsai
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Clinical Medicine Research Center, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Dos Sarbassov
- Biology Department, School of Sciences and Humanities, and National Laboratory Astana, Nazarbayev University, Nur-Sultan City, 010000, Kazakhstan.
| | - Hui-Kuan Lin
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA.
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16
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Tan R, Nie M, Long W. The role of B cells in cancer development. Front Oncol 2022; 12:958756. [PMID: 36033455 PMCID: PMC9403891 DOI: 10.3389/fonc.2022.958756] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 07/18/2022] [Indexed: 11/25/2022] Open
Abstract
B cells play a critical role in adaptive immune responses mainly due to antigen presentation and antibody production. Studies about the tumor-infiltrating immune cells so far demonstrated that the function of B cells in tumor immunity is quite different among various tumor types. The antigen presentation of B cells is mainly anti-tumoral, while the role of antibody production is controversial. Moreover, the immunosuppressive regulatory B cells are detrimental to anti-tumor immunity via the secretion of various anti-inflammatory cytokines. This review briefly summarizes the different roles of B cells classified by the primary function of B cells, antigen presentation, antibody production, and immunity regulation. Further, it discusses the potential therapeutic target of B cells in tumor immunity.
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Affiliation(s)
- Rongying Tan
- Clinical Nursing Teaching and Research Section, The Second Xiangya Hospital, Central South University, Changsha, China
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Manhua Nie
- Clinical Nursing Teaching and Research Section, The Second Xiangya Hospital, Central South University, Changsha, China
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- *Correspondence: Wang Long, ; Manhua Nie,
| | - Wang Long
- Department of Pathology, Nihon University, Tokyo, Japan
- *Correspondence: Wang Long, ; Manhua Nie,
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17
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Akhtar S, Hourani S, Therachiyil L, Al-Dhfyan A, Agouni A, Zeidan A, Uddin S, Korashy HM. Epigenetic Regulation of Cancer Stem Cells by the Aryl Hydrocarbon Receptor Pathway. Semin Cancer Biol 2022; 83:177-196. [PMID: 32877761 DOI: 10.1016/j.semcancer.2020.08.014] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/20/2020] [Accepted: 08/23/2020] [Indexed: 12/14/2022]
Abstract
Compelling evidence has demonstrated that tumor bulk comprises distinctive subset of cells generally referred as cancer stem cells (CSCs) that have been proposed as a strong sustainer and promoter of tumorigenesis and therapeutic resistance. These distinguished properties of CSCs have raised interest in understanding the molecular mechanisms that govern the maintenance of these cells. Numerous experimental and epidemiological studies have demonstrated that exposure to environmental toxins such as the polycyclic aromatic hydrocarbons (PAHs) is strongly involved in cancer initiation and progression. The PAH-induced carcinogenesis is shown to be mediated through the activation of a cytosolic receptor, aryl hydrocarbon receptor (AhR)/Cytochrome P4501A pathway, suggesting a possible direct link between AhR and CSCs. Several recent studies have investigated the role of AhR in CSCs self-renewal and maintenance, however the molecular mechanisms and particularly the epigenetic regulations of CSCs by the AhR/CYP1A pathway have not been reviewed before. In this review, we first summarize the crosstalk between AhR and cancer genetics, with a particular emphasis on the mechanisms relevant to CSCs such as Wnt/β-catenin, Notch, NF-κB, and PTEN-PI3K/Akt signaling pathways. The second part of this review discusses the recent advances and studies highlighting the epigenetic mechanisms mediated by the AhR/CYP1A pathway that control CSC gene expression, self-renewal, and chemoresistance in various human cancers. Furthermore, the review also sheds light on the importance of targeting the epigenetic pathways as a novel therapeutic approach against CSCs.
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Affiliation(s)
- Sabah Akhtar
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Shireen Hourani
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Lubna Therachiyil
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar; Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Abdullah Al-Dhfyan
- Stem Cell & Tissue Re-Engineering, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia
| | - Abdelali Agouni
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Asad Zeidan
- Department of Biomedical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Hesham M Korashy
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar.
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18
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Patel M, Pennel KAF, Quinn JA, Hood H, Chang DK, Biankin AV, Rebus S, Roseweir AK, Park JH, Horgan PG, McMillan DC, Edwards J. Spatial expression of IKK-alpha is associated with a differential mutational landscape and survival in primary colorectal cancer. Br J Cancer 2022; 126:1704-1714. [PMID: 35173303 PMCID: PMC9174220 DOI: 10.1038/s41416-022-01729-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 12/31/2021] [Accepted: 01/28/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND To understand the relationship between key non-canonical NF-κB kinase IKK-alpha(α), tumour mutational profile and survival in primary colorectal cancer. METHODS Immunohistochemical expression of IKKα was assessed in a cohort of 1030 patients who had undergone surgery for colorectal cancer using immunohistochemistry. Mutational tumour profile was examined using a customised gene panel. Immunofluorescence was used to identify the cellular location of punctate IKKα expression. RESULTS Two patterns of IKKα expression were observed; firstly, in the tumour cell cytoplasm and secondly as discrete 'punctate' areas in a juxtanuclear position. Although cytoplasmic expression of IKKα was not associated with survival, high 'punctate' IKKα expression was associated with significantly reduced cancer-specific survival on multivariate analysis. High punctate expression of IKKα was associated with mutations in KRAS and PDGFRA. Dual immunofluorescence suggested punctate IKKα expression was co-located with the Golgi apparatus. CONCLUSIONS These results suggest the spatial expression of IKKα is a potential biomarker in colorectal cancer. This is associated with a differential mutational profile highlighting possible distinct signalling roles for IKKα in the context of colorectal cancer as well as potential implications for future treatment strategies using IKKα inhibitors.
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Affiliation(s)
- Meera Patel
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
| | - Kathryn A F Pennel
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Jean A Quinn
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Hannah Hood
- School of Medicine, Wolfson Medical School Building, University of Glasgow, Glasgow, UK
| | - David K Chang
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
- Academic Unit of Surgery, School of Medicine, University of Glasgow, Royal Infirmary, Glasgow, UK
| | - Andrew V Biankin
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Selma Rebus
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Antonia K Roseweir
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - James H Park
- Academic Unit of Surgery, School of Medicine, University of Glasgow, Royal Infirmary, Glasgow, UK
| | - Paul G Horgan
- Academic Unit of Surgery, School of Medicine, University of Glasgow, Royal Infirmary, Glasgow, UK
| | - Donald C McMillan
- Academic Unit of Surgery, School of Medicine, University of Glasgow, Royal Infirmary, Glasgow, UK
| | - Joanne Edwards
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
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19
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Li B, Wang P, Jiao J, Wei H, Xu W, Zhou P. Roles of the RANKL-RANK Axis in Immunity-Implications for Pathogenesis and Treatment of Bone Metastasis. Front Immunol 2022; 13:824117. [PMID: 35386705 PMCID: PMC8977491 DOI: 10.3389/fimmu.2022.824117] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 02/16/2022] [Indexed: 12/13/2022] Open
Abstract
A substantial amount patients with cancer will develop bone metastases, with 70% of metastatic prostate and breast cancer patients harboring bone metastasis. Despite advancements in systemic therapies for advanced cancer, survival remains poor for those with bone metastases. The interaction between bone cells and the immune system contributes to a better understanding of the role that the immune system plays in the bone metastasis of cancer. The immune and bone systems share various molecules, including transcription factors, signaling molecules, and membrane receptors, which can stimulate the differentiation and activation of bone-resorbing osteoclasts. The process of cancer metastasis to bone, which deregulates bone turnover and results in bone loss and skeletal-related events (SREs), is also controlled by primary cancer-related factors that modulate the intratumoral microenvironment as well as cellular immune process. The nuclear factor kappa B ligand (RANKL) and the receptor activator of nuclear factor kappa B (RANK) are key regulators of osteoclast development, bone metabolism, lymph node development, and T-cell/dendritic cell communication. RANKL is an osteoclastogenic cytokine that links the bone and the immune system. In this review, we highlight the role of RANKL and RANK in the immune microenvironment and bone metastases and review data on the role of the regulatory mechanism of immunity in bone metastases, which could be verified through clinical efficacy of RANKL inhibitors for cancer patients with bone metastases. With the discovery of the specific role of RANK signaling in osteoclastogenesis, the humanized monoclonal antibody against RANKL, such as denosumab, was available to prevent bone loss, SREs, and bone metastases, providing a unique opportunity to target RANKL/RANK as a future strategy to prevent bone metastases.
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Affiliation(s)
- Bo Li
- Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Pengru Wang
- Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jian Jiao
- Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Haifeng Wei
- Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Wei Xu
- Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Pingting Zhou
- Department of Radiation Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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20
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Stikbakke E, Wilsgaard T, Haugnes HS, Pedersen MI, Knutsen T, Støyten M, Giovannucci E, Eggen AE, Thune I, Richardsen E. Expression of miR-24-1-5p in Tumor Tissue Influences Prostate Cancer Recurrence: The PROCA- life Study. Cancers (Basel) 2022; 14:cancers14051142. [PMID: 35267449 PMCID: PMC8909269 DOI: 10.3390/cancers14051142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 02/18/2022] [Accepted: 02/21/2022] [Indexed: 12/22/2022] Open
Abstract
The role of miR-24-1-5p and its prognostic implications associated with prostate cancer are mainly unknown. In a population-based cohort, the Prostate Cancer Study throughout life (PROCA-life), all men had a general health examination at study entry and were followed between 1994 and 2016. Patients with available tissue samples after a prostatectomy with curative intent were identified (n = 189). The tissue expression of miR-24-1-5p in prostate cancer was examined by in situ hybridization (ISH) in tissue microarray (TMA) blocks by semi-quantitative scoring by two independent investigators. Multivariable Cox regression models were used to study the associations between miR-24-1-5p expression and prostate cancer recurrence. The prostate cancer patients had a median age of 65.0 years (range 47−75 years). The Cancer of the Prostate Risk Assessment Postsurgical Score, International Society of Urological Pathology grade group, and European Association of Urology Risk group were all significant prognostic factors for five-year recurrence-free survival (p < 0.001). Prostate cancer patients with a high miR-24-1-5p expression (≥1.57) in the tissue had a doubled risk of recurrence compared to patients with low expression (HR 1.99, 95% CI 1.13−3.51). Our study suggests that a high expression of miR-24-1-5p is associated with an increased risk of recurrence of prostate cancer after radical prostatectomy, which points to the potential diagnostic and therapeutic value of detecting miR-24-1-5p in prostate cancer cases.
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Affiliation(s)
- Einar Stikbakke
- Department of Clinical Medicine, Faculty of Health Sciences, UiT, The Arctic University of Norway, 9037 Tromsø, Norway; (H.S.H.); (T.K.); (M.S.); (I.T.)
