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Feng Y, Jiang Y, Yang L, Lu D, Li N, Zhang Q, Yang H, Qin H, Zhang J, Gou X, Jiang F. Interactions and communications in lung tumour microenvironment: chemo/radiotherapy resistance mechanisms and therapeutic targets. J Drug Target 2025; 33:817-836. [PMID: 39815747 DOI: 10.1080/1061186x.2025.2453730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 12/28/2024] [Accepted: 01/08/2025] [Indexed: 01/18/2025]
Abstract
The lung tumour microenvironment (TME) is composed of various cell types, including cancer cells, stromal and immune cells, as well as extracellular matrix (ECM). These cells and surrounding ECM create a stiff, hypoxic, acidic and immunosuppressive microenvironment that can augment the resistance of lung tumours to different forms of cell death and facilitate invasion and metastasis. This environment can induce chemo/radiotherapy resistance by inducing anti-apoptosis mediators such as phosphoinositide 3-kinase (PI3K)/Akt, signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-κB), leading to the exhaustion of antitumor immunity and further resistance to chemo/radiotherapy. In addition, lung tumour cells can resist chemo/radiotherapy by boosting multidrug resistance mechanisms and antioxidant defence systems within cancer cells and other TME components. In this review, we discuss the interactions and communications between these different components of the lung TME and also the effects of hypoxia, immune evasion and ECM remodelling on lung cancer resistance. Finally, we review the current strategies in preclinical and clinical studies, including the inhibition of checkpoint molecules, chemoattractants, cytokines, growth factors and immunosuppressive mediators such as programmed death 1 (PD-1), insulin-like growth factor 2 (IGF-2) for targeting the lung TME to overcome resistance to chemotherapy and radiotherapy.
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Affiliation(s)
- Yuan Feng
- Guangxi University of Chinese Medicine, Nanning, China
| | - Ying Jiang
- Department of Neurology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Lin Yang
- Guangxi University of Chinese Medicine, Nanning, China
| | - Danni Lu
- Guangxi University of Chinese Medicine, Nanning, China
| | - Ning Li
- Guangxi University of Chinese Medicine, Nanning, China
| | - Qun Zhang
- Guangxi University of Chinese Medicine, Nanning, China
| | - Haiyan Yang
- Guangxi University of Chinese Medicine, Nanning, China
| | - Huiyuan Qin
- Guangxi University of Chinese Medicine, Nanning, China
| | - Jiaxin Zhang
- Guangxi University of Chinese Medicine, Nanning, China
| | - Xinyun Gou
- Guangxi University of Chinese Medicine, Nanning, China
| | - Feng Jiang
- Science and Technology Department, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
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Jiang Y, Yang H, Ye Z, Huang Y, Li P, Jiang Z, Han S, Ma L. Multi-omic analyses reveal aberrant DNA methylation patterns and the associated biomarkers of nasopharyngeal carcinoma and its cancer stem cells. Sci Rep 2025; 15:9733. [PMID: 40118861 PMCID: PMC11928619 DOI: 10.1038/s41598-025-87038-z] [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: 05/31/2024] [Accepted: 01/15/2025] [Indexed: 03/24/2025] Open
Abstract
Aberrant DNA methylation is a hallmark of nasopharyngeal carcinoma (NPC) pathogenesis. The aberrant DNA methylation patterns in NPC, particularly in its cancer stem cells (CSCs), and their underlying significance require further elucidation. We integratively performed DNA methylome and transcriptome combined with single-nucleus RNA sequencing to investigate DNA methylation and gene expression patterns of NPC and CSCs. Unlike Epstein-Barr virus (EBV)-negative cells, NPC and CSCs harboring EBV displayed global DNA hypermethylation and they were more oncogenic and immunosuppressive. By correlating DNA methylation and gene expression profiles, we disclosed potential relationships between aberrant DNA methylation, tumorigenesis, metastasis, immunotherapy response, and radiotherapy resistance of NPC. After validating with datasets from GEO and TCGA, we identified aberrant DNA methylation-associated biomarkers including 9 NPC-specific diagnostic markers that had significantly higher DNA methylation levels in NPC than in normal tissues and 8 types of cancers, and 12 potential prognostic markers that were highly correlated to cell cycle dysregulation. Notably, 2 of these potential biomarkers highly expressed in CSCs were validated at the single-cell level. Our study not only identified new potential diagnostic and prognostic biomarkers but also provided new insight into aberrant DNA methylation-associated pathogenesis of NPC, which is beneficial for the development of precision diagnosis and treatment schemes.
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Affiliation(s)
- Yike Jiang
- Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China
| | - Hongtian Yang
- Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, China
| | - Zilu Ye
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, China
- Department of Chemistry, Tsinghua University, Beijing, 100084, China
| | - Yunchuanxiang Huang
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, China
- Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, 518055, China
| | - Ping Li
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, China
| | - Ziyi Jiang
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, China
| | - Sanyang Han
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, China.
- Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China.
| | - Lan Ma
- Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China.
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, China.
- Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, 518055, China.
- State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, China.
- Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China.
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Kah G, Chandran R, Abrahamse H. Green silver nanoparticles curcumin conjugate induced photodynamic therapy of lung cancer and lung cancer stem cells. RSC Adv 2025; 15:5020-5041. [PMID: 39957816 PMCID: PMC11827557 DOI: 10.1039/d4ra06035k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 01/27/2025] [Indexed: 02/18/2025] Open
Abstract
Lung cancer remains a dreaded disease globally due to its high mortality rates. New cases of lung cancer are estimated at 1.8 million a year, with about 1.6 million deaths. Conventional treatment regimens are inefficient due to their failure to eradicate lung cancer stem cells (LCSCs). LCSCs are noted to self-renew, cause relapse, strengthen metastasis, preserve tumorigenicity, and are very resistant to treatment. This shows the need for a novel treatment modality that can target lung cancer and its stem cells. In this study, a photoactive curcumin-silver nanoparticle-polymer conjugate (Cum-PEG-BpAgNPs) was developed to enhance lung cancer photodynamic therapy (PDT). Lung cancer cells and LCSCs were treated with Cum-PEG-BpAgNPs followed by light irradiation at 470 nm. Post-analytical assays including 3-[4,5-dimethylthiazole-2yl]-2,5-diphenyl tetrazolium bromide, lactate dehydrogenase, adenosine triphosphate, ROS by DCFH-DA, annexin V-FITC/PI cell death studies, and morphological analysis were performed. The characterization analysis confirmed the bio-formulation of Cum-PEG-BpAgNPs conjugate. The LCSCs characterization indicated the presence of LCSCs in the isolated cell population. The biochemical assays post-PDT revealed substantial cytotoxicity when lower concentrations of Cum-PEG-BpAgNPs were used. The IC50 value of the conjugate was noted at 4.014 μg mL-1 and 2.373 μg mL-1 for lung cancer cells and LCSCs, respectively. An elevated ROS production was induced, leading to apoptosis post-PDT. Therefore, Cum-PEG-BpAgNPs could be used in the mediation PDT to eliminate lung cancer cells effectively.
