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Peng X, Feng J, Yang H, Xia P, Pu F. Nrf2: A key regulator in chemoradiotherapy resistance of osteosarcoma. Genes Dis 2025; 12:101335. [PMID: 40242036 PMCID: PMC12000747 DOI: 10.1016/j.gendis.2024.101335] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 01/24/2024] [Accepted: 04/03/2024] [Indexed: 04/18/2025] Open
Abstract
Osteosarcoma (OS), frequently observed in children and adolescents, is one of the most common primary malignant tumors of the bone known to be associated with a high capacity for invasion and metastasis. The incidence of osteosarcoma in children and adolescents is growing annually, although improvements in survival remain limited. With the clinical application of neoadjuvant chemotherapy, chemotherapy combined with limb-preserving surgery has gained momentum as a major intervention. However, certain patients with OS experience treatment failure owing to chemoradiotherapy resistance or metastasis. Nuclear factor E2-related factor 2 (Nrf2), a key antioxidant factor in organisms, plays a crucial role in maintaining cellular physiological homeostasis; however, its overactivation in cancer cells restricts reactive oxygen species production, promotes DNA repair and drug efflux, and ultimately leads to chemoradiotherapy resistance. Recent studies have also identified the functions of Nrf2 beyond its antioxidative function, including the promotion of proliferation, metastasis, and regulation of metabolism. The current review describes the multiple mechanisms of chemoradiotherapy resistance in OS and the substantial role of Nrf2 in the signaling regulatory network to elucidate the function of Nrf2 in promoting OS chemoradiotherapy resistance and formulating relevant therapeutic strategies.
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Affiliation(s)
- Xianglin Peng
- Department of Orthopedics, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Department of Orthopedics, Wuhan No.1 Hospital, Wuhan 430022, China
| | - Jing Feng
- Department of Orthopedics, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Department of Orthopedics, Wuhan No.1 Hospital, Wuhan 430022, China
| | - Han Yang
- Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Ping Xia
- Department of Orthopedics, Wuhan Fourth Hospital, Wuhan 430030, China
| | - Feifei Pu
- Department of Orthopedics, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Department of Orthopedics, Wuhan No.1 Hospital, Wuhan 430022, China
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Wu IT, Chang YT, Su CH, Lan YH, Hung CC. Novel dihydrochalcone from Fissistigma latifolium targets STAT3 and survivin to overcome multidrug resistance cancers in vitro and in vivo. Biomed Pharmacother 2025; 187:118125. [PMID: 40327991 DOI: 10.1016/j.biopha.2025.118125] [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: 01/23/2025] [Revised: 04/28/2025] [Accepted: 04/30/2025] [Indexed: 05/08/2025] Open
Abstract
BACKGROUND Multidrug resistance (MDR) remains a significant challenge in cancer chemotherapy, with no FDA-approved drugs currently available for its treatment. Natural chalcones, known for their diverse bioactivities, have emerged as potential therapeutic candidates. PURPOSE This study aimed to investigate the potential of 4,6-dimethoxy-2,5-quinodihydrochalcone (DODHC), a compound derived from Fissistigma latifolium, in overcoming MDR in cancer and to elucidate its underlying molecular mechanisms. METHODS The reversal effects of DODHC on MDR were evaluated using cytotoxicity assays. The molecular mechanisms were explored through apoptosis- and cell cycle-related assays, STAT3 ELISA, western blotting, docking simulations, and a zebrafish model. The impact of DODHC on P-glycoprotein (P-gp) activity was assessed using the Calcein-AM uptake assay. RESULTS DODHC promoted apoptosis in MDR cancer cells by suppressing survivin expression and activating the extrinsic apoptotic pathway. It also induced G2/M phase cell cycle arrest by downregulating cell division control protein 2 (CDC2) and cyclin B1 (CCNB1), thereby inhibiting cell proliferation. Additionally, DODHC reduced both total and phosphorylated STAT3 levels in MDR cancer cells without affecting P-gp activity. In vivo, DODHC significantly inhibited tumor growth in MDR cancer models, both as a monotherapy and in combination with paclitaxel. CONCLUSION This study highlights DODHC as a dual inhibitor of STAT3 and survivin, demonstrating its potential as a promising candidate for the treatment of MDR cancers.
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Affiliation(s)
- I-Ting Wu
- Department of Pharmacy, China Medical University, No. 100, Section 1, Jingmao Rd., Beitun Dist., Taichung 406040, Taiwan
| | - Ying-Tzu Chang
- Department of Pharmacy, China Medical University, No. 100, Section 1, Jingmao Rd., Beitun Dist., Taichung 406040, Taiwan
| | - Ching-Hui Su
- Department of Pharmacy, China Medical University, No. 100, Section 1, Jingmao Rd., Beitun Dist., Taichung 406040, Taiwan
| | - Yu-Hsuan Lan
- Department of Pharmacy, China Medical University, No. 100, Section 1, Jingmao Rd., Beitun Dist., Taichung 406040, Taiwan.
| | - Chin-Chuan Hung
- Department of Pharmacy, China Medical University, No. 100, Section 1, Jingmao Rd., Beitun Dist., Taichung 406040, Taiwan; Department of Pharmacy, China Medical University Hospital, No. 2, Yude Rd., North Dist., Taichung 404332, Taiwan; Department of Healthcare Administration, Asia University, 500, Lioufeng Rd., Wufeng, Taichung 41354, Taiwan.