- Department of Oncology, University Hospital of North Norway, 9038 Tromsø, Norway
- Correspondence:
| | - Tom Wilsgaard
- Department of Community Medicine, Faculty of Health Sciences, UiT, The Arctic University of Norway, 9037 Tromsø, Norway; (T.W.); (A.E.E.)
| | - Hege Sagstuen Haugnes
- Department of Clinical Medicine, Faculty of Health Sciences, UiT, The Arctic University of Norway, 9037 Tromsø, Norway; (H.S.H.); (T.K.); (M.S.); (I.T.)
- Department of Oncology, University Hospital of North Norway, 9038 Tromsø, Norway
| | - Mona Irene Pedersen
- Translational Cancer Research Group, Institute of Clinical Medicine, UiT, The Arctic University of Norway, 9037 Tromsø, Norway; (M.I.P.); (E.R.)
| | - Tore Knutsen
- Department of Clinical Medicine, Faculty of Health Sciences, UiT, The Arctic University of Norway, 9037 Tromsø, Norway; (H.S.H.); (T.K.); (M.S.); (I.T.)
- Department of Urology, University Hospital of North Norway, 9038 Tromsø, Norway
| | - Martin Støyten
- Department of Clinical Medicine, Faculty of Health Sciences, UiT, The Arctic University of Norway, 9037 Tromsø, Norway; (H.S.H.); (T.K.); (M.S.); (I.T.)
- Department of Oncology, University Hospital of North Norway, 9038 Tromsø, Norway
| | - Edward Giovannucci
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA;
- Departments of Nutrition and Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Anne Elise Eggen
- Department of Community Medicine, Faculty of Health Sciences, UiT, The Arctic University of Norway, 9037 Tromsø, Norway; (T.W.); (A.E.E.)
| | - Inger Thune
- Department of Clinical Medicine, Faculty of Health Sciences, UiT, The Arctic University of Norway, 9037 Tromsø, Norway; (H.S.H.); (T.K.); (M.S.); (I.T.)
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway
- Department of Oncology, The Cancer Centre, Oslo University Hospital, 0424 Oslo, Norway
| | - Elin Richardsen
- Translational Cancer Research Group, Institute of Clinical Medicine, UiT, The Arctic University of Norway, 9037 Tromsø, Norway; (M.I.P.); (E.R.)
- Department of Medical Biology, Faculty of Health Sciences, UiT, The Arctic University of Norway, 9037 Tromsø, Norway
- Department of Clinical Pathology, University Hospital of North Norway, 9038 Tromsø, Norway
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21
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Petruzzelli M, Ferrer M, Schuijs MJ, Kleeman SO, Mourikis N, Hall Z, Perera D, Raghunathan S, Vacca M, Gaude E, Lukey MJ, Jodrell DI, Frezza C, Wagner EF, Venkitaraman AR, Halim TYF, Janowitz T. Early Neutrophilia Marked by Aerobic Glycolysis Sustains Host Metabolism and Delays Cancer Cachexia. Cancers (Basel) 2022; 14:963. [PMID: 35205709 PMCID: PMC8870098 DOI: 10.3390/cancers14040963] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 02/09/2022] [Accepted: 02/09/2022] [Indexed: 02/01/2023] Open
Abstract
An elevated neutrophil-lymphocyte ratio negatively predicts the outcome of patients with cancer and is associated with cachexia, the terminal wasting syndrome. Here, using murine model systems of colorectal and pancreatic cancer we show that neutrophilia in the circulation and multiple organs, accompanied by extramedullary hematopoiesis, is an early event during cancer progression. Transcriptomic and metabolic assessment reveals that neutrophils in tumor-bearing animals utilize aerobic glycolysis, similar to cancer cells. Although pharmacological inhibition of aerobic glycolysis slows down tumor growth in C26 tumor-bearing mice, it precipitates cachexia, thereby shortening the overall survival. This negative effect may be explained by our observation that acute depletion of neutrophils in pre-cachectic mice impairs systemic glucose homeostasis secondary to altered hepatic lipid processing. Thus, changes in neutrophil number, distribution, and metabolism play an adaptive role in host metabolic homeostasis during cancer progression. Our findings provide insight into early events during cancer progression to cachexia, with implications for therapy.
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Affiliation(s)
- Michele Petruzzelli
- Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; (M.P.); (M.F.); (D.P.); (E.G.); (C.F.)
| | - Miriam Ferrer
- Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; (M.P.); (M.F.); (D.P.); (E.G.); (C.F.)
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; (S.O.K.); (N.M.); (M.J.L.)
| | - Martijn J. Schuijs
- CRUK Cambridge Institute, University of Cambridge Li Ka Shing Centre, Cambridge CB2 0RE, UK; (M.J.S.); (S.R.); (D.I.J.); (T.Y.F.H.)
| | - Sam O. Kleeman
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; (S.O.K.); (N.M.); (M.J.L.)
| | - Nicholas Mourikis
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; (S.O.K.); (N.M.); (M.J.L.)
| | - Zoe Hall
- Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK;
| | - David Perera
- Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; (M.P.); (M.F.); (D.P.); (E.G.); (C.F.)
| | - Shwethaa Raghunathan
- CRUK Cambridge Institute, University of Cambridge Li Ka Shing Centre, Cambridge CB2 0RE, UK; (M.J.S.); (S.R.); (D.I.J.); (T.Y.F.H.)
| | - Michele Vacca
- Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK;
| | - Edoardo Gaude
- Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; (M.P.); (M.F.); (D.P.); (E.G.); (C.F.)
| | - Michael J. Lukey
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; (S.O.K.); (N.M.); (M.J.L.)
| | - Duncan I. Jodrell
- CRUK Cambridge Institute, University of Cambridge Li Ka Shing Centre, Cambridge CB2 0RE, UK; (M.J.S.); (S.R.); (D.I.J.); (T.Y.F.H.)
| | - Christian Frezza
- Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; (M.P.); (M.F.); (D.P.); (E.G.); (C.F.)
| | - Erwin F. Wagner
- Laboratory Genes and Disease, Department of Laboratory Medicine Department of Dermatology, Medical University of Vienna (MUV), 1090 Vienna, Austria;
- Laboratory Genes and Disease, Department of Dermatology, Medical University of Vienna (MUV), 1090 Vienna, Austria
| | - Ashok R. Venkitaraman
- Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; (M.P.); (M.F.); (D.P.); (E.G.); (C.F.)
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
- Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
| | - Timotheus Y. F. Halim
- CRUK Cambridge Institute, University of Cambridge Li Ka Shing Centre, Cambridge CB2 0RE, UK; (M.J.S.); (S.R.); (D.I.J.); (T.Y.F.H.)
| | - Tobias Janowitz
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; (S.O.K.); (N.M.); (M.J.L.)
- Northwell Health Cancer Institute, New Hyde Park, NY 11042, USA
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22
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Kwon OJ, Zhang B, Jia D, Zhang L, Wei X, Zhou Z, Liu D, Huynh KT, Zhang K, Zhang Y, Labhart P, Sboner A, Barbieri C, Haffner MC, Creighton CJ, Xin L. Elevated expression of the colony-stimulating factor 1 (CSF1) induces prostatic intraepithelial neoplasia dependent of epithelial-Gp130. Oncogene 2022; 41:1309-1323. [PMID: 34999736 PMCID: PMC8882147 DOI: 10.1038/s41388-021-02169-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 12/06/2021] [Accepted: 12/22/2021] [Indexed: 11/24/2022]
Abstract
Macrophages are increased in human benign prostatic hyperplasia and prostate cancer. We generate a Pb-Csf1 mouse model with prostate-specific overexpression of macrophage colony-stimulating factor (M-Csf/Csf1). Csf1 overexpression promotes immune cell infiltration into the prostate, modulates the macrophage polarity in a lobe-specific manner, and induces senescence and low-grade prostatic intraepithelial neoplasia (PIN). The Pb-Csf1 prostate luminal cells exhibit increased stem cell features and undergo an epithelial-to-mesenchymal transition. Human prostate cancer patients with high CSF-1 expression display similar transcriptional alterations with the Pb-Csf1 model. P53 knockout alleviates senescence but fails to progress PIN lesions. Ablating epithelial Gp130 but not Il1r1 substantially blocks PIN lesion formation. The androgen receptor (AR) is downregulated in Pb-Csf1 mice. ChIP-Seq analysis reveals altered AR binding in 2482 genes although there is no significant widespread change in global AR transcriptional activity. Collectively, our study demonstrates that increased macrophage infiltration causes PIN formation but fails to transform prostate cells.
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Affiliation(s)
- Oh-Joon Kwon
- Department of Urology, University of Washington, Seattle, WA, 98109, USA
| | - Boyu Zhang
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Deyong Jia
- Department of Urology, University of Washington, Seattle, WA, 98109, USA
| | - Li Zhang
- Department of Urology, University of Washington, Seattle, WA, 98109, USA
| | - Xing Wei
- Department of Urology, University of Washington, Seattle, WA, 98109, USA
| | - Zhicheng Zhou
- Department of Urology, University of Washington, Seattle, WA, 98109, USA
| | - Deli Liu
- Sandra and Edward Meyer Cancer Center and Department of Urology, Weill Cornell Medicine, New York, NY, USA
| | - Khoi Trung Huynh
- Department of Biology, University of Washington, Seattle, WA, 98109, USA
| | - Kai Zhang
- Department of Urology, University of Washington, Seattle, WA, 98109, USA
| | - Yiqun Zhang
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | | | - Andrea Sboner
- Sandra and Edward Meyer Cancer Center and Department of Urology, Weill Cornell Medicine, New York, NY, USA
| | - Chris Barbieri
- Sandra and Edward Meyer Cancer Center and Department of Urology, Weill Cornell Medicine, New York, NY, USA
| | - Michael C Haffner
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, 98109, USA
| | - Chad J Creighton
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Li Xin
- Department of Urology, University of Washington, Seattle, WA, 98109, USA.
- Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, 98109, USA.