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Affiliation(s)
- Glory Kah
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg Johannesburg 2028 South Africa
| | - Rahul Chandran
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg Johannesburg 2028 South Africa
| | - Heidi Abrahamse
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg Johannesburg 2028 South Africa
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Amer H, Kampan NC, Itsiopoulos C, Flanagan KL, Scott CL, Kartikasari AER, Plebanski M. Interleukin-6 Modulation in Ovarian Cancer Necessitates a Targeted Strategy: From the Approved to Emerging Therapies. Cancers (Basel) 2024; 16:4187. [PMID: 39766086 PMCID: PMC11674514 DOI: 10.3390/cancers16244187] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 11/27/2024] [Accepted: 11/29/2024] [Indexed: 01/11/2025] Open
Abstract
Despite significant advances in treatments, ovarian cancer (OC) remains one of the most prevalent and lethal gynecological cancers in women. The frequent detection at the advanced stages has contributed to low survival rates, resistance to various treatments, and disease recurrence. Thus, a more effective approach is warranted to combat OC. The cytokine Interleukin-6 (IL6) has been implicated in various stages of OC development. High IL6 levels are also correlated with a lower survival rate in OC patients. In this current review, we summarized the pivotal roles of IL6 in OC, including the initiation, development, invasion, metastasis, and drug resistance mechanisms. This article systematically highlights how targeting IL6 improves OC outcomes by altering various cancer processes and reports the ongoing clinical trials that would further shape the IL6-based targeted therapies. This review also suggests how combining IL6-targeted therapies with other therapeutic strategies could further enhance their efficacy to combat OC.
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Affiliation(s)
- Hina Amer
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3082, Australia; (H.A.); (A.E.R.K.)
| | - Nirmala C. Kampan
- Department of Obstetrics and Gynecology, Faculty of Medicine, University Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Catherine Itsiopoulos
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3082, Australia; (H.A.); (A.E.R.K.)
| | - Katie L. Flanagan
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3082, Australia; (H.A.); (A.E.R.K.)
- School of Medicine and School of Health Sciences, University of Tasmania, Launceston, TAS 7250, Australia
- Tasmanian Vaccine Trial Centre, Clifford Craig Foundation, Launceston General Hospital, Launceston, TAS 7250, Australia
| | - Clare L. Scott
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
- Faculty of Medicine, Dentistry, and Health Sciences, The University of Melbourne, Parkville, VIC 3052, Australia
- The Royal Women’s Hospital, Parkville, VIC 3052, Australia
| | - Apriliana E. R. Kartikasari
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3082, Australia; (H.A.); (A.E.R.K.)
| | - Magdalena Plebanski
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3082, Australia; (H.A.); (A.E.R.K.)
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Tan J, Tang Y, Li B, Shi L, Zhang Y, Chen Y, Chen Y, Li J, Xiang M, Zhou Y, Xing HR, Wang J. Exosomal lncRNA Mir100hg derived from cancer stem cells enhance glycolysis and promote metastasis of melanoma through miR-16-5p and miR-23a-3p. Exp Cell Res 2024; 443:114319. [PMID: 39527976 DOI: 10.1016/j.yexcr.2024.114319] [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: 08/04/2024] [Revised: 10/28/2024] [Accepted: 11/02/2024] [Indexed: 11/16/2024]
Abstract
Increasing evidence demonstrate that the significant role of long non-coding RNA (lncRNA) in metastasis and the remodeling of the tumor microenvironment. However, the precise mechanisms of lncRNAs in cancer metastasis are still poorly understood. The function of lncRNA-Mir100hg in melanoma and its involvement in mediating communication between tumor stem cells and non-stemness tumor cells remains unknown. We found that Mir100hg is upregulated in melanoma stem cells (CSCs) known as OLSD. Furthermore, Mir100hg can be transferred from OLSD to non-stem cancer cells (OL) through exosomes. Once Mir100hg enters OL cells, it operates through a competitive endogenous RNA (ceRNA) mechanism. It competes with microRNAs (miR-16-5p and miR-23a-3p) by binding to them, thus preventing these miRNAs from targeting their mRNAs. As a result, the expression of glycolysis-related mRNA was restored. This ultimately enhances the metastatic capability of OL cells. In summary, our study uncovers a network used by CSCs to transfer their high metastatic activity to non-stem cancer cells through the exosomal Mir100hg. This mechanism sheds new light on the communication between heterogeneous cancer cell populations in melanoma. Importantly, it provides novel insights into the role of lncRNAs in cancer metastasis and highlights the significance of the tumor microenvironment in facilitating metastasis.
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Affiliation(s)
- Jiyu Tan
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China
| | - Yao Tang
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China
| | - Bowen Li
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China
| | - Lei Shi
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China
| | - Yuhan Zhang
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China
| | - Yuting Chen
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China
| | - Yan Chen
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China
| | - Jie Li
- Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Meng Xiang
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China
| | - Yufeng Zhou
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China.
| | - H Rosie Xing
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China.
| | - Jianyu Wang
- Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China.
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Tan N, Li Y, Ying J, Chen W. Histological transformation in lung adenocarcinoma: Insights of mechanisms and therapeutic windows. J Transl Int Med 2024; 12:452-465. [PMID: 39513032 PMCID: PMC11538883 DOI: 10.1515/jtim-2024-0019] [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] [Indexed: 11/15/2024] Open
Abstract
Histological transformation from lung adenocarcinoma (ADC) to small cell lung carcinoma (SCLC), large cell neuroendocrine carcinoma (LCNEC), squamous cell carcinoma (SCC), and sarcomatoid carcinoma (PSC) after targeted therapies is recognized as a mechanism of resistance in ADC treatments. Patients with transformed lung cancer typically experience a poor prognosis and short survival time. However, effective treatment options for these patients are currently lacking. Therefore, understanding the mechanisms underlying histological transformation is crucial for the development of effective therapies. Hypotheses including intratumoral heterogeneity, cancer stem cells, and alteration of suppressor genes have been proposed to explain the mechanism of histological transformation. In this review, we provide a comprehensive overview of the known molecular features and signaling pathways of transformed tumors, and summarized potential therapies based on previous findings.