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Luo YY, Ba XY, Wang L, Zhang YP, Xu H, Chen PQ, Zhang LB, Han J, Luo H. LEF1 influences diabetic retinopathy and retinal pigment epithelial cell ferroptosis via the miR-495-3p/GRP78 axis through lnc-MGC. World J Diabetes 2025; 16:92003. [PMID: 40093269 PMCID: PMC11885969 DOI: 10.4239/wjd.v16.i3.92003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 11/10/2024] [Accepted: 12/11/2024] [Indexed: 01/21/2025] Open
Abstract
BACKGROUND Diabetic retinopathy (DR) is one of the major eye diseases contributing to blindness worldwide. Endoplasmic reticulum (ER) stress in retinal cells is a key factor leading to retinal inflammation and vascular leakage in DR, but its mechanism is still unclear. AIM To investigate the potential mechanism of LEF1 and related RNAs in DR. METHODS ARPE-19 cells were exposed to high levels of glucose for 24 hours to simulate a diabetic environment. Intraperitoneally injected streptozotocin was used to induce the rat model of DR. The expression levels of genes and related proteins were measured by RT-qPCR and Western blotting; lnc-MGC and miR-495-3p were detected by fluorescent in situ hybridization; CCK-8 and TUNEL assays were used to detect cell viability and apoptosis; enzyme-linked immunosorbent assay was used to detect inflammatory factors; dual-luciferase gene assays were used to verify the targeting relationship; and the retina was observed by HE staining. RESULTS LEF1 and lnc-MGC have binding sites, and lnc-MGC can regulate the miR-495-3p/GRP78 molecular axis. In high glucose-treated cells, inflammation was aggravated, the intracellular reactive oxygen species concentration was increased, cell viability was reduced, apoptosis was increased, the ER response was intensified, and ferroptosis was increased. As an ER molecular chaperone, GRP78 regulates the ER and ferroptosis under the targeting of miR-495-3p, whereas inhibiting LEF1 can further downregulate the expression of lnc-MGC, increase the level of miR-495-3p, and sequentially regulate the level of GRP78 to alleviate the occurrence and development of DR. Animal experiments indicated that the knockdown of LEF1 can affect the lnc-MGC/miR-495-3p/GRP78 signaling axis to restrain the progression of DR. CONCLUSION LEF1 knockdown can regulate the miR-495-3p/GRP78 molecular axis through lnc-MGC, which affects ER stress and restrains the progression of DR and ferroptosis in retinal pigment epithelial cells.
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Affiliation(s)
- Yi-Yi Luo
- Precision Medicine Center of Chuxiong Yi Autonomous Prefecture, The People's Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of DaLi University, Chuxiong 675000, Yunnan Province, China
| | - Xue-Ying Ba
- Precision Medicine Center of Chuxiong Yi Autonomous Prefecture, The People's Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of DaLi University, Chuxiong 675000, Yunnan Province, China
| | - Ling Wang
- Department of Endocrinology, The People's Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of DaLi University, Chuxiong 675000, Yunnan Province, China
| | - Ye-Pin Zhang
- Department of Pathology, The People's Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of DaLi University, Chuxiong 675000, Yunnan Province, China
| | - Hong Xu
- Department of Ophthalmology, The People's Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of DaLi University, Chuxiong 675000, Yunnan Province, China
| | - Pei-Qi Chen
- Department of Endocrinology, The People's Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of DaLi University, Chuxiong 675000, Yunnan Province, China
| | - Li-Bo Zhang
- Department of Ophthalmology, The People's Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of DaLi University, Chuxiong 675000, Yunnan Province, China
| | - Jian Han
- Precision Medicine Center of Chuxiong Yi Autonomous Prefecture, The People's Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of DaLi University, Chuxiong 675000, Yunnan Province, China
| | - Heng Luo
- Precision Medicine Center of Chuxiong Yi Autonomous Prefecture, The People's Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of DaLi University, Chuxiong 675000, Yunnan Province, China
- Department of Ophthalmology, The People's Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of DaLi University, Chuxiong 675000, Yunnan Province, China
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Mohammadi F, Nejatollahi M, Sheikhnia F, Ebrahimi Y, Mohammadi M, Rashidi V, Alizadeh-Fanalou S, Azizzadeh B, Majidinia M. MiRNAs: main players of cancer drug resistance target ABC transporters. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-024-03719-y. [PMID: 39808313 DOI: 10.1007/s00210-024-03719-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 12/08/2024] [Indexed: 01/16/2025]
Abstract
Chemotherapy remains the cornerstone of cancer treatment; however, its efficacy is frequently compromised by the development of chemoresistance. Multidrug resistance (MDR), characterized by the refractoriness of cancer cells to a wide array of chemotherapeutic agents, presents a significant barrier to achieving successful and sustained cancer remission. One critical factor contributing to this chemoresistance is the overexpression of ATP-binding cassette (ABC) transporters. Furthermore, additional mechanisms, such as the malfunctioning of apoptosis, alterations in DNA repair systems, and resistance mechanisms inherent to cancer stem cells, exacerbate the issue. Intriguingly, microRNAs (miRNAs) have demonstrated potential in modulating chemoresistance by specifically targeting ABC transporters, thereby offering promising new avenues for overcoming drug resistance. This narrative review aims to elucidate the molecular underpinnings of drug resistance, with a particular focus on the roles of ABC transporters and the regulatory influence of miRNAs on these transporters.