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23
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García-García VA, Alameda JP, Page A, Mérida-García A, Navarro M, Tejero A, Paramio JM, García-Fernández RA, Casanova ML. IKKα Induces Epithelial–Mesenchymal Changes in Mouse Skin Carcinoma Cells That Can Be Partially Reversed by Apigenin. Int J Mol Sci 2022; 23:ijms23031375. [PMID: 35163299 PMCID: PMC8836221 DOI: 10.3390/ijms23031375] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/21/2022] [Accepted: 01/21/2022] [Indexed: 11/30/2022] Open
Abstract
NMSC (non-melanoma skin cancer) is a common tumor in the Caucasian population, accounting for 90% of skin cancers. Among them, squamous cell carcinomas (SCCs) can metastasize and, due to its high incidence, constitute a severe health problem. It has been suggested that cutaneous SCCs with more risk to metastasize express high levels of nuclear IKKα. However, the molecular mechanisms that lead to this enhanced aggressiveness are largely unknown. To understand in depth the influence of nuclear IKKα in skin SCC progression, we have generated murine PDVC57 skin carcinoma cells expressing exogenous IKKα either in the nucleus or in the cytoplasm to further distinguish the tumor properties of IKKα in both localizations. Our results show that IKKα promotes changes in both subcellular compartments, resembling EMT (epithelial–mesenchymal transition), which are more pronounced when IKKα is in the nucleus of these tumor cells. These EMT-related changes include a shift toward a migratory phenotype and induction of the expression of proteins involved in cell matrix degradation, cell survival and resistance to apoptosis. Additionally, we have found that apigenin, a flavonoid with anti-cancer properties, inhibits the expression of IKKα and attenuates most of the pro-tumoral EMT changes induced by IKKα in mouse tumor keratinocytes. Nevertheless, we have found that apigenin only inhibits the expression of the IKKα protein when it is localized in the cytoplasm.
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Affiliation(s)
- Verónica A. García-García
- Molecular and Translational Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), 28040 Madrid, Spain; (V.A.G.-G.); (J.P.A.); (A.P.); (A.M.-G.); (M.N.); (A.T.); (J.M.P.)
- Biomedical Research Institute I+12, 12 de Octubre University Hospital, 28040 Madrid, Spain
| | - Josefa P. Alameda
- Molecular and Translational Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), 28040 Madrid, Spain; (V.A.G.-G.); (J.P.A.); (A.P.); (A.M.-G.); (M.N.); (A.T.); (J.M.P.)
- Biomedical Research Institute I+12, 12 de Octubre University Hospital, 28040 Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Angustias Page
- Molecular and Translational Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), 28040 Madrid, Spain; (V.A.G.-G.); (J.P.A.); (A.P.); (A.M.-G.); (M.N.); (A.T.); (J.M.P.)
- Biomedical Research Institute I+12, 12 de Octubre University Hospital, 28040 Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Antonio Mérida-García
- Molecular and Translational Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), 28040 Madrid, Spain; (V.A.G.-G.); (J.P.A.); (A.P.); (A.M.-G.); (M.N.); (A.T.); (J.M.P.)
- Complejo Asistencial de Zamora, 49022 Zamora, Spain
| | - Manuel Navarro
- Molecular and Translational Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), 28040 Madrid, Spain; (V.A.G.-G.); (J.P.A.); (A.P.); (A.M.-G.); (M.N.); (A.T.); (J.M.P.)
- Biomedical Research Institute I+12, 12 de Octubre University Hospital, 28040 Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Adrián Tejero
- Molecular and Translational Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), 28040 Madrid, Spain; (V.A.G.-G.); (J.P.A.); (A.P.); (A.M.-G.); (M.N.); (A.T.); (J.M.P.)
| | - Jesús M. Paramio
- Molecular and Translational Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), 28040 Madrid, Spain; (V.A.G.-G.); (J.P.A.); (A.P.); (A.M.-G.); (M.N.); (A.T.); (J.M.P.)
- Biomedical Research Institute I+12, 12 de Octubre University Hospital, 28040 Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Rosa A. García-Fernández
- Department of Animal Medicine and Surgery, Facultad de Veterinaria, Complutense University of Madrid (UCM), 28040 Madrid, Spain;
| | - M. Llanos Casanova
- Molecular and Translational Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), 28040 Madrid, Spain; (V.A.G.-G.); (J.P.A.); (A.P.); (A.M.-G.); (M.N.); (A.T.); (J.M.P.)
- Biomedical Research Institute I+12, 12 de Octubre University Hospital, 28040 Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
- Correspondence:
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24
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Targeting Inflammatory Signaling in Prostate Cancer Castration Resistance. J Clin Med 2021; 10:jcm10215000. [PMID: 34768524 PMCID: PMC8584457 DOI: 10.3390/jcm10215000] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/04/2021] [Accepted: 10/21/2021] [Indexed: 12/24/2022] Open
Abstract
Although castration-resistant prostate cancer (CRPC) as a whole, by its name, refers to the tumors that relapse and/or regrow independently of androgen after androgen deprivation therapy (ADT), untreated tumor, even in early-stage primary prostate cancer (PCa), contains androgen-independent (AI) PCa cells. The transformation of androgen-dependent (AD) PCa to AI PCa under ADT is a forced evolutionary process, in which the small group of AI PCa cells that exist in primary tumors has the unique opportunity to proliferate and expand selectively and dominantly, while some AD PCa cells that have escaped from ADT-induced death acquire the capability to survive in an androgen-depleted environment. The adaptation and reprogramming of both PCa cells and the tumor microenvironment (TME) under ADT make PCa much stronger than primary tumors so that, currently, there are no effective therapeutic methods available for the treatment of CRPC. Many mechanisms have been found to be related to the emergence and maintenance of PCa castration resistance; in this review, we focus on the role of inflammatory signaling in both PCa cells and the TME for the emergence and maintenance of CRPC and summarize the recent advances of therapeutic strategies that target inflammatory signaling for the treatment of CRPC.
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25
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Zhong S, Jeong JH, Huang C, Chen X, Dickinson SI, Dhillon J, Yang L, Luo JL. Targeting INMT and interrupting its methylation pathway for the treatment of castration resistant prostate cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:307. [PMID: 34587977 PMCID: PMC8482636 DOI: 10.1186/s13046-021-02109-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 09/19/2021] [Indexed: 02/07/2023]
Abstract
Background Castration-resistant prostate cancer (CRPC) is associated with a very poor prognosis, and the treatment of which remains a serious clinical challenge. Methods RNA-seq, qPCR, western blot and immunohistochemistry were employed to identify and confirm the high expression of indolethylamine N-methyltransferase (INMT) in CRPC and the clinical relevance. Chip assay was used to identify Histone-Lysine N-Methyltransferase (SMYD3) as a major epigenetic regulator of INMT. LC-MS/MS were used to identify new substrates of INMT methylation in CRPC tissues. Gene knockdown/overexpression, MTT and mouse cancer models were used to examine the role of INMT as well as the anticancer efficacy of INMT inhibitor N,N-dimethyltryptamine (DMT), the SMYD3 inhibitor BCl-12, the selenium compounds methaneseleninic acid (MSA) and Se-(Methyl)selenocysteine hydrochloride (MSC), and the newly identified endogenous INMT substrate Bis(7)-tacrine. Results We found that the expression of INMT was highly increased in CRPC and was correlated with poor prognosis of clinical prostate cancer (PCa). INMT promoted PCa castration resistance via detoxification of anticancer metabolites. Knockdown of INMT or treatment with INMT inhibitor N,N-dimethyltryptamine (DMT) significantly suppressed CRPC development. Histone-Lysine N-Methyltransferase SMYD3 was a major epigenetic regulator of INMT expression, treatment with SMYD3 inhibitor BCl-121 suppressed INMT expression and inhibits CRPC development. Importantly, INMT knockdown significantly increased the anticancer effect of the exogenous selenium compounds methaneseleninic acid (MSA) and Se-(Methyl)selenocysteine hydrochloride (MSC) as well as the endogenous metabolite Bis(7)-tacrine. Conclusions Our study suggests that INMT drives PCa castration resistance through detoxification of anticancer metabolites, targeting INMT or its regulator SMYD3 or/and its methylation metabolites represents an effective therapeutic avenue for CRPC treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02109-z.
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Affiliation(s)
- Shangwei Zhong
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA
| | - Ji-Hak Jeong
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA.,College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea
| | - Changhao Huang
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA
| | - Xueyan Chen
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA
| | | | - Jasreman Dhillon
- Department of Pathology, Moffitt Cancer Center, 2902 Magnolia Drive, Tampa, FL, 33612, USA
| | - Li Yang
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA. .,Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China.
| | - Jun-Li Luo
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA.
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26
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The Roadmap of RANKL/RANK Pathway in Cancer. Cells 2021; 10:cells10081978. [PMID: 34440747 PMCID: PMC8393235 DOI: 10.3390/cells10081978] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 07/30/2021] [Accepted: 08/02/2021] [Indexed: 01/02/2023] Open
Abstract
The receptor activator of the nuclear factor-κB ligand (RANKL)/RANK signaling pathway was identified in the late 1990s and is the key mediator of bone remodeling. Targeting RANKL with the antibody denosumab is part of the standard of care for bone loss diseases, including bone metastases (BM). Over the last decade, evidence has implicated RANKL/RANK pathway in hormone and HER2-driven breast carcinogenesis and in the acquisition of molecular and phenotypic traits associated with breast cancer (BCa) aggressiveness and poor prognosis. This marked a new era in the research of the therapeutic use of RANKL inhibition in BCa. RANKL/RANK pathway is also an important immune mediator, with anti-RANKL therapy recently linked to improved response to immunotherapy in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). This review summarizes and discusses the pre-clinical and clinical evidence of the relevance of the RANKL/RANK pathway in cancer biology and therapeutics, focusing on bone metastatic disease, BCa onset and progression, and immune modulation.
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27
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Combination of chemotherapy with BRAF inhibitors results in effective eradication of malignant melanoma by preventing ATM-dependent DNA repair. Oncogene 2021; 40:5042-5048. [PMID: 34140639 DOI: 10.1038/s41388-021-01879-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 05/11/2021] [Accepted: 06/01/2021] [Indexed: 01/07/2023]
Abstract
Invasive malignant melanoma (MM) is an aggressive tumor with no curative therapy in advanced stages. Chemotherapy has not demonstrated its efficacy in MM and current treatment for tumors carrying the most frequent BRAFV600E mutation consists of BRAF inhibitors alone or in combination with MAPK pathway inhibitors. We previously found that BRAF inhibition prevents activation of the DNA-damage repair (DDR) pathway in colorectal cancer thus potentiating the effect of chemotherapy. We now show that different chemotherapy agents inflict DNA damage in MM cells, which is efficiently repaired, associated with activation of the ATM-dependent DDR machinery. Pharmacologic inhibition of BRAF impairs ATM and DDR activation in these cells, leading to sustained DNA damage. Combination treatments involving DNA-damaging agents and BRAF inhibitors increase tumor cell death in vitro and in vivo, and impede MM regrowth after treatment cessation. We propose to reconsider the use of chemotherapy in combination with BRAF inhibitors for MM treatment.