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Affiliation(s)
- Nuopei Tan
- Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yan Li
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianming Ying
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wanqing Chen
- Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Almarza C, Villalobos-Nova K, Toro MA, González M, Niechi I, Brown-Brown DA, López-Muñoz RA, Silva-Pavez E, Gaete-Ramírez B, Varas-Godoy M, Burzio VA, Jara L, Aguayo F, Tapia JC. Cisplatin-resistance and aggressiveness are enhanced by a highly stable endothelin-converting enzyme-1c in lung cancer cells. Biol Res 2024; 57:74. [PMID: 39443981 PMCID: PMC11515556 DOI: 10.1186/s40659-024-00551-9] [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: 03/25/2024] [Accepted: 09/26/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND Lung cancer constitutes the leading cause of cancer mortality. High levels of endothelin-1 (ET-1), its cognate receptor ETAR and its activating enzyme, the endothelin-converting enzyme-1 (ECE-1), have been reported in several cancer types, including lung cancer. ECE-1 comprises four isoforms, which only differ in their cytoplasmic N-terminus. Protein kinase CK2 phosphorylates the N-terminus of isoform ECE-1c, increasing its stability and leading to enhanced invasiveness in glioblastoma and colorectal cancer cells, which is believed to be mediated by the amino acid residue Lys-6, a conserved putative ubiquitination site neighboring the CK2-phosphorylated residues Ser-18 and Ser-20. Whether Lys-6 is linked to the acquisition of a cancer stem cell (CSC)-like phenotype and aggressiveness in human non-small cell lung cancer (NSCLC) cells has not been studied. METHODS In order to establish the role of Lys-6 in the stability of ECE-1c and its involvement in lung cancer aggressiveness, we mutated this residue to a non-ubiquitinable arginine and constitutively expressed the wild-type (ECE-1cWT) and mutant (ECE-1cK6R) proteins in A549 and H1299 human NSCLC cells by lentiviral transduction. We determined the protein stability of these clones alone or in the presence of the CK2 inhibitor silmitasertib, compared to ECE-1cWT and mock-transduced cells. In addition, the concentration of secreted ET-1 in the growth media was determined by ELISA. Expression of stemness genes were determined by Western blot and RT-qPCR. Chemoresistance to cisplatin was studied by MTS viability assay. Migration and invasion were measured through transwell and Matrigel assays, respectively, and the side-population was determined using flow cytometry. RESULTS ECE-1cK6R displayed higher stability in NSCLC cells compared to ECE-1cWT-expressing cells, but ET-1 secreted levels showed no difference up to 48 h. Most importantly, ECE-1cK6R promoted expression of the stemness genes c-Myc, Sox-2, Oct-4, CD44 and CD133, which enhance cellular self-renewal capability. Also, the ECE-1cK6R-expressing cells showed higher cisplatin chemoresistance, correlating with an augmented side-population abundance due to the increased expression of the ABCG2 efflux pump. Finally, the ECE-1cK6R-expressing cells showed enhanced invasiveness, which correlated with the regulated expression of known EMT markers. CONCLUSIONS Our findings suggest an important role of ECE-1c in lung cancer. ECE-1c is key in a non-canonical ET-1-independent mechanism which triggers a CSC-like phenotype, leading to enhanced lung cancer aggressiveness. Underlying this mechanism, ECE-1c is stabilized upon phosphorylation by CK2, which is upregulated in many cancers. Thus, phospho-ECE-1c may be considered as a novel prognostic biomarker of recurrence, as well as the CK2 inhibitor silmitasertib as a potential therapy for lung cancer patients.
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Affiliation(s)
- Cristopher Almarza
- Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Karla Villalobos-Nova
- Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - María A Toro
- Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Manuel González
- Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Ignacio Niechi
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - David A Brown-Brown
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Rodrigo A López-Muñoz
- Instituto de Farmacología y Morfofisiología, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile
| | - Eduardo Silva-Pavez
- Facultad de Odontología y Ciencias de la Rehabilitación, Universidad San Sebastián, Santiago, Chile
| | - Belén Gaete-Ramírez
- Centro de Biología Celular y Biomedicina, Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile
| | - Manuel Varas-Godoy
- Centro de Biología Celular y Biomedicina, Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile
| | - Verónica A Burzio
- Departamento de Ciencias Biológicas, Facultad de Ciencias de la Vida, Facultad de Medicina, Universidad Andrés Bello, Santiago, Chile
| | - Lilian Jara
- Programa de Genética, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Francisco Aguayo
- Departamento de Biomedicina, Facultad de Medicina, Universidad de Tarapacá, Arica, Chile
| | - Julio C Tapia
- Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
- Laboratorio de Transformación Celular, Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Av. Independencia 1027, Santiago, 8380453, Chile.
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Ye B, Hongting G, Zhuang W, Chen C, Yi S, Tang X, Jiang A, Zhong Y. Deciphering lung adenocarcinoma prognosis and immunotherapy response through an AI-driven stemness-related gene signature. J Cell Mol Med 2024; 28:e18564. [PMID: 39046884 PMCID: PMC11268368 DOI: 10.1111/jcmm.18564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 06/03/2024] [Accepted: 06/27/2024] [Indexed: 07/27/2024] Open
Abstract
Lung adenocarcinoma (LUAD) is a leading cause of cancer-related deaths, and improving prognostic accuracy is vital for personalised treatment approaches, especially in the context of immunotherapy. In this study, we constructed an artificial intelligence (AI)-driven stemness-related gene signature (SRS) that deciphered LUAD prognosis and immunotherapy response. CytoTRACE analysis of single-cell RNA sequencing data identified genes associated with stemness in LUAD epithelial cells. An AI network integrating traditional regression, machine learning, and deep learning algorithms constructed the SRS based on genes associated with stemness. Subsequently, we conducted a comprehensive exploration of the connection between SRS and both intrinsic and extrinsic immune environments using multi-omics data. Experimental validation through siRNA knockdown in LUAD cell lines, followed by assessments of proliferation, migration, and invasion, confirmed the functional role of CKS1B, a top SRS gene. The SRS demonstrated high precision in predicting LUAD prognosis and likelihood of benefiting from immunotherapy. High-risk groups classified by the SRS exhibited decreased immunogenicity and reduced immune cell infiltration, indicating challenges for immunotherapy. Conversely, in vitro experiments revealed CKS1B knockdown significantly impaired aggressive cancer phenotypes like proliferation, migration, and invasion of LUAD cells, highlighting its pivotal role. These results underscore a close association between stemness and tumour immunity, offering predictive insights into the immune landscape and immunotherapy responses in LUAD. The newly established SRS holds promise as a valuable tool for selecting LUAD populations likely to benefit from future clinical stratification efforts.
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Affiliation(s)
- Bicheng Ye
- School of Clinical MedicineYangzhou Polytechnic CollegeYangzhouChina
| | - Ge Hongting
- Department of Respiratory and Critical Care MedicineHuai'an Hospital Affiliated to Yangzhou University (The Fifth People's Hospital of Huai'an)Huai'anChina
| | - Wen Zhuang
- Huai'an Second People's Hospital Affiliated to Xuzhou Medical UniversityHuai'anJiangsuChina
| | - Cheng Chen
- School of Clinical MedicineYangzhou Polytechnic CollegeYangzhouChina
| | - Shulin Yi
- School of Clinical MedicineYangzhou Polytechnic CollegeYangzhouChina
| | - Xinyan Tang
- Department of NursingJiangsu Vocational College of MedicineYanchengChina
| | - Aimin Jiang
- Department of Urology, Changhai HospitalNaval Medical University (Second Military Medical University)ShanghaiChina
| | - Yating Zhong
- Department of OncologyShuyang County Hospital of Traditional Chinese MedicineSuqianChina
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Dechbumroong P, Hu R, Keaswejjareansuk W, Namdee K, Liang XJ. Recent advanced lipid-based nanomedicines for overcoming cancer resistance. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2024; 7:24. [PMID: 39050885 PMCID: PMC11267154 DOI: 10.20517/cdr.2024.19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 06/09/2024] [Accepted: 06/17/2024] [Indexed: 07/27/2024]
Abstract
The increasing prevalence of cancer drug resistance not only critically limits the efficiency of traditional therapies but also causes relapses or recurrences of cancer. Consequently, there remains an urgent need to address the intricate landscape of drug resistance beyond traditional cancer therapies. Recently, nanotechnology has played an important role in the field of various drug delivery systems for the treatment of cancer, especially therapy-resistant cancer. Among advanced nanomedicine technologies, lipid-based nanomaterials have emerged as effective drug carriers for cancer treatment, significantly improving therapeutic effects. Due to their biocompatibility, simplicity of preparation, and potential for functionalization, lipid-based nanomaterials are considered powerful competitors for resistant cancer. In this review, an overview of lipid-based nanomaterials for addressing cancer resistance is discussed. We summarize the recent progress in overcoming drug resistance in cancer by these lipid-based nanomaterials, and highlight their potential in future applications to reverse cancer resistance.