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Affiliation(s)
- Forogh Mohammadi
- Department of Veterinary, Agriculture Faculty, Kermanshah Branch, Islamic Azad University, Kermanshah, Iran
| | - Masoumeh Nejatollahi
- Research Center for High School Students, Education System Zanjan Province, Zanjan, Iran
| | - Farhad Sheikhnia
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Yaser Ebrahimi
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Mahya Mohammadi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Rashidi
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Shahin Alizadeh-Fanalou
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Bita Azizzadeh
- Department of Biochemistry, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
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Lu XY, Jin H. MiRNAs function in the development of resistance against doxorubicin in cancer cells: targeting ABC transporters. Front Pharmacol 2024; 15:1486783. [PMID: 39679367 PMCID: PMC11638538 DOI: 10.3389/fphar.2024.1486783] [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: 08/26/2024] [Accepted: 10/23/2024] [Indexed: 12/17/2024] Open
Abstract
Resistance to chemotherapeutic agents poses a significant challenge in cancer treatment, particularly with doxorubicin, a widely used drug for various cancers, including breast cancer, leukaemia, osteosarcoma, and gastrointestinal cancers. This review aims to elucidate the critical role of microRNAs (miRNAs) in the development of doxorubicin resistance, focusing on their interactions with ATP-binding cassette (ABC) transporters. Despite extensive research, the molecular mechanisms governing doxorubicin resistance still need to be completed, particularly regarding the regulatory influence of miRNAs on ABC transporter expression. By analyzing current literature, this review identifies a notable gap: the lack of comprehensive insight into how specific miRNAs modulate the expression and activity of ABC transporters in cancer cells, contributing to doxorubicin resistance. We systematically examine recent findings on the interplay between miRNAs and ABC transporters, providing a detailed assessment of potential therapeutic strategies that leverage miRNA modulation to overcome drug resistance. Ultimately, this review underscores the significance of integrating miRNA research into existing therapeutic frameworks to enhance the efficacy of doxorubicin in cancer treatment.
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Affiliation(s)
- Xin-Yan Lu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Hongxu Jin
- Emergency Medicine Department of General Hospital of Northern Theater Command, Shenyang, Liaoning, China
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Chaiyawat P, Sangkhathat S, Chiangjong W, Wongtrakoongate P, Hongeng S, Pruksakorn D, Chutipongtanate S. Targeting pediatric solid tumors in the new era of RNA therapeutics. Crit Rev Oncol Hematol 2024; 200:104406. [PMID: 38834094 DOI: 10.1016/j.critrevonc.2024.104406] [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: 07/31/2023] [Revised: 04/26/2024] [Accepted: 05/29/2024] [Indexed: 06/06/2024] Open
Abstract
Despite substantial progress in pediatric cancer treatment, poor prognosis remained for patients with recurrent or metastatic disease, given the limitations of approved targeted treatments and immunotherapies. RNA therapeutics offer significant potential for addressing a broad spectrum of diseases, including cancer. Advances in manufacturing and delivery systems are paving the way for the rapid development of therapeutic RNAs for clinical applications. This review summarizes therapeutic RNA classifications and the mechanisms of action, highlighting their potential in manipulating major cancer-related pathways and biological effects. We also focus on the pre-clinical investigation of RNA molecules with efficient delivery systems for their therapeutic potential targeting pediatric solid tumors.
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Affiliation(s)
- Parunya Chaiyawat
- Musculoskeletal Science and Translational Research Center, Department of Orthopedics, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Extracellular Vesicle Working Group, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Surasak Sangkhathat
- Department of Biomedical Science, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand; Department of Surgery, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand; Extracellular Vesicle Working Group, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Wararat Chiangjong
- Pediatric Translational Research Unit, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; Extracellular Vesicle Working Group, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Patompon Wongtrakoongate
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; Extracellular Vesicle Working Group, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Suradej Hongeng
- Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Ra-mathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; Extracellular Vesicle Working Group, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Dumnoensun Pruksakorn
- Musculoskeletal Science and Translational Research Center, Department of Orthopedics, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Extracellular Vesicle Working Group, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
| | - Somchai Chutipongtanate
- Pediatric Translational Research Unit, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Ra-mathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; MILCH and Novel Therapeutics Lab, Division of Epidemiology, Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Extracellular Vesicle Working Group, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
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7
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Yan C, Dou Y, Xia R, Liu S, Fu J, Li D, Wang R, Tie F, Li L, Jin H, An F. Research progress on the role of lncRNA, circular RNA, and microRNA networks in regulating ferroptosis in osteosarcoma. Biomed Pharmacother 2024; 176:116924. [PMID: 38876052 DOI: 10.1016/j.biopha.2024.116924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 06/07/2024] [Accepted: 06/09/2024] [Indexed: 06/16/2024] Open
Abstract
Noncoding RNAs (ncRNAs) do not participate in protein-coding. Ferroptosis is a newly discovered form of cell death mediated by reactive oxygen species and lipid peroxidation. Recent studies have shown that ncRNAs such as microRNAs, long noncoding RNAs, circular RNAs, and ferroptosis are involved in the occurrence and development of osteosarcoma (OS). Studies have confirmed that ncRNAs participate in the development of OS by regulating the ferroptosis. However, systematic summary on this topic are still lacking. This review summarises the potential role of ncRNAs in the diagnosis, treatment, drug resistance, and prognosis of OS and the basis for diagnosing, preventing, and treating clinical OS and developing effective drugs. This review summarises the latest research progress on ncRNAs that regulate ferroptosis in OS, attempts to clarify the molecular mechanisms by which ncRNAs regulate ferroptosis in the pathogenesis of OS, and elaborates on the involvement of ferroptosis in OS from the perspective of ncRNAs.