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28
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Lv S, Luo T, Yang Y, Li Y, Yang J, Xu J, Zheng J, Zeng Y. Naa10p and IKKα interaction regulates EMT in oral squamous cell carcinoma via TGF-β1/Smad pathway. J Cell Mol Med 2021; 25:6760-6772. [PMID: 34060226 PMCID: PMC8278082 DOI: 10.1111/jcmm.16680] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 05/08/2021] [Accepted: 05/11/2021] [Indexed: 12/11/2022] Open
Abstract
Epithelial‐mesenchymal transition (EMT) has been contributed to increase migration and invasion of cancer cells. However, the correlate of Naa10p and IKKα with EMT in oral squamous cell carcinoma (OSCC) is not yet fully understood. In our present study, we found N‐α‐acetyltransferase 10 protein (Naa10p) and IκB kinase α (IKKα) were abnormally abundant in oral squamous cell carcinoma (OSCC). Bioinformatic results indicate that the expression of Naa10p and IKKα is correlated with TGF‐β1/Smad and EMT‐related molecules. The Transwell migration, invasion, qRT‐PCR and Western blot assay indicated that Naa10p repressed OSCC cell migration, invasion and EMT, whereas IKKα promoted TGF‐β1–mediated OSCC cell migration, invasion and EMT. Mechanistically, Naa10p inhibited IKKα activation of Smad3 through the interaction with IKKα directly in OSCC cells after TGF‐β1 stimulation. Notably, knockdown of Naa10p reversed the IKKα‐induced change in the migration, invasion and EMT‐related molecules in OSCC cells after TGF‐β1 stimulation. These findings suggest that Naa10p interacted with IKKα mediates EMT in OSCC cells through TGF‐β1/Smad, a novel pathway for preventing OSCC.
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Affiliation(s)
- Sai Lv
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, China.,Department of Stomatology, The First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, China
| | - Ting Luo
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, China
| | - Yongyong Yang
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Yuqing Li
- Department of Urological Surgery, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, China
| | - Jie Yang
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, China.,Department of Stomatology, The First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, China
| | - Jiang Xu
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, China.,Department of Stomatology, The First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, China
| | - Jun Zheng
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, China.,Department of Stomatology, The First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, China
| | - Yan Zeng
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, China.,Department of Stomatology, The First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, China
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RANK promotes colorectal cancer migration and invasion by activating the Ca 2+-calcineurin/NFATC1-ACP5 axis. Cell Death Dis 2021; 12:336. [PMID: 33795653 PMCID: PMC8016848 DOI: 10.1038/s41419-021-03642-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 03/13/2021] [Accepted: 03/15/2021] [Indexed: 12/16/2022]
Abstract
The tumor necrosis factor (TNF) receptor superfamily member 11a (TNFRSF11a, also known as RANK) was demonstrated to play an important role in tumor metastasis. However, the specific function of RANK in colorectal cancer (CRC) metastasis and the underlying mechanism are unknown. In this study, we found that RANK expression was markedly upregulated in CRC tissues compared with that in matched noncancerous tissues. Increased RANK expression correlated positively with metastasis, higher TNM stage, and worse prognosis in patients with CRC. Overexpression of RANK promoted CRC cell metastasis in vitro and in vivo, while knockdown of RANK decreased cell migration and invasion. Mechanistically, RANK overexpression significantly upregulated the expression of tartrate-resistant acid phosphatase 5 (TRAP/ACP5) in CRC cells. Silencing of ACP5 in RANK-overexpressing CRC cells attenuated RANK-induced migration and invasion, whereas overexpression of ACP5 increased the migration and invasion of RANK-silencing cells. The ACP5 expression was transcriptionally regulated by calcineurin/nuclear factor of activated T cells c1 (NFATC1) axis. The inhibition of calcineurin/NFATC1 significantly decreased ACP5 expression, and attenuated RANK-induced cell migration and invasion. Furthermore, RANK induced phospholipase C-gamma (PLCγ)-mediated inositol-1,4,5-trisphosphate receptor (IP3R) axis and stromal interaction molecule 1 (STIM1) to evoke calcium (Ca2+) oscillation. The RANK-mediated intracellular Ca2+ mobilization stimulated calcineurin to dephosphorylate NFATC1 and induce NFATC1 nuclear translocation. Both blockage of PLCγ-IP3R axis and STIM1 rescued RANK-induced NFATC1 nuclear translocation, ACP5 expression, and cell metastasis. Our study revealed the functional expression of RANK in human CRC cells and demonstrated that RANK induced the Ca2+-calcineurin/NFATC1-ACP5 axis in the regulation of CRC metastasis, that might be amenable to therapeutic targeting.
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Ollauri-Ibáñez C, Ayuso-Íñigo B, Pericacho M. Hot and Cold Tumors: Is Endoglin (CD105) a Potential Target for Vessel Normalization? Cancers (Basel) 2021; 13:1552. [PMID: 33800564 PMCID: PMC8038031 DOI: 10.3390/cancers13071552] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 03/24/2021] [Accepted: 03/26/2021] [Indexed: 12/15/2022] Open
Abstract
Tumors are complex masses formed by malignant but also by normal cells. The interaction between these cells via cytokines, chemokines, growth factors, and enzymes that remodel the extracellular matrix (ECM) constitutes the tumor microenvironment (TME). This TME can be determinant in the prognosis and the response to some treatments such as immunotherapy. Depending on their TME, two types of tumors can be defined: hot tumors, characterized by an immunosupportive TME and a good response to immunotherapy; and cold tumors, which respond poorly to this therapy and are characterized by an immunosuppressive TME. A therapeutic strategy that has been shown to be useful for the conversion of cold tumors into hot tumors is vascular normalization. In this review we propose that endoglin (CD105) may be a useful target of this strategy since it is involved in the three main processes involved in the generation of the TME: angiogenesis, inflammation, and cancer-associated fibroblast (CAF) accumulation. Moreover, the analysis of endoglin expression in tumors, which is already used in the clinic to study the microvascular density and that is associated with worse prognosis, could be used to predict a patient's response to immunotherapy.
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Affiliation(s)
| | | | - Miguel Pericacho
- Renal and Cardiovascular Research Unit, Group of Physiopathology of the Vascular Endothelium (ENDOVAS), Biomedical Research Institute of Salamanca (IBSAL), Department of Physiology and Pharmacology, University of Salamanca, 37007 Salamanca, Spain; (C.O.-I.); (B.A.-Í.)
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31
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Abstract
Viral infections lead to the death of more than a million people each year around the world, both directly and indirectly. Viruses interfere with many cell functions, particularly critical pathways for cell death, by affecting various intracellular mediators. MicroRNAs (miRNAs) are a major example of these mediators because they are involved in many (if not most) cellular mechanisms. Virus-regulated miRNAs have been implicated in three cell death pathways, namely, apoptosis, autophagy, and anoikis. Several molecules (e.g., BECN1 and B cell lymphoma 2 [BCL2] family members) are involved in both apoptosis and autophagy, while activation of anoikis leads to cell death similar to apoptosis. These mechanistic similarities suggest that common regulators, including some miRNAs (e.g., miR-21 and miR-192), are involved in different cell death pathways. Because the balance between cell proliferation and cell death is pivotal to the homeostasis of the human body, miRNAs that regulate cell death pathways have drawn much attention from researchers. miR-21 is regulated by several viruses and can affect both apoptosis and anoikis via modulating various targets, such as PDCD4, PTEN, interleukin (IL)-12, Maspin, and Fas-L. miR-34 can be downregulated by viral infection and has different effects on apoptosis, depending on the type of virus and/or host cell. The present review summarizes the existing knowledge on virus-regulated miRNAs involved in the modulation of cell death pathways. Understanding the mechanisms for virus-mediated regulation of cell death pathways could provide valuable information to improve the diagnosis and treatment of many viral diseases.
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32
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Li X, Hu Y. Attribution of NF-κB Activity to CHUK/IKKα-Involved Carcinogenesis. Cancers (Basel) 2021; 13:cancers13061411. [PMID: 33808757 PMCID: PMC8003426 DOI: 10.3390/cancers13061411] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/08/2021] [Accepted: 03/15/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary CHUK/IKKα has emerged as a novel tumor suppressor in several organs of humans and mice. In general, activation of NF-κB promotes inflammation and tumorigenesis. IKKα reduction stimulates inflammatory responses including NF-κB’s targets and NF-κB-independent pathways for tumor promotion. Specific phenomena from genetically-modified mice and human TCGA database show the crosstalk between IKKα and NF-κB although their nature paths for normal organ development and the disease and cancer pathogenesis remains largely under investigation. In this review, we focus on the interplay between IKKα and NF-κB signaling during carcinogenesis. A better understanding of their relationship will provide insight into therapeutic targets of cancer. Abstract Studies analyzing human cancer genome sequences and genetically modified mouse models have extensively expanded our understanding of human tumorigenesis, even challenging or reversing the dogma of certain genes as originally characterized by in vitro studies. Inhibitor-κB kinase α (IKKα), which is encoded by the conserved helix-loop-helix ubiquitous kinase (CHUK) gene, is first identified as a serine/threonine protein kinase in the inhibitor-κB kinase complex (IKK), which is composed of IKKα, IKKβ, and IKKγ (NEMO). IKK phosphorylates serine residues 32 and 36 of IκBα, a nuclear factor-κB (NF-κB) inhibitor, to induce IκBα protein degradation, resulting in the nuclear translocation of NF-κB dimers that function as transcriptional factors to regulate immunity, infection, lymphoid organ/cell development, cell death/growth, and tumorigenesis. NF-κB and IKK are broadly and differentially expressed in the cells of our body. For a long time, the idea that the IKK complex acts as a direct upstream activator of NF-κB in carcinogenesis has been predominately accepted in the field. Surprisingly, IKKα has emerged as a novel suppressor for skin, lung, esophageal, and nasopharyngeal squamous cell carcinoma, as well as lung and pancreatic adenocarcinoma (ADC). Thus, Ikkα loss is a tumor driver in mice. On the other hand, lacking the RANKL/RANK/IKKα pathway impairs mammary gland development and attenuates oncogene- and chemical carcinogen-induced breast and prostate tumorigenesis and metastasis. In general, NF-κB activation leads one of the major inflammatory pathways and stimulates tumorigenesis. Since IKKα and NF-κB play significant roles in human health, revealing the interplay between them greatly benefits the diagnosis, treatment, and prevention of human cancer. In this review, we discuss the intriguing attribution of NF-κB to CHUK/IKKα-involved carcinogenesis.