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Affiliation(s)
- Piroonrat Dechbumroong
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100049, China
- School of Nanoscience and Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
- National Nanotechnology Center (NANOTEC), National Science and Technology Development Agency, Pathum Thani 12120, Thailand
- Authors contributed equally
| | - Runjing Hu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100049, China
- School of Nanoscience and Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
- Authors contributed equally
| | - Wisawat Keaswejjareansuk
- National Nanotechnology Center (NANOTEC), National Science and Technology Development Agency, Pathum Thani 12120, Thailand
| | - Katawut Namdee
- National Nanotechnology Center (NANOTEC), National Science and Technology Development Agency, Pathum Thani 12120, Thailand
| | - Xing-Jie Liang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100049, China
- School of Nanoscience and Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
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10
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Wu H, Li ZX, Fang K, Zhao ZY, Sun MC, Feng AQ, Leng ZY, Zhang ZH, Chu Y, Zhang L, Chen T, Xu MD. IGF-1-mediated FOXC1 overexpression induces stem-like properties through upregulating CBX7 and IGF-1R in esophageal squamous cell carcinoma. Cell Death Discov 2024; 10:102. [PMID: 38413558 PMCID: PMC10899262 DOI: 10.1038/s41420-024-01864-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 01/27/2024] [Accepted: 02/12/2024] [Indexed: 02/29/2024] Open
Abstract
Substantial evidence attests to the pivotal role of cancer stem cells (CSC) in both tumorigenesis and drug resistance. A member of the forkhead box (FOX) family, FOXC1, assumes significance in embryonic development and organogenesis. Furthermore, FOXC1 functions as an overexpressed transcription factor in various tumors, fostering proliferation, enhancing migratory capabilities, and promoting drug resistance, while maintaining stem-cell-like properties. Despite these implications, scant attention has been devoted to its role in esophageal squamous cell carcinoma. Our investigation revealed a pronounced upregulation of FOXC1 expression in ESCC, correlating with a poor prognosis. The downregulation of FOXC1 demonstrated inhibitory effects on ESCC tumorigenesis, proliferation, and tolerance to chemotherapeutic agents, concurrently reducing the levels of stemness-related markers CD133 and CD44. Further studies validated that FOXC1 induces ESCC stemness by transactivating CBX7 and IGF-1R. Additionally, IGF-1 activated the PI3K/AKT/NF-κB and MEK/ERK/NF-κB pathways through its binding to IGF-1R, thereby augmenting FOXC1 expression. Conversely, suppressing FOXC1 impeded ESCC stemness induced by IGF-1. The presence of a positive feedback loop, denoted by IGF-1-FOXC1-IGF-1R, suggests the potential of FOXC1 as a prognostic biomarker for ESCC. Taken together, targeting the IGF-1-FOXC1-IGF-1R axis emerges as a promising approach for anti-CSC therapy in ESCC.
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Affiliation(s)
- Hao Wu
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China
| | - Zhao-Xing Li
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China
| | - Kang Fang
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China
| | - Zi-Ying Zhao
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China
| | - Ming-Chuang Sun
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China
| | - An-Qi Feng
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China
| | - Zhu-Yun Leng
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China
| | - Ze-Hua Zhang
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China
| | - Yuan Chu
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China
| | - Li Zhang
- Department of Pathology, Shanghai East Hospital, School of Medicine, Tongji 8 University, 200120, Shanghai, China
| | - Tao Chen
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China.
| | - Mei-Dong Xu
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China.
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11
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Huang YH, Chiu LY, Tseng JS, Hsu KH, Chen CH, Sheu GT, Yang TY. Attenuation of PI3K-Akt-mTOR Pathway to Reduce Cancer Stemness on Chemoresistant Lung Cancer Cells by Shikonin and Synergy with BEZ235 Inhibitor. Int J Mol Sci 2024; 25:616. [PMID: 38203787 PMCID: PMC10779050 DOI: 10.3390/ijms25010616] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/15/2023] [Accepted: 12/27/2023] [Indexed: 01/12/2024] Open
Abstract
Lung cancer is considered the number one cause of cancer-related deaths worldwide. Although current treatments initially reduce the lung cancer burden, relapse occurs in most cases; the major causes of mortality are drug resistance and cancer stemness. Recent investigations have provided evidence that shikonin generates various bioactivities related to the treatment of cancer. We used shikonin to treat multi-resistant non-small lung cancer cells (DOC-resistant A549/D16, VCR-resistant A549/V16 cells) and defined the anti-cancer efficacy of shikonin. Our results showed shikonin induces apoptosis in these ABCB1-dependent and independent chemoresistance cancer sublines. Furthermore, we found that low doses of shikonin inhibit the proliferation of lung cancer stem-like cells by inhibiting spheroid formation. Concomitantly, the mRNA level and protein of stemness genes (Nanog and Oct4) were repressed significantly on both sublines. Shikonin reduces the phosphorylated Akt and p70s6k levels, indicating that the PI3K/Akt/mTOR signaling pathway is downregulated by shikonin. We further applied several signaling pathway inhibitors that have been used in anti-cancer clinical trials to test whether shikonin is suitable as a sensitizer for various signaling pathway inhibitors. In these experiments, we found that low doses shikonin and dual PI3K-mTOR inhibitor (BEZ235) have a synergistic effect that inhibits the spheroid formation from chemoresistant lung cancer sublines. Inhibiting the proliferation of lung cancer stem cells is believed to reduce the recurrence of lung cancer; therefore, shikonin's anti-drug resistance and anti-cancer stem cell activities make it a highly interesting molecule for future combined lung cancer therapy.
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Affiliation(s)
- Yen-Hsiang Huang
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan; (Y.-H.H.); (L.-Y.C.); (J.-S.T.)
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Ling-Yen Chiu
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan; (Y.-H.H.); (L.-Y.C.); (J.-S.T.)
| | - Jeng-Sen Tseng
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan; (Y.-H.H.); (L.-Y.C.); (J.-S.T.)