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Affiliation(s)
- Chunlu Yan
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu 730000, China
| | - Yinnan Dou
- The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu 730000, China
| | - Ruoliu Xia
- The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu 730000, China
| | - Shiqing Liu
- The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu 730000, China
| | - Jianchao Fu
- The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu 730000, China
| | - Duo Li
- The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu 730000, China
| | - Rong Wang
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu 730000, China
| | - Feng Tie
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu 730000, China
| | - Linxin Li
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu 730000, China
| | - Hua Jin
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu 730000, China.
| | - Fangyu An
- Teaching Experiment Training Center, Gansu University of Chinese Medicine, Lanzhou, Gansu 730000, China.
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Wu B, Li P, Qiu E, Chen J. Metformin alleviates adriamycin resistance of osteosarcoma by declining YY1 to inhibit MDR1 transcriptional activity. BMC Pharmacol Toxicol 2023; 24:50. [PMID: 37828612 PMCID: PMC10571298 DOI: 10.1186/s40360-023-00685-8] [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: 11/28/2022] [Accepted: 09/02/2023] [Indexed: 10/14/2023] Open
Abstract
Chemotherapy resistance hinders the successful treatment of osteosarcoma (OS) to some extent. Previous studies have confirmed that metformin (Met) enhances apoptosis induced by chemotherapeutic drugs, but the underlying mechanism remains unclear. To establish adriamycin (ADM)-resistant MG-63 (MG-63/ADM) cells, the dosage of ADM was progressively increased. The results of qRT-PCR and Western blotting demonstrated that the expression level of Yin Yang 1 (YY1) and multi-drug resistance-1 (MDR1) in MG-63/ADM cells were remarkably increased compared with those in MG-63 cells. Met dramatically enhanced ADM cytotoxicity and accelerated apoptosis of MG-63/ADM cells. Moreover, Met suppressed the expressions of YY1 and MDR1 in MG-63/ADM cells. YY1 promoted its transcriptional expression by directly binding to the MDR1 promoter. Furthermore, the effects of Met on ADM sensitivity in MG-63/ADM cells was reversed due to overexpression of YY1 or MDR1. Collectively, these findings suggested that Met inhibited YY1/MDR1 pathway to reverse ADM resistance in OS, providing a new insight into the mechanism of Met in ADM resistance of OS.
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Affiliation(s)
- Bowen Wu
- Department of Orthopedics, Zhuzhou central hospital, 116 Changjiangnan Road, Tianyuan District, Zhuzhou, 412007, Hunan, China.
| | - Peng Li
- Department of Orthopedics, Zhuzhou central hospital, 116 Changjiangnan Road, Tianyuan District, Zhuzhou, 412007, Hunan, China
| | - Eryue Qiu
- Trauma center, Zhuzhou central hospital, Zhuzhou, 412007, Hunan, China
| | - Jian Chen
- Department of Orthopedics, Zhuzhou central hospital, 116 Changjiangnan Road, Tianyuan District, Zhuzhou, 412007, Hunan, China
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Li G, Zhang H, Lai H, Liang G, Huang J, Zhao F, Xie X, Peng C. Erianin: A phytoestrogen with therapeutic potential. Front Pharmacol 2023; 14:1197056. [PMID: 37608888 PMCID: PMC10440559 DOI: 10.3389/fphar.2023.1197056] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 07/03/2023] [Indexed: 08/24/2023] Open
Abstract
Erianin, a phytoestrogen with therapeutic potential, is one of the major active components of Dendrobll caulis. Erianin has a variety of pharmacological effects, such as anti-tumor, anti-inflammatory, anti-diabetic retinopathy, anti-psoriasis, and antibacterial effects. Especially, in regard to the anti-tumor effect of erianin, the underlying molecular mechanism has been partly clarified. In fact, the numerous pharmacological actions of erianin are complex and interrelated, mainly including ERK1/2, PI3K/Akt, JAK2/STAT3, HIF-1α/PD-L1, PPT1/mTOR, JNK/c-Jun, and p38 MAPK signal pathway. However, on account of the poor water solubility and the low bioavailability of erianin, greatly affected and limited its further development and application. And it is worthwhile and meaningful to explore more extensive pharmacological effects and mechanisms, clarify pharmacokinetics, and synthesize the derivatives of erianin. Conclusively, in this paper, the pharmacological effects of erianin and its mechanism, pharmacokinetics, and derivatives studies were reviewed, in order to provide a reference for the development and application of erianin.