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33
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Liang Y, Jeganathan S, Marastoni S, Sharp A, Figueiredo I, Marcellus R, Mawson A, Shalev Z, Pesic A, Sweet J, Guo H, Uehling D, Gurel B, Neeb A, He HH, Montgomery B, Koritzinsky M, Oakes S, de Bono JS, Gleave M, Zoubeidi A, Wouters BG, Joshua AM. Emergence of Enzalutamide Resistance in Prostate Cancer is Associated with BCL-2 and IKKB Dependencies. Clin Cancer Res 2021; 27:2340-2351. [PMID: 33542074 DOI: 10.1158/1078-0432.ccr-20-3260] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 12/23/2020] [Accepted: 02/02/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Although enzalutamide (ENZ) has been widely used to treat de novo or castration-resistant metastatic prostate cancer, resistance develops and disease progression is ultimately inevitable. There are currently no approved targeted drugs to specifically delay or overcome ENZ resistance. EXPERIMENTAL DESIGN We selected several ENZ-resistant cell lines that replicated clinical characteristics of the majority of patients with ENZ-resistant disease. A high-throughput pharmacologic screen was utilized to identify compounds with greater cytotoxic effect for ENZ-resistant cell lines, compared with parental ENZ-sensitive cells. We validated the potential hits in vitro and in vivo, and used knockdown and overexpression assays to study the dependencies in ENZ-resistant prostate cancer. RESULTS ABT199 (BCL-2 inhibitor) and IMD0354 (IKKB inhibitor) were identified as potent and selective inhibitors of cell viability in ENZ-resistant cell lines in vitro and in vivo which were further validated using loss-of-function assays of BCL-2 and IKKB. Notably, we observed that overexpression of BCL-2 and IKKB in ENZ-sensitive cell lines was sufficient for the emergence of ENZ resistance. In addition, we confirmed that BCL-2 or IKKB inhibitors suppressed the development of ENZ resistance in xenografts. However, validation of both BCL-2 and IKKB in matched castration-sensitive/resistant clinical samples showed that, concurrent with the development of ENZ/abiraterone resistance in patients, only the protein levels of IKKB were increased. CONCLUSIONS Our findings identify BCL-2 and IKKB dependencies in clinically relevant ENZ-resistant prostate cancer cells in vitro and in vivo, but indicate that IKKB upregulation appears to have greater relevance to the progression of human castrate-resistant prostate cancer.
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Affiliation(s)
- Yi Liang
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Sujeeve Jeganathan
- Quality Control Analytical Excellence, Sanofi Pasteur, Toronto, Ontario, Canada
| | - Stefano Marastoni
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Adam Sharp
- Royal Marsden Hospital, Sutton, Surrey, United Kingdom.,The Institute of Cancer Research, London, United Kingdom
| | | | - Richard Marcellus
- Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Amanda Mawson
- Garvan Institute of Medical Research, Sydney, Australia
| | - Zvi Shalev
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Aleksandra Pesic
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Joan Sweet
- Department of Laboratory Medicine and Pathobiology, University Health Network, Toronto, Ontario, Canada
| | - Haiyang Guo
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - David Uehling
- Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Bora Gurel
- The Institute of Cancer Research, London, United Kingdom
| | - Antje Neeb
- The Institute of Cancer Research, London, United Kingdom
| | - Housheng Hansen He
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Bruce Montgomery
- Department of Medicine and Oncology, University of Washington, Seattle Cancer Care Alliance, Seattle, Washington
| | - Marianne Koritzinsky
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Radiation Oncology, Department of Medical Biophysics, Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Samantha Oakes
- Garvan Institute of Medical Research, Sydney, Australia.,Faculty of Medicine, UNSW Sydney, Australia
| | - Johann S de Bono
- Royal Marsden Hospital, Sutton, Surrey, United Kingdom.,The Institute of Cancer Research, London, United Kingdom
| | - Martin Gleave
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada
| | - Amina Zoubeidi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada
| | - Bradly G Wouters
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Radiation Oncology, Department of Medical Biophysics, University of Toronto, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Anthony M Joshua
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. .,Garvan Institute of Medical Research, Sydney, Australia.,Faculty of Medicine, UNSW Sydney, Australia.,Department of Medical Oncology, Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, Australia
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34
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Moser B, Hochreiter B, Basílio J, Gleitsmann V, Panhuber A, Pardo-Garcia A, Hoesel B, Salzmann M, Resch U, Noreen M, Schmid JA. The inflammatory kinase IKKα phosphorylates and stabilizes c-Myc and enhances its activity. Mol Cancer 2021; 20:16. [PMID: 33461590 PMCID: PMC7812655 DOI: 10.1186/s12943-021-01308-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 01/04/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The IκB kinase (IKK) complex, comprising the two enzymes IKKα and IKKβ, is the main activator of the inflammatory transcription factor NF-κB, which is constitutively active in many cancers. While several connections between NF-κB signaling and the oncogene c-Myc have been shown, functional links between the signaling molecules are still poorly studied. METHODS Molecular interactions were shown by co-immunoprecipitation and FRET microscopy. Phosphorylation of c-Myc was shown by kinases assays and its activity by improved reporter gene systems. CRISPR/Cas9-mediated gene knockout and chemical inhibition were used to block IKK activity. The turnover of c-Myc variants was determined by degradation in presence of cycloheximide and by optical pulse-chase experiments.. Immunofluorescence of mouse prostate tissue and bioinformatics of human datasets were applied to correlate IKKα- and c-Myc levels. Cell proliferation was assessed by EdU incorporation and apoptosis by flow cytometry. RESULTS We show that IKKα and IKKβ bind to c-Myc and phosphorylate it at serines 67/71 within a sequence that is highly conserved. Knockout of IKKα decreased c-Myc-activity and increased its T58-phosphorylation, the target site for GSK3β, triggering polyubiquitination and degradation. c-Myc-mutants mimicking IKK-mediated S67/S71-phosphorylation exhibited slower turnover, higher cell proliferation and lower apoptosis, while the opposite was observed for non-phosphorylatable A67/A71-mutants. A significant positive correlation of c-Myc and IKKα levels was noticed in the prostate epithelium of mice and in a variety of human cancers. CONCLUSIONS Our data imply that IKKα phosphorylates c-Myc on serines-67/71, thereby stabilizing it, leading to increased transcriptional activity, higher proliferation and decreased apoptosis.
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Affiliation(s)
- Bernhard Moser
- Institute of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria
| | - Bernhard Hochreiter
- Institute of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria
| | - José Basílio
- Institute of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria
| | - Viola Gleitsmann
- Institute of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria
| | - Anja Panhuber
- Institute of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria
| | - Alan Pardo-Garcia
- Institute of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria
| | - Bastian Hoesel
- Institute of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria
| | - Manuel Salzmann
- Institute of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria
| | - Ulrike Resch
- Institute of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria
| | - Mamoona Noreen
- Institute of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria
| | - Johannes A. Schmid
- Institute of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria
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35
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Abstract
Bone metastasis involves tumor-induced osteoclast activation, resulting in skeletal tumor progression as well as skeletal disorders. Aberrant expression of receptor activator of NF-κB ligand (RANKL), an essential cytokine for osteoclast differentiation, induced by the metastatic tumor cells is responsible for the pathological bone resorption in bone metastasis. A fully human anti-RANKL neutralizing antibody has been developed to block osteoclast activation and is now used for the treatment of patients with bone metastasis and multiple myeloma. On the other hand, numerous studies have revealed that the RANKL/RANK system also contributes to primary tumorigenesis as well as metastasis through osteoclast-independent processes. Furthermore, emerging clinical and preclinical evidence has suggested anti-tumor immune effects of RANKL blockade when added to immune checkpoint inhibitor therapies. Study on the pleiotropic functions of RANKL in tumorigenesis and metastasis is now expanding beyond the bone field and has been established as one of the most important areas of "RANKL biology".
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Affiliation(s)
- Kazuo Okamoto
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033, Japan.
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36
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Abstract
Almost a quarter century has passed since discovery of receptor activator of NF-κB ligand (RANKL). This discovery had a major impact on identification of mechanisms regulating osteoclast differentiation and function, establishment of a research field bridging bone and the immune system (osteoimmunology), and development of a fully human anti-RANKL neutralizing antibody (denosumab). Denosumab is now clinically available for treatment of osteoporosis and cancer-induced bone diseases in the US, Europe and many other countries, including Japan. Denosumab is a so-called blockbuster drug, with sales of 5.0 billion US dollars in 2019. This is a real success story from bench to bedside. In this review, the pivotal roles of the RANKL/RANK/OPG system in osteoclast differentiation and function are shown. RANKL is a ligand required for osteoclast generation, RANK is the receptor for RANKL, and osteoprotegerin (OPG) is a decoy receptor for RANKL. The review covers recent results showing the importance of RANKL on osteoblasts in regulation of osteogenesis and the role of RANKL-RANK dual signaling in coupling of bone resorption and formation, including demonstration of RANKL reverse signaling that we had previously hypothesized. Possible applications of anti-RANKL antibody in treatment of cancer are also discussed.
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Affiliation(s)
- Hisataka Yasuda
- Nagahama Institute for Biochemical Science, Oriental Yeast Co., Ltd., 50, Kano-cho, Nagahama, Shiga, 526-0804, Japan.
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37
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Annand JR, Henderson AR, Cole KS, Maurais AJ, Becerra J, Liu Y, Weerapana E, Koehler AN, Mapp AK, Schindler CS. Gibberellin JRA-003: A Selective Inhibitor of Nuclear Translocation of IKKα. ACS Med Chem Lett 2020; 11:1913-1918. [PMID: 33062173 DOI: 10.1021/acsmedchemlett.9b00613] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 05/21/2020] [Indexed: 01/02/2023] Open
Abstract
The small molecule gibberellin JRA-003 was identified as an inhibitor of the NF-kB (nuclear kappa-light-chain-enhancer of activated B cells) pathway. Here we find that JRA-003 binds to and significantly inhibits the nuclear translocation of pathway-activating kinases IKKα (IκB kinase alpha) and IKKβ (IκB kinase beta). Analogs of JRA-003 were synthesized and NF-κB-inhibiting gibberellins were found to be cytotoxic in cancer-derived cell lines (HS 578T, HCC 1599, RC-K8, Sud-HL4, CA 46, and NCIH 4466). Not only was JRA-003 identified as the most potent synthetic gibberellin against cancer-derived cell lines, it displayed no cytotoxicity in cells derived from noncancerous sources (HEK 293T, HS 578BST, HS 888Lu, HS 895Sk, HUVEC). This selectivity suggests a promising approach for the development of new therapeutics.