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Kuo-Hsuan Hsu
- Division of Critical Care and Respiratory Therapy, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan;
| | - Chang-Han Chen
- Department of Applied Chemistry, Graduate Institute of Biomedicine and Biomedical Technology, National Chi Nan University, Nantou 545, Taiwan;
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan
| | - Gwo-Tarng Sheu
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Department of Medical Oncology and Chest Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Tsung-Ying Yang
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan; (Y.-H.H.); (L.-Y.C.); (J.-S.T.)
- Department of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan
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12
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Zhang YH, Chen Y, Shi L, Han X, Xie JC, Chen Y, Xiang M, Li BW, Li J, Xing HR, Wang JY. A novel lung cancer stem cell extracellular vesicles lncRNA ROLLCSC modulate non-stemness cancer cell plasticity through miR-5623-3p and miR-217-5p targeting lipid metabolism. Int J Biol Macromol 2024; 256:128412. [PMID: 38029909 DOI: 10.1016/j.ijbiomac.2023.128412] [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: 07/25/2023] [Revised: 11/19/2023] [Accepted: 11/22/2023] [Indexed: 12/01/2023]
Abstract
BACKGROUND The high mortality rate of lung cancer is largely attributed to metastasis. Lung cancer stem cells (CSC) are conducive to cancer heterogeneity. Long noncoding RNAs are known to participate in various biological processes regulating the development of lung cancer. However, characterization of the role and mechanisms of lncRNA in lung cancer metastasis remains a challenge. RESULTS We demonstrate that ROLLCSC, a highly expressed lncRNA in LLC-SDs, promotes the metastasis of the low metastatic LLCs both in vitro and in vivo. ROLLCSC can be transferred from LLC-SD to LLC through encapsulation in extracellular vesicles (EVs), ultimately leading to the enhancement of the metastatic phenotype of LLCs. Mechanistically, we demonstrate that the pro-metastatic activity of ROLLCSC is achieved through its function as a competing endogenous RNA (ceRNA) of miR-5623-3p and miR-217-5p to stimulate lipid metabolism. CONCLUSION In this study, we have characterized ROLLCSC, a novel lncRNA, as a pivotal regulator in the metastasis of lung cancer, highlighting its potential as a therapeutic target. Specifically, we show that ROLLCSC is encapsulated by the EVs of LLC-SDs and transmitted to the LLCs, where it acts as a ceRNA of miR-5623-3p and miR-217-5p to stimulate lipid metabolism and ultimately augments metastatic colonization of LLCs.
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Affiliation(s)
- Yu-Han Zhang
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China
| | - Yan Chen
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China
| | - Lei Shi
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China
| | - Xue Han
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Jia-Cheng Xie
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China
| | - Yuting Chen
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China
| | - Meng Xiang
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China
| | - Bo-Wen Li
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China
| | - Jie Li
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - H Rosie Xing
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China.
| | - Jian-Yu Wang
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China.
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13
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Koltai T, Fliegel L. The Relationship between Trop-2, Chemotherapeutic Drugs, and Chemoresistance. Int J Mol Sci 2023; 25:87. [PMID: 38203255 PMCID: PMC10779383 DOI: 10.3390/ijms25010087] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/08/2023] [Accepted: 12/17/2023] [Indexed: 01/12/2024] Open
Abstract
Trop-2 is a highly conserved one-pass transmembrane mammalian glycoprotein that is normally expressed in tissues such as the lung, intestines, and kidney during embryonic development. It is overexpressed in many epithelial cancers but is absent in non-epithelial tumors. Trop-2 is an intracellular calcium signal transducer that participates in the promotion of cell proliferation, migration, invasion, metastasis, and probably stemness. It also has some tumor suppressor effects. The pro-tumoral actions have been thoroughly investigated and reported. However, Trop-2's activity in chemoresistance is less well known. We review a possible relationship between Trop-2, chemotherapy, and chemoresistance. We conclude that there is a clear role for Trop-2 in some specific chemoresistance events. On the other hand, there is no clear evidence for its participation in multidrug resistance through direct drug transport. The development of antibody conjugate drugs (ACD) centered on anti-Trop-2 monoclonal antibodies opened the gates for the treatment of some tumors resistant to classic chemotherapies. Advanced urothelial tumors and breast cancer were among the first malignancies for which these ACDs have been employed. However, there is a wide group of other tumors that may benefit from anti-Trop-2 therapy as soon as clinical trials are completed.
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Affiliation(s)
- Tomas Koltai
- Hospital del Centro Gallego de Buenos Aires, Buenos Aires 2199, Argentina;
| | - Larry Fliegel
- Department of Biochemistry, Faculty of Medicine, University of Alberta, 347 Medical Science Bldg., Edmonton, AB T6G 2H7, Canada
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14
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Yan G, Dai M, Poulet S, Wang N, Boudreault J, Daliah G, Ali S, Lebrun JJ. Combined in vitro/in vivo genome-wide CRISPR screens in triple negative breast cancer identify cancer stemness regulators in paclitaxel resistance. Oncogenesis 2023; 12:51. [PMID: 37932309 PMCID: PMC10628277 DOI: 10.1038/s41389-023-00497-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 10/23/2023] [Accepted: 10/26/2023] [Indexed: 11/08/2023] Open
Abstract
Triple negative breast cancer (TNBC) is defined as lacking the expressions of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC patients exhibit relatively poor clinical outcomes due to lack of molecular markers for targeted therapies. As such chemotherapy often remains the only systemic treatment option for these patients. While chemotherapy can initially help shrink TNBC tumor size, patients eventually develop resistance to drug, leading to tumor recurrence. We report a combined in vitro/in vivo genome-wide CRISPR synthetic lethality screening approach in a relevant TNBC cell line model to identify several targets responsible for the chemotherapy drug, paclitaxel resistance. Computational analysis integrating in vitro and in vivo data identified a set of genes, for which specific loss-of-function deletion enhanced paclitaxel resistance in TNBC. We found that several of these genes (ATP8B3, FOXR2, FRG2, HIST1H4A) act as cancer stemness negative regulators. Finally, using in vivo orthotopic transplantation TNBC models we showed that FRG2 gene deletion reduced paclitaxel efficacy and promoted tumor metastasis, while increasing FRG2 expression by means of CRISPR activation efficiently sensitized TNBC tumors to paclitaxel treatment and inhibited their metastatic abilities. In summary, the combined in vitro/in vivo genome-wide CRISPR screening approach proved effective as a tool to identify novel regulators of paclitaxel resistance/sensitivity and highlight the FRG2 gene as a potential therapeutical target overcoming paclitaxel resistance in TNBC.
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Affiliation(s)
- Gang Yan
- Department of Medicine, Cancer Research Program, McGill University Health Center, Montreal, QC, H4A 3J1, Canada
| | - Meiou Dai
- Department of Medicine, Cancer Research Program, McGill University Health Center, Montreal, QC, H4A 3J1, Canada
| | - Sophie Poulet
- Department of Medicine, Cancer Research Program, McGill University Health Center, Montreal, QC, H4A 3J1, Canada
| | - Ni Wang
- Department of Medicine, Cancer Research Program, McGill University Health Center, Montreal, QC, H4A 3J1, Canada
| | - Julien Boudreault
- Department of Medicine, Cancer Research Program, McGill University Health Center, Montreal, QC, H4A 3J1, Canada
| | - Girija Daliah
- Department of Medicine, Cancer Research Program, McGill University Health Center, Montreal, QC, H4A 3J1, Canada
| | - Suhad Ali
- Department of Medicine, Cancer Research Program, McGill University Health Center, Montreal, QC, H4A 3J1, Canada
| | - Jean-Jacques Lebrun
- Department of Medicine, Cancer Research Program, McGill University Health Center, Montreal, QC, H4A 3J1, Canada.