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Affiliation(s)
- Gangmin Li
- Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Huiqiong Zhang
- Safety Evaluation Center, Sichuan Institute for Drug Control (Sichuan Testing Center of Medical Devices), Chengdu, China
| | - Hui Lai
- Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Gang Liang
- Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Jiang Huang
- Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Fulan Zhao
- Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Xiaofang Xie
- State Key Laboratory of Traditional Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cheng Peng
- State Key Laboratory of Traditional Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Doghish AS, Hegazy M, Ismail A, El-Mahdy HA, Elsakka EGE, Elkhawaga SY, Elkady MA, Yehia AM, Abdelmaksoud NM, Mokhtar MM. A spotlight on the interplay of signaling pathways and the role of miRNAs in osteosarcoma pathogenesis and therapeutic resistance. Pathol Res Pract 2023; 245:154442. [PMID: 37031532 DOI: 10.1016/j.prp.2023.154442] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/02/2023] [Accepted: 04/03/2023] [Indexed: 04/11/2023]
Abstract
Osteosarcoma (OS) is one of the most common bone cancers that constantly affects children, teenagers, and young adults. Numerous epigenetic elements, such as miRNAs, have been shown to influence OS features like progression, initiation, angiogenesis, and treatment resistance. The expression of numerous genes implicated in OS pathogenesis might be regulated by miRNAs. This effect is ascribed to miRNAs' roles in the invasion, angiogenesis, metastasis, proliferation, cell cycle, and apoptosis. Important OS-related mechanistic networks like the WNT/b-catenin signaling, PTEN/AKT/mTOR axis, and KRAS mutations are also affected by miRNAs. In addition to pathophysiology, miRNAs may influence how the OS reacts to therapies like radiotherapy and chemotherapy. With a focus on how miRNAs affect OS signaling pathways, this review seeks to show how miRNAs and OS are related.
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Affiliation(s)
- Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
| | - Maghawry Hegazy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Ahmed Ismail
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Hesham A El-Mahdy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
| | - Elsayed G E Elsakka
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Samy Y Elkhawaga
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Mohamed A Elkady
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Amr Mohamed Yehia
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Nourhan M Abdelmaksoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mahmoud Mohamed Mokhtar
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
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11
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Tippett VL, Tattersall L, Ab Latif NB, Shah KM, Lawson MA, Gartland A. The strategy and clinical relevance of in vitro models of MAP resistance in osteosarcoma: a systematic review. Oncogene 2023; 42:259-277. [PMID: 36434179 PMCID: PMC9859755 DOI: 10.1038/s41388-022-02529-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 10/21/2022] [Accepted: 10/26/2022] [Indexed: 11/27/2022]
Abstract
Over the last 40 years osteosarcoma (OS) survival has stagnated with patients commonly resistant to neoadjuvant MAP chemotherapy involving high dose methotrexate, adriamycin (doxorubicin) and platinum (cisplatin). Due to the rarity of OS, the generation of relevant cell models as tools for drug discovery is paramount to tackling this issue. Four literature databases were systematically searched using pre-determined search terms to identify MAP resistant OS cell lines and patients. Drug exposure strategies used to develop cell models of resistance and the impact of these on the differential expression of resistance associated genes, proteins and non-coding RNAs are reported. A comparison to clinical studies in relation to chemotherapy response, relapse and metastasis was then made. The search retrieved 1891 papers of which 52 were relevant. Commonly, cell lines were derived from Caucasian patients with epithelial or fibroblastic subtypes. The strategy for model development varied with most opting for continuous over pulsed chemotherapy exposure. A diverse resistance level was observed between models (2.2-338 fold) with 63% of models exceeding clinically reported resistance levels which may affect the expression of chemoresistance factors. In vitro p-glycoprotein overexpression is a key resistance mechanism; however, from the available literature to date this does not translate to innate resistance in patients. The selection of models with a lower fold resistance may better reflect the clinical situation. A comparison of standardised strategies in models and variants should be performed to determine their impact on resistance markers. Clinical studies are required to determine the impact of resistance markers identified in vitro in poor responders to MAP treatment, specifically with respect to innate and acquired resistance. A shift from seeking disputed and undruggable mechanisms to clinically relevant resistance mechanisms may identify key resistance markers that can be targeted for patient benefit after a 40-year wait.
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Affiliation(s)
- Victoria L Tippett
- The Mellanby Centre for Musculoskeletal Research, Department of Oncology and Metabolism, The University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK
| | - Luke Tattersall
- The Mellanby Centre for Musculoskeletal Research, Department of Oncology and Metabolism, The University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK
| | - Norain B Ab Latif
- The Mellanby Centre for Musculoskeletal Research, Department of Oncology and Metabolism, The University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK
- Universiti Kuala Lumpur Royal College of Medicine Perak, No. 3 Jalan Greentown, 30450, Ipoh, Perak, Malaysia
| | - Karan M Shah
- The Mellanby Centre for Musculoskeletal Research, Department of Oncology and Metabolism, The University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK
| | - Michelle A Lawson
- The Mellanby Centre for Musculoskeletal Research, Department of Oncology and Metabolism, The University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK
| | - Alison Gartland
- The Mellanby Centre for Musculoskeletal Research, Department of Oncology and Metabolism, The University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK.