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Affiliation(s)
- James R. Annand
- Department of Chemistry, Willard-Henry-Dow Laboratory, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
- Program in Chemical Biology, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109, United States
| | - Andrew R. Henderson
- Program in Chemical Biology, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109, United States
| | - Kyle S. Cole
- Department of Chemistry, Merkert Center, Boston College, 2609 Beacon Street., Chestnut Hill, Massachusetts 02467, United States
| | - Aaron J. Maurais
- Department of Chemistry, Merkert Center, Boston College, 2609 Beacon Street., Chestnut Hill, Massachusetts 02467, United States
| | - Jorge Becerra
- Program in Chemical Biology, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109, United States
| | - Yejun Liu
- Program in Chemical Biology, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109, United States
| | - Eranthie Weerapana
- Department of Chemistry, Merkert Center, Boston College, 2609 Beacon Street., Chestnut Hill, Massachusetts 02467, United States
| | - Angela N. Koehler
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02139, United States
| | - Anna K. Mapp
- Department of Chemistry, Willard-Henry-Dow Laboratory, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
- Program in Chemical Biology, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109, United States
| | - Corinna S. Schindler
- Department of Chemistry, Willard-Henry-Dow Laboratory, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
- Program in Chemical Biology, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109, United States
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38
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Montes M, MacKenzie L, McAllister MJ, Roseweir A, McCall P, Hatziieremia S, Underwood MA, Boyd M, Paul A, Plevin R, MacKay SP, Edwards J. Determining the prognostic significance of IKKα in prostate cancer. Prostate 2020; 80:1188-1202. [PMID: 33258506 DOI: 10.1002/pros.24045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 07/02/2020] [Indexed: 01/25/2023]
Abstract
BACKGROUND As the survival of castration-resistant prostate cancer (CRPC) remains poor, and the nuclear factor-κB (NF-κB) pathways play key roles in prostate cancer (PC) progression, several studies have focused on inhibiting the NF-κB pathway through generating inhibitory κB kinase subunit α (IKKα) small molecule inhibitors. However, the identification of prognostic markers able to discriminate which patients could benefit from IKKα inhibitors is urgently required. The present study investigated the prognostic value of IKKα, IKKα phosphorylated at serine 180 (p-IKKα S180) and threonine 23 (p-IKKα T23), and their relationship with the androgen receptor (AR) and Ki67 proliferation index to predict patient outcome. METHODS A cohort of 115 patients with hormone-naïve PC (HNPC) and CRPC specimens available were used to assess tumor cell expression of proteins within both the cytoplasm and the nucleus by immunohistochemistry. The expression levels were dichotomized (low vs high) to determine the associations between IKKα, AR, Ki67, and patients'Isurvival. In addition, an analysis was performed to assess potential IKKα associations with clinicopathological and inflammatory features, and potential IKKα correlations with other cancer pathways essential for CRPC growth. RESULTS High levels of cytoplasmic IKKα were associated with a higher cancer-specific survival in HNPC patients with low AR expression (hazards ratio [HR], 0.33; 95% confidence interval [CI] log-rank, 0.11-0.98; P = .04). Furthermore, nuclear IKKα (HR, 2.60; 95% CI, 1.27-5.33; P = .01) and cytoplasmic p-IKKα S180 (HR, 2.10; 95% CI, 1.17-3.76; P = .01) were associated with a lower time to death from recurrence in patients with CRPC. In addition, high IKKα expression was associated with high levels of T-cells (CD3+ P = .01 and CD8+ P = .03) in HNPC; however, under castration conditions, high IKKα expression was associated with high levels of CD68+ macrophages (P = .04), higher Gleason score (P = .01) and more prostate-specific antigen concentration (P = .03). Finally, we identified crosstalk between IKKα and members of the canonical NF-κB pathway in the nucleus of HNPC. Otherwise, IKKα phosphorylated by noncanonical NF-κB and Akt pathways correlated with members of the canonical NF-κB pathway in CRPC. CONCLUSION The present study reports that patients with CRPC expressing high levels of nuclear IKKα or cytoplasmic p-IKKα S180, which associated with a lower time to death from recurrence, may benefit from IKKα inhibitors.
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Affiliation(s)
- Melania Montes
- Unit of Gastrointestinal and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, Institute of Cancer Science, University of Glasgow, Glasgow, UK
| | - Lewis MacKenzie
- Strathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Milly J McAllister
- Unit of Gastrointestinal and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, Institute of Cancer Science, University of Glasgow, Glasgow, UK
| | - Antonia Roseweir
- Unit of Gastrointestinal and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, Institute of Cancer Science, University of Glasgow, Glasgow, UK
- Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow, UK
| | - Pamela McCall
- Unit of Gastrointestinal and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, Institute of Cancer Science, University of Glasgow, Glasgow, UK
| | - Sophia Hatziieremia
- Unit of Gastrointestinal and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, Institute of Cancer Science, University of Glasgow, Glasgow, UK
| | - Mark A Underwood
- Department of Urology, Queen Elizabeth University Hospital, Glasgow, UK
| | - Marie Boyd
- Strathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Andrew Paul
- Strathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Robin Plevin
- Strathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Simon P MacKay
- Strathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Joanne Edwards
- Unit of Gastrointestinal and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, Institute of Cancer Science, University of Glasgow, Glasgow, UK
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39
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Abbas SZ, Qadir MI, Muhammad SA. Systems-level differential gene expression analysis reveals new genetic variants of oral cancer. Sci Rep 2020; 10:14667. [PMID: 32887903 PMCID: PMC7473858 DOI: 10.1038/s41598-020-71346-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 07/20/2020] [Indexed: 01/28/2023] Open
Abstract
Oral cancer (OC) ranked as eleventh malignancy worldwide, with the increasing incidence among young patients. Limited understanding of complications in cancer progression, its development system, and their interactions are major restrictions towards the progress of optimal and effective treatment strategies. The system-level approach has been designed to explore genetic complexity of the disease and to identify novel oral cancer related genes to detect genomic alterations at molecular level, through cDNA differential analysis. We analyzed 21 oral cancer-related cDNA datasets and listed 30 differentially expressed genes (DEGs). Among 30, we found 6 significant DEGs including CYP1A1, CYP1B1, ADCY2, C7, SERPINB5, and ANAPC13 and studied their functional role in OC. Our genomic and interactive analysis showed significant enrichment of xenobiotics metabolism, p53 signaling pathway and microRNA pathways, towards OC progression and development. We used human proteomic data for post-translational modifications to interpret disease mutations and inter-individual genetic variations. The mutational analysis revealed the sequence predicted disordered region of 14%, 12.5%, 10.5% for ADCY2, CYP1B1, and C7 respectively. The MiRNA target prediction showed functional molecular annotation including specific miRNA-targets hsa-miR-4282, hsa-miR-2052, hsa-miR-216a-3p, for CYP1B1, C7, and ADCY2 respectively associated with oral cancer. We constructed the system level network and found important gene signatures. The drug-gene interaction of OC source genes with seven FDA approved OC drugs help to design or identify new drug target or establishing novel biomedical linkages regarding disease pathophysiology. This investigation demonstrates the importance of system genetics for identifying 6 OC genes (CYP1A1, CYP1B1, ADCY2, C7, SERPINB5, and ANAPC13) as potential drugs targets. Our integrative network-based system-level approach would help to find the genetic variants of OC that can accelerate drug discovery outcomes to develop a better understanding regarding treatment strategies for many cancer types.
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Affiliation(s)
- Syeda Zahra Abbas
- Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Pakistan
| | - Muhammad Imran Qadir
- Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Pakistan
| | - Syed Aun Muhammad
- Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Pakistan.
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40
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Franko A, Shao Y, Heni M, Hennenlotter J, Hoene M, Hu C, Liu X, Zhao X, Wang Q, Birkenfeld AL, Todenhöfer T, Stenzl A, Peter A, Häring HU, Lehmann R, Xu G, Lutz SZ. Human Prostate Cancer is Characterized by an Increase in Urea Cycle Metabolites. Cancers (Basel) 2020; 12:E1814. [PMID: 32640711 PMCID: PMC7408908 DOI: 10.3390/cancers12071814] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/30/2020] [Accepted: 07/01/2020] [Indexed: 12/18/2022] Open
Abstract
Despite it being the most common incident of cancer among men, the pathophysiological mechanisms contributing to prostate cancer (PCa) are still poorly understood. Altered mitochondrial metabolism is postulated to play a role in the development of PCa. To determine the key metabolites (which included mitochondrial oncometabolites), benign prostatic and cancer tissues of patients with PCa were analyzed using capillary electrophoresis and liquid chromatography coupled with mass spectrometry. Gene expression was studied using real-time PCR. In PCa tissues, we found reduced levels of early tricarboxylic acid cycle metabolites, whereas the contents of urea cycle metabolites including aspartate, argininosuccinate, arginine, proline, and the oncometabolite fumarate were higher than that in benign controls. Fumarate content correlated positively with the gene expression of oncogenic HIF1α and NFκB pathways, which were significantly higher in the PCa samples than in the benign controls. Furthermore, data from the TCGA database demonstrated that prostate cancer patients with activated NFκB pathway had a lower survival rate. In summary, our data showed that fumarate content was positively associated with carcinogenic genes.
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Affiliation(s)
- Andras Franko
- Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, 72076 Tübingen, Germany; (A.F.); (M.H.); (A.L.B.); (H.-U.H); (S.Z.L.)
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, 72076 Tübingen, Germany
- German Center for Diabetes Research (DZD), 72076 Tübingen, Germany
| | - Yaping Shao
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; (Y.S.); (C.H.); (X.L.); (X.Z.); (Q.W)
| | - Martin Heni
- Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, 72076 Tübingen, Germany; (A.F.); (M.H.); (A.L.B.); (H.-U.H); (S.Z.L.)
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, 72076 Tübingen, Germany
- German Center for Diabetes Research (DZD), 72076 Tübingen, Germany
| | - Jörg Hennenlotter
- Department of Urology, University Hospital Tübingen, 72076 Tübingen, Germany; (J.H.); (T.T.); (A.S.)
| | - Miriam Hoene
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, 72076 Tübingen, Germany; (M.H.); (A.P.)
| | - Chunxiu Hu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; (Y.S.); (C.H.); (X.L.); (X.Z.); (Q.W)
| | - Xinyu Liu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; (Y.S.); (C.H.); (X.L.); (X.Z.); (Q.W)
| | - Xinjie Zhao
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; (Y.S.); (C.H.); (X.L.); (X.Z.); (Q.W)
| | - Qingqing Wang
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; (Y.S.); (C.H.); (X.L.); (X.Z.); (Q.W)
| | - Andreas L. Birkenfeld
- Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, 72076 Tübingen, Germany; (A.F.); (M.H.); (A.L.B.); (H.-U.H); (S.Z.L.)
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, 72076 Tübingen, Germany
- German Center for Diabetes Research (DZD), 72076 Tübingen, Germany
| | - Tilman Todenhöfer
- Department of Urology, University Hospital Tübingen, 72076 Tübingen, Germany; (J.H.); (T.T.); (A.S.)
| | - Arnulf Stenzl
- Department of Urology, University Hospital Tübingen, 72076 Tübingen, Germany; (J.H.); (T.T.); (A.S.)
| | - Andreas Peter
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, 72076 Tübingen, Germany; (M.H.); (A.P.)
| | - Hans-Ulrich Häring
- Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, 72076 Tübingen, Germany; (A.F.); (M.H.); (A.L.B.); (H.-U.H); (S.Z.L.)