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15
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Li YR, Fang Y, Lyu Z, Zhu Y, Yang L. Exploring the dynamic interplay between cancer stem cells and the tumor microenvironment: implications for novel therapeutic strategies. J Transl Med 2023; 21:686. [PMID: 37784157 PMCID: PMC10546755 DOI: 10.1186/s12967-023-04575-9] [Citation(s) in RCA: 63] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 09/28/2023] [Indexed: 10/04/2023] Open
Abstract
Cancer stem cells (CSCs) have emerged as key contributors to tumor initiation, growth, and metastasis. In addition, CSCs play a significant role in inducing immune evasion, thereby compromising the effectiveness of cancer treatments. The reciprocal communication between CSCs and the tumor microenvironment (TME) is observed, with the TME providing a supportive niche for CSC survival and self-renewal, while CSCs, in turn, influence the polarization and persistence of the TME, promoting an immunosuppressive state. Consequently, these interactions hinder the efficacy of current cancer therapies, necessitating the exploration of novel therapeutic approaches to modulate the TME and target CSCs. In this review, we highlight the intricate strategies employed by CSCs to evade immune surveillance and develop resistance to therapies. Furthermore, we examine the dynamic interplay between CSCs and the TME, shedding light on how this interaction impacts cancer progression. Moreover, we provide an overview of advanced therapeutic strategies that specifically target CSCs and the TME, which hold promise for future clinical and translational studies in cancer treatment.
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Affiliation(s)
- Yan-Ruide Li
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
| | - Ying Fang
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Zibai Lyu
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Yichen Zhu
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Lili Yang
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
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16
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Forster S, Radpour R, Ochsenbein AF. Molecular and immunological mechanisms of clonal evolution in multiple myeloma. Front Immunol 2023; 14:1243997. [PMID: 37744361 PMCID: PMC10516567 DOI: 10.3389/fimmu.2023.1243997] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 08/21/2023] [Indexed: 09/26/2023] Open
Abstract
Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells in the bone marrow (BM). It is known that early genetic mutations in post-germinal center B/plasma cells are the cause of myelomagenesis. The acquisition of additional chromosomal abnormalities and distinct mutations further promote the outgrowth of malignant plasma cell populations that are resistant to conventional treatments, finally resulting in relapsed and therapy-refractory terminal stages of MM. In addition, myeloma cells are supported by autocrine signaling pathways and the tumor microenvironment (TME), which consists of diverse cell types such as stromal cells, immune cells, and components of the extracellular matrix. The TME provides essential signals and stimuli that induce proliferation and/or prevent apoptosis. In particular, the molecular pathways by which MM cells interact with the TME are crucial for the development of MM. To generate successful therapies and prevent MM recurrence, a thorough understanding of the molecular mechanisms that drive MM progression and therapy resistance is essential. In this review, we summarize key mechanisms that promote myelomagenesis and drive the clonal expansion in the course of MM progression such as autocrine signaling cascades, as well as direct and indirect interactions between the TME and malignant plasma cells. In addition, we highlight drug-resistance mechanisms and emerging therapies that are currently tested in clinical trials to overcome therapy-refractory MM stages.
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Affiliation(s)
- Stefan Forster
- Tumor Immunology, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Ramin Radpour
- Tumor Immunology, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Adrian F. Ochsenbein
- Tumor Immunology, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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17
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Park CR, Lee M, Lee SY, Kang D, Park SJ, Lee DC, Koo H, Park YG, Yu SL, Jeong IB, Kwon SJ, Kang J, Lee EB, Son JW. Regulating POLR3G by MicroRNA-26a-5p as a promising therapeutic target of lung cancer stemness and chemosensitivity. Noncoding RNA Res 2023; 8:273-281. [PMID: 36949748 PMCID: PMC10025963 DOI: 10.1016/j.ncrna.2023.03.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 03/03/2023] [Accepted: 03/03/2023] [Indexed: 03/12/2023] Open
Abstract
Cancer stem cells (CSCs) identified in lung cancer exhibit resistance to chemotherapy, radiotherapy, and targeted therapy. Therefore, a technology for controlling CSCs is needed to overcome such resistance to cancer therapy. Various evidences about the association between epithelial-mesenchymal transition related transcriptomic alteration and acquisition of CSC phenotype have been proposed recently. Down-regulated miR-26a-5p is closely related to mesenchymal-like lung cancer cell lines. These findings suggest that miR-26a-5p might be involved in lung cancer stemness. RNA polymerase III subunit G (POLR3G) was selected as a candidate target of miR-26a-5p related to cancer stemness. It was found that miR-26a-5p directly regulates the expression of POLR3G.Overexpression of miR-26a-5p induced a marked reduction of colony formation and sphere formation. Co-treatment of miR-26a-5p and paclitaxel decreased cell growth, suggesting that miR-26a-5p might play a role as a chemotherapy sensitizer. In the cancer genome atlas data, high miR-26a-5p and low POLR3G expression were also related to higher survival rate of patients with lung adenocarcinoma. These results suggest that miR-26a-5p can suppress lung cancer stemness and make cancer cell become sensitive to chemotherapy. This finding provides a novel insight into a potential lung cancer treatment by regulating stemness.
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Affiliation(s)
- Chang Ryul Park
- Thoracic and Cardiovascular Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, 44033, Republic of Korea
| | - Minhyeok Lee
- Department of Internal Medicine, Konyang University Hospital, Daejeon, 35365, Republic of Korea
| | - Su Yel Lee
- Myunggok Research Institute for Medical Science, Konyang University, Daejeon, 35365, Republic of Korea
| | - Daeun Kang
- Department of Internal Medicine, Konyang University Hospital, Daejeon, 35365, Republic of Korea
| | - Se Jin Park
- Department of Internal Medicine, Konyang University Hospital, Daejeon, 35365, Republic of Korea
| | - Dong Chul Lee
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
| | - Han Koo
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
| | - Young Gyu Park
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seong Lan Yu
- Myunggok Research Institute for Medical Science, Konyang University, Daejeon, 35365, Republic of Korea
| | - In Beom Jeong
- Department of Internal Medicine, Konyang University Hospital, Daejeon, 35365, Republic of Korea
| | - Sun Jung Kwon
- Department of Internal Medicine, Konyang University Hospital, Daejeon, 35365, Republic of Korea
| | - Jaeku Kang
- Department of Pharmacology, College of Medicine, Konyang University, Daejeon, 35365, Republic of Korea
| | - Eung Bae Lee
- Department of Thoracic Surgery, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea
- Corresponding author. Department of Thoracic Surgery, School of Medicine, Kyungpook National University, 130, Dongdeok-ro, Jung-gu, Daegu, 41944, Republic of Korea.
| | - Ji Woong Son
- Department of Internal Medicine, Konyang University Hospital, Daejeon, 35365, Republic of Korea
- Corresponding author. Department of Internal Medicine, Konyang University Hospital, 158, Gwanjeodong-ro, Seo-gu, Daejeon, 35365, Republic of Korea.