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12
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Zhang L, Ye B, Chen Z, Chen ZS. Progress in the studies on the molecular mechanisms associated with multidrug resistance in cancers. Acta Pharm Sin B 2022; 13:982-997. [PMID: 36970215 PMCID: PMC10031261 DOI: 10.1016/j.apsb.2022.10.002] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/28/2022] [Accepted: 08/18/2022] [Indexed: 11/01/2022] Open
Abstract
Chemotherapy is one of the important methods to treat cancer, and the emergence of multidrug resistance (MDR) is one major cause for the failure of cancer chemotherapy. Almost all anti-tumor drugs develop drug resistance over a period of time of application in cancer patients, reducing their effects on killing cancer cells. Chemoresistance can lead to a rapid recurrence of cancers and ultimately patient death. MDR may be induced by multiple mechanisms, which are associated with a complex process of multiple genes, factors, pathways, and multiple steps, and today the MDR-associated mechanisms are largely unknown. In this paper, from the aspects of protein-protein interactions, alternative splicing (AS) in pre-mRNA, non-coding RNA (ncRNA) mediation, genome mutations, variance in cell functions, and influence from the tumor microenvironment, we summarize the molecular mechanisms associated with MDR in cancers. In the end, prospects for the exploration of antitumor drugs that can reverse MDR are briefly discussed from the angle of drug systems with improved targeting properties, biocompatibility, availability, and other advantages.
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13
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Dong Y, Yu C, Ma N, Xu X, Wu Q, Lu H, Gong L, Chen J, Ren J. MicroRNA-379-5p regulates free cholesterol accumulation and relieves diet induced-liver damage in db/db mice via STAT1/HMGCS1 axis. MOLECULAR BIOMEDICINE 2022; 3:25. [PMID: 35945406 PMCID: PMC9363541 DOI: 10.1186/s43556-022-00089-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 06/28/2022] [Indexed: 11/30/2022] Open
Abstract
Lipotoxicity induced by the overload of lipid in the liver, especially excess free cholesterol (FC), has been recognized as one of driving factors in the transition from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH). MicroRNA (miR)-379-5p has been reported to play regulatory roles in hepatic triglyceride homeostasis, but the relationship of miR-379-5p and hepatic cholesterol homeostasis has never been touched. In the current study, we found that hepatic miR-379-5p levels were decreased obviously in NAFLD patients and model mice compared with their controls. Moreover, miR-379-5p was discovered to be able to inhibit intracellular FC accumulation and alleviate mitochondrial damage induced by palmitic acid (PA) in vitro. Furthermore, overexpression of miR-379-5p in HFHC-fed db/db mice could reduce the level of hepatic total cholesterol (TC) and FC, and ameliorate hepatic injury reflected by the lower serum alanine aminotransferase (ALT) and aspartate transaminase (AST). Subsequently, by combining spectrometry (MS) and luciferase assay, we identified miR-379-5p suppressed STAT1 through transcriptional and translational regulation. Finally, we confirmed that STAT1 was a transcriptional factor of HMGCS1. In conclusion, miR-379-5p inhibits STAT1 expression and regulates cholesterol metabolism through the STAT1/HMGCS1 axis, suggesting miR-379-5p might be applied to improve lipotoxicity in the future.
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14
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Vaghari-Tabari M, Hassanpour P, Sadeghsoltani F, Malakoti F, Alemi F, Qujeq D, Asemi Z, Yousefi B. CRISPR/Cas9 gene editing: a new approach for overcoming drug resistance in cancer. Cell Mol Biol Lett 2022; 27:49. [PMID: 35715750 PMCID: PMC9204876 DOI: 10.1186/s11658-022-00348-2] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 05/24/2022] [Indexed: 12/18/2022] Open
Abstract
The CRISPR/Cas9 system is an RNA-based adaptive immune system in bacteria and archaea. Various studies have shown that it is possible to target a wide range of human genes and treat some human diseases, including cancers, by the CRISPR/Cas9 system. In fact, CRISPR/Cas9 gene editing is one of the most efficient genome manipulation techniques. Studies have shown that CRISPR/Cas9 technology, in addition to having the potential to be used as a new therapeutic approach in the treatment of cancers, can also be used to enhance the effectiveness of existing treatments. Undoubtedly, the issue of drug resistance is one of the main obstacles in the treatment of cancers. Cancer cells resist anticancer drugs by a variety of mechanisms, such as enhancing anticancer drugs efflux, enhancing DNA repair, enhancing stemness, and attenuating apoptosis. Mutations in some proteins of different cellular signaling pathways are associated with these events and drug resistance. Recent studies have shown that the CRISPR/Cas9 technique can be used to target important genes involved in these mechanisms, thereby increasing the effectiveness of anticancer drugs. In this review article, studies related to the applications of this technique in overcoming drug resistance in cancer cells will be reviewed. In addition, we will give a brief overview of the limitations of the CRISP/Cas9 gene-editing technique.