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, 72076 Tübingen, Germany
- German Center for Diabetes Research (DZD), 72076 Tübingen, Germany
| | - Rainer Lehmann
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, 72076 Tübingen, Germany
- German Center for Diabetes Research (DZD), 72076 Tübingen, Germany
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, 72076 Tübingen, Germany; (M.H.); (A.P.)
| | - Guowang Xu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; (Y.S.); (C.H.); (X.L.); (X.Z.); (Q.W)
| | - Stefan Z. Lutz
- Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, 72076 Tübingen, Germany; (A.F.); (M.H.); (A.L.B.); (H.-U.H); (S.Z.L.)
- Clinic for Geriatric and Orthopedic Rehabilitation Bad Sebastiansweiler, 72116 Mössingen, Germany
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Cytokines and Chemokines as Mediators of Prostate Cancer Metastasis. Int J Mol Sci 2020; 21:ijms21124449. [PMID: 32585812 PMCID: PMC7352203 DOI: 10.3390/ijms21124449] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 06/19/2020] [Accepted: 06/21/2020] [Indexed: 12/16/2022] Open
Abstract
The consequences of prostate cancer metastasis remain severe, with huge impact on the mortality and overall quality of life of affected patients. Despite the convoluted interplay and cross talk between various cell types and secreted factors in the metastatic process, cytokine and chemokines, along with their receptors and signaling axis, constitute important factors that help drive the sequence of events that lead to metastasis of prostate cancer. These proteins are involved in extracellular matrix remodeling, epithelial-mesenchymal-transition, angiogenesis, tumor invasion, premetastatic niche creation, extravasation, re-establishment of tumor cells in secondary organs as well as the remodeling of the metastatic tumor microenvironment. This review presents an overview of the main cytokines/chemokines, including IL-6, CXCL12, TGFβ, CXCL8, VEGF, RANKL, CCL2, CX3CL1, IL-1, IL-7, CXCL1, and CXCL16, that exert modulatory roles in prostate cancer metastasis. We also provide extensive description of their aberrant expression patterns in both advanced disease states and metastatic sites, as well as their functional involvement in the various stages of the prostate cancer metastatic process.
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42
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Thomas A, Smitha T. Can B- cell based immunotherapy be our new perspective to exit cancer? J Oral Maxillofac Pathol 2020; 24:15-17. [PMID: 32508441 PMCID: PMC7269306 DOI: 10.4103/jomfp.jomfp_121_20] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 04/04/2020] [Indexed: 01/11/2023] Open
Affiliation(s)
- Anela Thomas
- Department of Oral Pathology, VSDC, Bengaluru, Karnataka, India E-mail:
| | - T Smitha
- Department of Oral Pathology, VSDC, Bengaluru, Karnataka, India E-mail:
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43
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Wang N, Chang LL. The potential function of IKKα in gastric precancerous lesion via mediating Maspin. Tissue Cell 2020; 65:101349. [PMID: 32746986 DOI: 10.1016/j.tice.2020.101349] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 02/26/2020] [Accepted: 03/01/2020] [Indexed: 01/15/2023]
Abstract
OBJECTIVE To know the potential role of IKKα (an NF-κB noncanonical pathway) in gastric precancerous lesion via mediating Maspin. METHODS Gastric cancer, precancerous lesion and control tissues (chronic non-atrophic gastritis) were collected for determining the expression of IKKα and Maspin by immunohistochemistry. Thereafter, gastric precancerous models were established and divided into the Control group, Model group and Model + shIKKα group. All rats were subjected to observe the pathological changes and ultramicro structure of the gastric mucosa by HE staining or electron microscope, and to measure the serum levels of inflammatory cytokines by ELISA, the expression of apoptosis-related proteins by immunohistochemistry, as well as the expression of IKKα and Maspin by quantitative real-time PCR and Western blotting. RESULTS Precancerous lesion and gastric cancer tissues manifested significant upregulation of IKKα positive expression, concomitant with downregulation of the positive expression of Maspin, and these changes were more evident in the gastric cancer tissues. In comparison with the Control group, rats in the Model group had significant increases in serum levels of TNF-α, IL-1β, IL-6 and COX-2, with up-regulations of Bcl-2, CyclinD1, IKKα and p-IKKα, and down-regulations of Bax, Caspase-3 and Maspin. shIKKα treatment attenuate inflammation and apoptosis in gastric precancerous lesion (GPL) rat, with the downregulation of IKKα and p-IKKα, and upregulation of Maspin. CONCLUSION Inhibiting IKKα, via upregulating Maspin, can mitigate the inflammation and promote cell apoptosis in precancerous rats, thereby delaying the development of the precancerous lesions.
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Affiliation(s)
- Ning Wang
- Department of Gastroenterology No.1 Ward, ShiJiaZhuang No. 1 Hospital, Shijiazhuang 050011, China
| | - Li-Li Chang
- Department of Gastroenterology No.1 Ward, ShiJiaZhuang No. 1 Hospital, Shijiazhuang 050011, China.
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44
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Deligiorgi MV, Panayiotidis MI, Griniatsos J, Trafalis DT. Harnessing the versatile role of OPG in bone oncology: counterbalancing RANKL and TRAIL signaling and beyond. Clin Exp Metastasis 2020; 37:13-30. [PMID: 31578655 DOI: 10.1007/s10585-019-09997-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Accepted: 09/24/2019] [Indexed: 12/15/2022]
Abstract
More than 2 decades ago, the discovery of osteoprotegerin (OPG) as inhibitor of the receptor of activator of nuclear factor Kb (RANK) ligand (RANKL) revolutionized our understanding of bone biology and oncology. Besides acting as decoy receptor for RANKL, OPG acts as decoy receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). OPG, RANKL, and TRAIL are ubiquitously expressed, stimulating per se pivotal signaling cascades implicated in cancer. In the context of cancer cell-bone cell interactions, cancer cells skew the OPG/RANKL/RANK (RANKL cognate receptor) balance towards bone destruction and tumor growth through favoring the RANKL/RANK interface, circumventing OPG. Numerous preclinical and clinical studies demonstrate the dual role of OPG in cancer: antitumor and tumor-promoting. OPG potentially conveys an antitumor signal through inhibiting the tumor-promoting RANKL signaling-both the osteoclast-dependent and the osteoclast-independent-and the tumor-promoting TRAIL signaling. On the other hand, the presumed tumor-promoting functions of OPG are: (i) abrogation of TRAIL-induced apoptosis of cancer cells; (ii) abrogation of RANKL-induced antitumor immunity; and (iii) stimulation of oncogenic and prometastatic signaling cascades downstream of the interaction of OPG with diverse proteins. The present review dissects the role of OPG in bone oncology. It presents the available preclinical and clinical data sustaining the dual role of OPG in cancer and focuses on the imbalanced RANKL/RANK/OPG interplay in the landmark "vicious cycle" of skeletal metastatic disease, osteosarcoma, and multiple myeloma. Finally, current challenges and future perspectives in exploiting OPG signaling in bone oncology therapeutics are discussed.
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Affiliation(s)
- Maria V Deligiorgi
- Clinical Pharmacology Unit, Laboratory of Pharmacology, Faculty of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias Str, Goudi, 11527, Athens, Greece.
| | - Mihalis I Panayiotidis
- Department of Applied Sciences, Northumbria University, Ellison Building, Room A516, Newcastle upon Tyne, NE1 8ST, UK
| | - John Griniatsos
- 1st Department of Surgery, Faculty of Medicine, National and Kapodistrian University of Athens, Laikon General Hospital, 17 Agiou Thoma Str, Goudi, 115-27, Athens, Greece
| | - Dimitrios T Trafalis
- Clinical Pharmacology Unit, Laboratory of Pharmacology, Faculty of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias Str, Goudi, 11527, Athens, Greece
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45
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Hu M, Yang J, Qu L, Deng X, Duan Z, Fu R, Liang L, Fan D. Ginsenoside Rk1 induces apoptosis and downregulates the expression of PD-L1 by targeting the NF-κB pathway in lung adenocarcinoma. Food Funct 2020; 11:456-471. [DOI: 10.1039/c9fo02166c] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Ginsenoside Rk1 can function as an antitumor modulator that induces apoptosis in lung adenocarcinoma cells by inhibiting NF-κB transcription and triggering cell cycle arrest.
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Affiliation(s)
- Manling Hu
- Shaanxi Key Laboratory of Degradable Biomedical Materials
- School of Chemical Engineering
- Northwest University
- Xi'an
- China
| | - Jing Yang
- Shaanxi Key Laboratory of Degradable Biomedical Materials
- School of Chemical Engineering
- Northwest University
- Xi'an
- China
| | - Linlin Qu
- Shaanxi Key Laboratory of Degradable Biomedical Materials
- School of Chemical Engineering
- Northwest University
- Xi'an
- China
| | - Xuqian Deng
- Shaanxi Key Laboratory of Degradable Biomedical Materials
- School of Chemical Engineering
- Northwest University
- Xi'an
- China
| | - Zhiguang Duan
- Shaanxi Key Laboratory of Degradable Biomedical Materials
- School of Chemical Engineering
- Northwest University
- Xi'an
- China
| | - Rongzhan Fu
- Shaanxi Key Laboratory of Degradable Biomedical Materials
- School of Chemical Engineering
- Northwest University
- Xi'an
- China
| | - Lihua Liang
- Shaanxi Key Laboratory of Degradable Biomedical Materials
- School of Chemical Engineering
- Northwest University
- Xi'an
- China
| | - Daidi Fan
- Shaanxi Key Laboratory of Degradable Biomedical Materials
- School of Chemical Engineering
- Northwest University
- Xi'an
- China
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46
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Giotopoulou GA, Stathopoulos GT. Effects of Inhaled Tobacco Smoke on the Pulmonary Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1225:53-69. [PMID: 32030647 DOI: 10.1007/978-3-030-35727-6_4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Tobacco smoke is a multicomponent mixture of chemical, organic, and inorganic compounds, as well as additive substances and radioactive materials. Many studies have proved the carcinogenicity of various of these compounds through the induction of DNA adducts, mutational potential, epigenetic changes, gene fusions, and chromosomal events. The tumor microenvironment plays an important role in malignant tumor formation and progression through the regulation of expression of key molecules which mediate the recruitment of immune cells to the tumor site and subsequently regulate tumor growth and metastasis. In this chapter, we discuss the effects of inhaled tobacco smoke in the tumor microenvironment of the respiratory tract. The mechanisms underlying these effects as well as their link with tumor progression are analyzed.
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Affiliation(s)
- Georgia A Giotopoulou
- Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), University Hospital, Ludwig-Maximilians University and Helmholtz Center Munich, Member of the German Center for Lung Research (DZL), Munich, Bavaria, Germany.
- Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras, Rio, Greece.
| | - Georgios T Stathopoulos
- Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), University Hospital, Ludwig-Maximilians University and Helmholtz Center Munich, Member of the German Center for Lung Research (DZL), Munich, Bavaria, Germany
- Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras, Rio, Greece
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Baxevanis CN, Fortis SP, Perez SA. The balance between breast cancer and the immune system: Challenges for prognosis and clinical benefit from immunotherapies. Semin Cancer Biol 2019; 72:76-89. [PMID: 31881337 DOI: 10.1016/j.semcancer.2019.12.018] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 12/16/2019] [Accepted: 12/17/2019] [Indexed: 02/06/2023]
Abstract
Cancer evolution is a complex process influenced by genetic factors and extracellular stimuli that trigger signaling pathways to coordinate the continuous and dynamic interaction between tumor cells and the elements of the immune system. For over 20 years now, the immune mechanisms controlling cancer progression have been the focus of intensive research. It is well established that the immune system conveys protective antitumor immunity by destroying immunogenic tumor variants, but also facilitates tumor progression by shaping tumor immunogenicity in a process called "immunoediting". It is also clear that immune-guided tumor editing is associated with tumor evasion from immune surveillance and therefore reinforcing the endogenous antitumor immunity is a desired goal in the context of cancer therapies. The tumor microenvironment (TME) is a complex network which consists of various cell types and factors having important roles regarding tumor development and progression. Tumor infiltrating lymphocytes (TILs) and other tumor infiltrating immune cells (TIICs) are key to our understanding of tumor immune surveillance based on tumor immunogenicity, whereby the densities and location of TILs and TIICs in the tumor regions, as well as their functional programs (comprising the "immunoscore") have a prominent role for prognosis and prediction for several cancers. The presence of tertiary lymphoid structures (TLS) in the TME or in peritumoral areas has an influence on the locally produced antitumor immune response, and therefore also has a significant prognostic impact. The cross-talk between elements of the immune system with tumor cells in the TME is greatly influenced by hypoxia, the gut and/or the local microbiota, and several metabolic elements, which, in a dynamic interplay, have a crucial role for tumor cell heterogeneity and reprogramming of immune cells along their activation and differentiation pathways. Taking into consideration the recent clinical success with the application immunotherapies for the treatment of several cancer types, increasing endeavors have been made to gain better insights into the mechanisms underlying phenotypic and metabolic profiles in the context of tumor progression and immunotherapy. In this review we will address (i) the role of TILs, TIICs and TLS in breast cancer (BCa); (ii) the different metabolic-based pathways used by immune and breast cancer cells; and (iii) implications for immunotherapy-based strategies in BCa.
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Affiliation(s)
- Constantin N Baxevanis
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras Ave., 11522, Athens, Greece.
| | - Sotirios P Fortis
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras Ave., 11522, Athens, Greece
| | - Sonia A Perez
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras Ave., 11522, Athens, Greece
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48
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Lv S, Wang F, Wang K, Fan Y, Xu J, Zheng J, Zeng Y. IκB kinase α: an independent prognostic factor that promotes the migration and invasion of oral squamous cell carcinoma. Br J Oral Maxillofac Surg 2019; 58:296-303. [PMID: 31859105 DOI: 10.1016/j.bjoms.2019.11.025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 11/27/2019] [Indexed: 02/07/2023]
Abstract
IκB kinase α (IKKα) is associated with tumourigenesis, metastasis, and poor prognosis. However, its expression and function in oral squamous cell carcinoma (SCC) remain unknown. The aim of this study was to elucidate the clinicopathological associations and functions of IKKα in oral squamous cell carcinoma (SCC). We made an immunohistochemical analysis of IKKα in 94 tissue microarrays of specimens of oral SCC. We also examined IKKα expression in the patients' samples by quantitative real-time polymerase chain reaction (qRT-PCR), as well as the migration, invasion, and matrix metalloproteinase (MMP) activity of the cells under IKKα knockdown treatment. In oral SCC, immunostaining for IKKα was found in 60 of the 94 patients, and it correlated with lymph node status and poor prognosis. Univariate and multivariate analysis using Cox's proportional hazards model identified that IKKα expression was an independent predictor of distant- disease-free survival (p<0.05) and overall survival in oral SCC (p<0.05). Knocking down IKKα suppressed cell migration and invasion in oral SCC cells. Our results indicate that IKKα has an important role in promoting oral SCC, and it may be a useful biomarker and therapeutic target for diagnosis and treatment.
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Affiliation(s)
- S Lv
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China; Department of Biochemistry, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - F Wang
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China; Department of Biochemistry, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - K Wang
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China; Department of Biochemistry, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Y Fan
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China; Department of Biochemistry, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - J Xu
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China; Department of Stomatology, The First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - J Zheng
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China; Department of Stomatology, The First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China.
| | - Y Zeng
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China; Department of Biochemistry, School of Medicine, Shihezi University, Shihezi, Xinjiang, China.
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49
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Chavdoula E, Habiel DM, Roupakia E, Markopoulos GS, Vasilaki E, Kokkalis A, Polyzos AP, Boleti H, Thanos D, Klinakis A, Kolettas E, Marcu KB. CHUK/IKK-α loss in lung epithelial cells enhances NSCLC growth associated with HIF up-regulation. Life Sci Alliance 2019; 2:2/6/e201900460. [PMID: 31792060 PMCID: PMC6892436 DOI: 10.26508/lsa.201900460] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 11/18/2019] [Accepted: 11/19/2019] [Indexed: 02/06/2023] Open
Abstract
IKKα is an NSCLC suppressor and its loss in mouse AT-II lung epithelial cells or in human NSCLC lines increased urethane-induced adenoma growth and xenograft burdens, respectively. IKKα loss can up-regulate HIF-1α, enhancing tumor growth under hypoxia. Through the progressive accumulation of genetic and epigenetic alterations in cellular physiology, non–small-cell lung cancer (NSCLC) evolves in distinct steps involving mutually exclusive oncogenic mutations in K-Ras or EGFR along with inactivating mutations in the p53 tumor suppressor. Herein, we show two independent in vivo lung cancer models in which CHUK/IKK-α acts as a major NSCLC tumor suppressor. In a novel transgenic mouse strain, wherein IKKα ablation is induced by tamoxifen (Tmx) solely in alveolar type II (AT-II) lung epithelial cells, IKKα loss increases the number and size of lung adenomas in response to the chemical carcinogen urethane, whereas IKK-β instead acts as a tumor promoter in this same context. IKKα knockdown in three independent human NSCLC lines (independent of K-Ras or p53 status) enhances their growth as tumor xenografts in immune-compromised mice. Bioinformatics analysis of whole transcriptome profiling followed by quantitative protein and targeted gene expression validation experiments reveals that IKKα loss can result in the up-regulation of activated HIF-1-α protein to enhance NSCLC tumor growth under hypoxic conditions in vivo.
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Affiliation(s)
- Evangelia Chavdoula
- Biomedical Research Foundation Academy of Athens, Athens, Greece.,Laboratory of Biology, School of Medicine, Faculty of Health Sciences, University of Ioannina, University Campus, Ioannina, Greece.,Biomedical Research Division, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Ioannina, Greece
| | | | - Eugenia Roupakia
- Laboratory of Biology, School of Medicine, Faculty of Health Sciences, University of Ioannina, University Campus, Ioannina, Greece.,Biomedical Research Division, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Ioannina, Greece
| | - Georgios S Markopoulos
- Laboratory of Biology, School of Medicine, Faculty of Health Sciences, University of Ioannina, University Campus, Ioannina, Greece.,Biomedical Research Division, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Ioannina, Greece
| | - Eleni Vasilaki
- Biomedical Research Foundation Academy of Athens, Athens, Greece
| | - Antonis Kokkalis
- Biomedical Research Foundation Academy of Athens, Athens, Greece
| | | | - Haralabia Boleti
- Intracellular Parasitism Laboratory, Department of Microbiology and Light Microscopy Unit, Hellenic Pasteur Institute, Athens, Greece
| | - Dimitris Thanos
- Biomedical Research Foundation Academy of Athens, Athens, Greece
| | | | - Evangelos Kolettas
- Laboratory of Biology, School of Medicine, Faculty of Health Sciences, University of Ioannina, University Campus, Ioannina, Greece .,Biomedical Research Division, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Ioannina, Greece
| | - Kenneth B Marcu
- Biomedical Research Foundation Academy of Athens, Athens, Greece .,Laboratory of Biology, School of Medicine, Faculty of Health Sciences, University of Ioannina, University Campus, Ioannina, Greece.,Biomedical Research Division, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Ioannina, Greece.,Departments of Biochemistry and Cell Biology and Pathology, Stony Brook University, Stony Brook, NY, USA.,Department of Biological Sciences, San Diego State University, San Diego, CA, USA
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50
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Zhong S, Jeong JH, Chen Z, Chen Z, Luo JL. Targeting Tumor Microenvironment by Small-Molecule Inhibitors. Transl Oncol 2019; 13:57-69. [PMID: 31785429 PMCID: PMC6909103 DOI: 10.1016/j.tranon.2019.10.001] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 10/01/2019] [Accepted: 10/03/2019] [Indexed: 12/12/2022] Open
Abstract
The tumor microenvironment (TME) is a hypoxic, acidic, and immune/inflammatory cell–enriched milieu that plays crucial roles in tumor development, growth, progression, and therapy resistance. Targeting TME is an attractive strategy for the treatment of solid tumors. Conventional cancer chemotherapies are mostly designed to directly kill cancer cells, and the effectiveness is always compromised by their penetration and accessibility to cancer cells. Small-molecule inhibitors, which exhibit good penetration and accessibility, are widely studied, and many of them have been successfully applied in clinics for cancer treatment. As TME is more penetrable and accessible than tumor cells, a lot of efforts have recently been made to generate small-molecule inhibitors that specifically target TME or the components of TME or develop special drug-delivery systems that release the cytotoxic drugs specifically in TME. In this review, we briefly summarize the recent advances of small-molecule inhibitors that target TME for the tumor treatment.
Tumor microenvironment (TME) is an indispensable part of tumor and is an important therapeutic target. TME is more penetrable and accessible than tumor cell area. Small-molecule inhibitors that target TME are very promising. The target efficiency can be improved by specific deliver and release systems.
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Affiliation(s)
- Shangwei Zhong
- The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Xiangya Hospital, Central South University, Hunan, 410008, China; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Ji-Hak Jeong
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Zhikang Chen
- The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Xiangya Hospital, Central South University, Hunan, 410008, China.
| | - Zihua Chen
- The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Xiangya Hospital, Central South University, Hunan, 410008, China.
| | - Jun-Li Luo
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, USA.
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