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18
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Pospieszna J, Dams-Kozlowska H, Udomsak W, Murias M, Kucinska M. Unmasking the Deceptive Nature of Cancer Stem Cells: The Role of CD133 in Revealing Their Secrets. Int J Mol Sci 2023; 24:10910. [PMID: 37446085 DOI: 10.3390/ijms241310910] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 06/27/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
Cancer remains a leading cause of death globally, and its complexity poses a significant challenge to effective treatment. Cancer stem cells and their markers have become key players in tumor growth and progression. CD133, a marker in various cancer types, is an active research area as a potential therapeutic target. This article explores the role of CD133 in cancer treatment, beginning with an overview of cancer statistics and an explanation of cancer stem cells and their markers. The rise of CD133 is discussed, including its structure, functions, and occurrence in different cancer types. Furthermore, the article covers CD133 as a therapeutic target, focusing on gene therapy, immunotherapy, and approaches to affect CD133 expression. Nanoparticles such as gold nanoparticles and nanoliposomes are also discussed in the context of CD133-targeted therapy. In conclusion, CD133 is a promising therapeutic target for cancer treatment. As research in this area progresses, it is hoped that CD133-targeted therapies will offer new and effective treatment options for cancer patients in the future.
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Affiliation(s)
- Julia Pospieszna
- Department of Toxicology, Poznan University of Medical Sciences, 30 Dojazd Street, 10 Uniwersytetu Poznanskiego Street, 60-631 Poznan, Poland
| | - Hanna Dams-Kozlowska
- Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary Street, 61-866 Poznan, Poland
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary Street, 61-866 Poznan, Poland
| | - Wachirawit Udomsak
- Department of Toxicology, Poznan University of Medical Sciences, 30 Dojazd Street, 10 Uniwersytetu Poznanskiego Street, 60-631 Poznan, Poland
| | - Marek Murias
- Department of Toxicology, Poznan University of Medical Sciences, 30 Dojazd Street, 10 Uniwersytetu Poznanskiego Street, 60-631 Poznan, Poland
- Center for Advanced Technology, Adam Mickiewicz University in Poznan, Uniwersytetu Poznanskiego 10 Street, 61-614 Poznan, Poland
| | - Malgorzata Kucinska
- Department of Toxicology, Poznan University of Medical Sciences, 30 Dojazd Street, 10 Uniwersytetu Poznanskiego Street, 60-631 Poznan, Poland
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19
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Fan L, Wang X, Cheng C, Wang S, Li X, Cui J, Zhang B, Shi L. Inhibitory Effect and Mechanism of Ursolic Acid on Cisplatin-Induced Resistance and Stemness in Human Lung Cancer A549 Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2023; 2023:1307323. [PMID: 37089712 PMCID: PMC10121351 DOI: 10.1155/2023/1307323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 02/21/2023] [Accepted: 03/17/2023] [Indexed: 04/25/2023]
Abstract
The survival rate of lung cancer patients remains low largely due to chemotherapy resistance during treatment, and cancer stem cells (CSCs) may hold the key to targeting this resistance. Cisplatin is a chemotherapy drug commonly used in cancer treatment, yet the mechanisms of intrinsic cisplatin resistance have not yet been determined because lung CSCs are hard to identify. In this paper, we proposed a mechanism relating to the function of ursolic acid (UA), a new drug, in reversing the cisplatin resistance of lung cancer cells regulated by CSCs. Human lung cancer cell line A549 was selected as the model cell and treated to become a cisplatin-resistant lung cancer cell line (A549-CisR), which was less sensitive to cisplatin and showed an enhanced capability of tumor sphere formation. Furthermore, in the A549-CisR cell line expression, levels of pluripotent stem cell transcription factors Oct-4, Sox-2, and c-Myc were increased, and activation of the Jak2/Stat3 signaling pathway was promoted. When UA was applied to the cisplatin-resistant cells, levels of the pluripotent stem cell transcription factors were restrained by the inhibition of the Jak2/Stat3 signaling pathway, which reduced the enrichment of tumor stem cells, and in turn, reversed cisplatin resistance in lung cancer cells. Hence, as a potential antitumor drug, UA may be able to inhibit the enrichment of the lung CSC population by inhibiting the activation of the Jak2-Stat3 pathway and preventing the resistance of lung cancer cells to cisplatin.
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Affiliation(s)
- Luxin Fan
- Department of Respiratory, Weifang People's Hospital, Weifang 261041, China
| | - Xiaodong Wang
- Microbiological Laboratory, Weifang Inspection and Testing Center, Weifang 261100, China
| | - Congcong Cheng
- Department of Oncology, Yidu Central Hospital of Weifang, Qingzhou 262500, China
| | - Shuxiao Wang
- Intravenous Drug Dispensing Center, Second Hospital of Shandong University, Jinan 250033, China
| | - Xuesong Li
- School of Clinical Medicine, Weifang Medical University, Weifang 261053, China
| | - Jiayu Cui
- School of Clinical Medicine, Weifang Medical University, Weifang 261053, China
| | - Baogang Zhang
- School of Pharmacy, Weifang Medical University, Weifang 261053, China
| | - Lihong Shi
- School of Pharmacy, Weifang Medical University, Weifang 261053, China
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20
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He J, Lan X, Liu X, Deng C, Luo H, Wang Y, Kang P, Sun Z, Zhao L, Zhou X. CA916798 predicts poor prognosis and promotes Gefitinib resistance for lung adenocarcinoma. BMC Cancer 2023; 23:266. [PMID: 36959566 PMCID: PMC10035219 DOI: 10.1186/s12885-023-10735-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 03/13/2023] [Indexed: 03/25/2023] Open
Abstract
Background Our previous studies have identified CA916798 as a chemotherapy resistance-associated gene in lung cancer. However, the histopathological relevance and biological function of CA916798 in lung adenocarcinoma (LUAD) remains to be delineated. In this study, we further investigated and explored the clinical and biological significance of CA916798 in LUAD. Methods The relationship between CA916798 and clinical features of LUAD was analyzed by tissue array and online database. CCK8 and flow cytometry were used to measure cell proliferation and cell cycle of LUAD after knockdown of CA916798 gene. qRT-PCR and western blotting were used to detect the changes of cell cycle-related genes after knockdown or overexpression of CA916798. The tumorigenesis of LUAD cells was evaluated with or without engineering manipulation of CA916798 gene expression. Response to Gefitinib was evaluated using LUAD cells with forced expression or knockdown of CA916798. Results The analysis on LUAD samples showed that high expression of CA916798 was tightly correlated with pathological progression and poor prognosis of LUAD patients. A critical methylation site in promoter region of CA916798 gene was identified to be related with CA916798 gene expression. Forced expression of CA916798 relieved the inhibitory effects of WEE1 on CDK1 and facilitated cell cycle progression from G2 phase to M phase. However, knockdown of CA916798 enhanced WEE1 function and resulted in G2/M phase arrest. Consistently, chemical suppression of CDK1 dramatically inhibited G2/M phase transition in LUAD cells with high expression of CA916798. Finally, we found that CA916798 was highly expressed in Gefitinib-resistant LUAD cells. Exogenous expression of CA916798 was sufficient to endow Gefitinib resistance with tumor cells, but interference of CA916798 expression largely rescued response of tumor cells to Gefitinib. Conclusions CA916798 played oncogenic roles and was correlated with the development of Gefitinib resistance in LUAD cells. Therefore, CA916798 could be considered as a promising prognostic marker and a therapeutic target for LUAD. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-023-10735-3.