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Affiliation(s)
- Mostafa Vaghari-Tabari
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parisa Hassanpour
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Sadeghsoltani
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Faezeh Malakoti
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Forough Alemi
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran.
| | - Bahman Yousefi
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. .,Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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15
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MicroRNAs and osteosarcoma: Potential targets for inhibiting metastasis and increasing chemosensitivity. Biochem Pharmacol 2022; 201:115094. [PMID: 35588853 DOI: 10.1016/j.bcp.2022.115094] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 05/10/2022] [Accepted: 05/11/2022] [Indexed: 12/12/2022]
Abstract
Osteosarcoma (OS) is the third most common cancer in young adults after lymphoma and brain cancer. Metastasis, like other cellular events, is dependent on signaling pathways; a series of changes in some proteins and signaling pathways pave the way for OS cells to invade and migrate. Ezrin, TGF-β, Notch, RUNX2, matrix metalloproteinases (MMPs), Wnt/β-catenin, and phosphoinositide 3-kinase (PI3K)/AKT are among the most important of these proteins and signaling pathways. Despite the improvements in treating OS, the overall survival of patients suffering from the metastatic disease has not experienced any significant change after surgical treatments and chemotherapy and 5-years overall survival in patients with metastatic OS is about 20%. Studies have shown that overexpression or inhibition of some microRNAs (miRNAs) has significant effects in limiting the invasion and migration of OS cells. The results of these studies highlight the potential of the clinical application of some miRNA mimics and miRNA inhibitors (antagomiRs) to inhibit OS metastasis in the future. In addition, some studies have shown that miRNAs are associated with the most important drug resistance mechanisms in OS, and some miRNAs are highly effective targets to increase chemosensitivity. The results of these studies suggest that miRNA mimics and antagomiRs may be helpful to increase the efficacy of conventional chemotherapy drugs in the treatment of metastatic OS. In this article, we discussed the role of various signaling pathways and the involved miRNAs in the metastasis of OS, attempting to provide a comprehensive review of the literature on OS metastasis and chemosensitivity.
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16
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Dong Z, Liao Z, He Y, Wu C, Meng Z, Qin B, Xu G, Li Z, Sun T, Wen Y, Li G. Advances in the Biological Functions and Mechanisms of miRNAs in the Development of Osteosarcoma. Technol Cancer Res Treat 2022; 21:15330338221117386. [PMID: 35950243 PMCID: PMC9379803 DOI: 10.1177/15330338221117386] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Osteosarcoma is one of the most common primary malignant bone tumors, mainly
occurring in children and adolescents, and is characterized by high morbidity
and poor prognosis. MicroRNAs, a class of noncoding RNAs consisting of 19 to 25
nucleotides, are involved in cell proliferation, invasion, metastasis, and
apoptosis to regulate the development and progression of osteosarcoma. Studies
have found that microRNAs are closely related to the diagnosis, treatment, and
prognosis of osteosarcoma patients and have an important role in improving drug
resistance in osteosarcoma. This paper reviews the role of microRNAs in the
pathogenesis of osteosarcoma and their clinical value, aiming to provide a new
research direction for diagnosing and treating osteosarcoma and achieving a
better prognosis.
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Affiliation(s)
- Zihe Dong
- The First School of Clinical Medicine, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Zhipeng Liao
- The Second School of Clinical Medicine, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Yonglin He
- The First School of Clinical Medicine, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Chengye Wu
- The First School of Clinical Medicine, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Zixiang Meng
- The First School of Clinical Medicine, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Baolong Qin
- The First School of Clinical Medicine, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Ge Xu
- The First School of Clinical Medicine, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Zeyang Li
- The First School of Clinical Medicine, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Tianxin Sun
- The First School of Clinical Medicine, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Yuyan Wen
- The First School of Clinical Medicine, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Guangjie Li
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
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17
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Tao X, Zhang X, Feng F. <i>Astragalus </i>polysaccharide suppresses cell proliferation and invasion by up-regulation of miR-195-5p in non-small cell lung cancer. Biol Pharm Bull 2022; 45:553-560. [DOI: 10.1248/bpb.b21-00634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Xingkui Tao
- School of Biological and Food Engineering, Suzhou University
| | - Xingtao Zhang
- School of Biological and Food Engineering, Suzhou University
| | - Fan Feng
- School of Biological and Food Engineering, Suzhou University
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18
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Casanova JM, Almeida JS, Reith JD, Sousa LM, Fonseca R, Freitas-Tavares P, Santos-Rosa M, Rodrigues-Santos P. Tumor-Infiltrating Lymphocytes and Cancer Markers in Osteosarcoma: Influence on Patient Survival. Cancers (Basel) 2021; 13:cancers13236075. [PMID: 34885185 PMCID: PMC8656728 DOI: 10.3390/cancers13236075] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/25/2021] [Accepted: 11/29/2021] [Indexed: 12/30/2022] Open
Abstract
Simple Summary Osteosarcoma (OST) is the most common type of high-grade primary bone tumor, which mainly affects young adults. Despite the efforts that have been made to address the importance of immune-related factors in OST, there is still a lot to understand. The purpose of the current study was to evaluate the tumor-infiltrating lymphocytes (TIL), the expression of proteins involved in tumor biology, and their impact on the clinical outcome of OST patients. Our results suggest that the presence of tumor-infiltrating CD4+ cells provides protection to patients, and that CD8+ cells have a significant impact on the patient’s overall survival (OS) and progression-free survival (PFS). In addition, a strong association of tumor-infiltrating CD4+ cells and the presence of CD44s expression in tumor samples was observed. These findings reinforce the idea that TIL and the expression of tumor markers should be taken into consideration in order to improve OST treatment and management. Abstract Osteosarcoma (OST) is the most common type of high-grade primary bone tumor, which mainly affects young adults. The current standard of care for OST combines surgical resection with chemotherapy. The clinical outcomes and the current options to treat OST patients are unsatisfactory and novel treatment strategies are needed. The crosstalk between tumor cells and immune cells is essential to the OST microenvironment. Despite the efforts that have been made to address the importance of immune-related factors in OST, there is still a lot to understand. The purpose of the current study was to evaluate the tumor-infiltrating lymphocytes (TIL), the expression of proteins involved in tumor biology, and their impact on the clinical outcome of OST patients. We studied 93 samples of OST patients using immunohistochemistry and histomorphometry. We looked for the infiltration of CD3+, CD4+, CD8+, TIA1+ and CD20+ cells and for the expression of CD44 standard (CD44s) and variant 6 (CD44v6), CD95/Fas, Fas-L, p53 and p-glycoprotein. All the parameters were analyzed for the influence on the occurrence of death and metastasis, plus patient overall survival (OS) and progression-free survival (PFS). The effect of sex, age, tumor location (distal femur or proximal tibia) and the combination with neoadjuvant chemotherapy was also assessed. Our results suggest that the presence of tumor-infiltrating CD4+ cells provides protection to OST patients, and that CD8+ cells have a significant impact on the patient’s overall survival (OS) and progression-free survival (PFS), which is more evident in male patients. In addition, a strong association between tumor-infiltrating CD4+ cells and the presence of CD44s expression in tumor samples was observed. Analysis of TIL and tumor markers related to tumor biology could be useful to stratify patients and monitor the response to therapy, as well as to assist with the development of immunotherapy strategies to improve the effects of cytotoxic TIL to eradicate the tumor cells.
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Affiliation(s)
- José Manuel Casanova
- Tumor Unit of the Locomotor Apparatus (UTAL), University Clinic of Orthopedics, Orthopedics Service, Coimbra Hospital and Universitary Centre (CHUC), 3000-075 Coimbra, Portugal; (J.M.C.); (R.F.); (P.F.-T.)
- Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (J.-S.A.); (M.S.-R.)
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Clinical Academic Centre of Coimbra (CACC), 3000-075 Coimbra, Portugal
- Department of Pathology, Robert J. Tomsich Pathology & Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA;
| | - Jani-Sofia Almeida
- Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (J.-S.A.); (M.S.-R.)
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Clinical Academic Centre of Coimbra (CACC), 3000-075 Coimbra, Portugal
- Department of Pathology, Robert J. Tomsich Pathology & Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA;
- Laboratory of Immunology and Oncology, Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal;
| | - John David Reith
- Department of Pathology, Robert J. Tomsich Pathology & Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA;
| | - Luana Madalena Sousa
- Laboratory of Immunology and Oncology, Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal;
| | - Ruben Fonseca
- Tumor Unit of the Locomotor Apparatus (UTAL), University Clinic of Orthopedics, Orthopedics Service, Coimbra Hospital and Universitary Centre (CHUC), 3000-075 Coimbra, Portugal; (J.M.C.); (R.F.); (P.F.-T.)
- Clinical Academic Centre of Coimbra (CACC), 3000-075 Coimbra, Portugal
| | - Paulo Freitas-Tavares
- Tumor Unit of the Locomotor Apparatus (UTAL), University Clinic of Orthopedics, Orthopedics Service, Coimbra Hospital and Universitary Centre (CHUC), 3000-075 Coimbra, Portugal; (J.M.C.); (R.F.); (P.F.-T.)
- Clinical Academic Centre of Coimbra (CACC), 3000-075 Coimbra, Portugal
| | - Manuel Santos-Rosa
- Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (J.-S.A.); (M.S.-R.)
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Clinical Academic Centre of Coimbra (CACC), 3000-075 Coimbra, Portugal
- Institute of Immunology, Faculty of Medicine (FMUC), University of Coimbra, 3004-504 Coimbra, Portugal
| | - Paulo Rodrigues-Santos
- Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (J.-S.A.); (M.S.-R.)
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Clinical Academic Centre of Coimbra (CACC), 3000-075 Coimbra, Portugal
- Institute of Immunology, Faculty of Medicine (FMUC), University of Coimbra, 3004-504 Coimbra, Portugal
- Correspondence: ; Tel.: +351-239-85-77-77 (ext. 24-28-44)
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