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Affiliation(s)
- Jian He
- grid.410570.70000 0004 1760 6682Department of Respiratory medicine, The First Hospital Affiliated to Army Medical University, 29 Gaotanyan Main Street, Chongqing, 400038 China
| | - Xi Lan
- grid.410570.70000 0004 1760 6682Department of Respiratory medicine, The First Hospital Affiliated to Army Medical University, 29 Gaotanyan Main Street, Chongqing, 400038 China
| | - Xiayan Liu
- grid.410570.70000 0004 1760 6682Department of Respiratory medicine, The First Hospital Affiliated to Army Medical University, 29 Gaotanyan Main Street, Chongqing, 400038 China
| | - Caixia Deng
- grid.410570.70000 0004 1760 6682Department of Respiratory medicine, The First Hospital Affiliated to Army Medical University, 29 Gaotanyan Main Street, Chongqing, 400038 China
| | - Hu Luo
- grid.410570.70000 0004 1760 6682Department of Respiratory medicine, The First Hospital Affiliated to Army Medical University, 29 Gaotanyan Main Street, Chongqing, 400038 China
| | - Yan Wang
- grid.416208.90000 0004 1757 2259Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038 China
| | - Ping Kang
- K2 Oncology Co., Ltd, Beijing, 100176 China
| | | | - Lintao Zhao
- grid.410570.70000 0004 1760 6682Department of Respiratory medicine, The First Hospital Affiliated to Army Medical University, 29 Gaotanyan Main Street, Chongqing, 400038 China
| | - Xiangdong Zhou
- grid.410570.70000 0004 1760 6682Department of Respiratory medicine, The First Hospital Affiliated to Army Medical University, 29 Gaotanyan Main Street, Chongqing, 400038 China
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21
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Muñoz-Bernart M, Budnick N, Castro A, Manzi M, Monge ME, Pioli J, Defranchi S, Parrilla G, Santilli JP, Davies K, Espinosa JM, Kobayashi K, Vigliano C, Perez-Castro C. S-adenosylhomocysteine hydrolase-like protein 1 (AHCYL1) inhibits lung cancer tumorigenesis by regulating cell plasticity. Biol Direct 2023; 18:8. [PMID: 36872327 PMCID: PMC9985837 DOI: 10.1186/s13062-023-00364-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 02/21/2023] [Indexed: 03/07/2023] Open
Abstract
BACKGROUND Lung cancer is one of the most frequently diagnosed cancers characterized by high mortality, metastatic potential, and recurrence. Deregulated gene expression of lung cancer, likewise in many other solid tumors, accounts for their cell heterogeneity and plasticity. S-adenosylhomocysteine hydrolase-like protein 1 (AHCYL1), also known as Inositol triphosphate (IP(3)) receptor-binding protein released with IP(3) (IRBIT), plays roles in many cellular functions, including autophagy and apoptosis but AHCYL1 role in lung cancer is largely unknown. RESULTS Here, we analyzed the expression of AHCYL1 in Non-Small Cell Lung Cancer (NSCLC) cells from RNA-seq public data and surgical specimens, which revealed that AHCYL1 expression is downregulated in tumors and inverse correlated to proliferation marker Ki67 and the stemness signature expression. AHCYL1-silenced NSCLC cells showed enhanced stem-like properties in vitro, which correlated with higher expression levels of stem markers POU5F1 and CD133. Also, the lack of AHCYL1 enhanced tumorigenicity and angiogenesis in mouse xenograft models highlighting stemness features. CONCLUSIONS These findings indicate that AHCYL1 is a negative regulator in NSCLC tumorigenesis by modulating cell differentiation state and highlighting AHCYL1 as a potential prognostic biomarker for lung cancer.
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Affiliation(s)
- Melina Muñoz-Bernart
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET, Partner Institute of the Max Planck Society, Buenos Aires, Argentina
| | - Nicolás Budnick
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET, Partner Institute of the Max Planck Society, Buenos Aires, Argentina
| | - Araceli Castro
- Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMeTTyB), Universidad Favaloro-CONICET, Solís 453, C1078AAI, Buenos Aires, Argentina
| | - Malena Manzi
- Centro de Investigaciones en Bionanociencias (CIBION), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Godoy Cruz 2390, C1425FQD, Ciudad de Buenos Aires, Argentina.,Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Intendente Güiraldes, 2160 C1428EGA, Buenos Aires, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Departamento de Desarrollo Analítico y Control de Procesos, Instituto Nacional de Tecnología Industrial, Av. General Paz 5445, B1650WAB, Buenos Aires, Argentina
| | - María Eugenia Monge
- Centro de Investigaciones en Bionanociencias (CIBION), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Godoy Cruz 2390, C1425FQD, Ciudad de Buenos Aires, Argentina
| | - Julieta Pioli
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET, Partner Institute of the Max Planck Society, Buenos Aires, Argentina
| | - Sebastián Defranchi
- Servicio de Cirugía Torácica, Hospital Universitario de la Fundación Favaloro, Av. Belgrano 1746, C1093AAS, Buenos Aires, Argentina
| | - Gustavo Parrilla
- Servicio de Cirugía Torácica, Hospital Universitario de la Fundación Favaloro, Av. Belgrano 1746, C1093AAS, Buenos Aires, Argentina
| | - Juan Pablo Santilli
- Servicio de Anatomía Patológica, Hospital Universitario de la Fundación Favaloro, Av. Belgrano 1746, C1093AAS, Buenos Aires, Argentina
| | - Kevin Davies
- Servicio de Anatomía Patológica, Hospital Universitario de la Fundación Favaloro, Av. Belgrano 1746, C1093AAS, Buenos Aires, Argentina
| | - Joaquín M Espinosa
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.,Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.,Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA
| | - Ken Kobayashi
- Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Intendente Güiraldes, 2160 C1428EGA, Buenos Aires, Argentina.,Laboratorio de Agrobiotecnología, Instituto de Biodiversidad y Biología Experimental Aplicada (IBBEA-CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Carlos Vigliano
- Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMeTTyB), Universidad Favaloro-CONICET, Solís 453, C1078AAI, Buenos Aires, Argentina.,Servicio de Anatomía Patológica, Hospital Universitario de la Fundación Favaloro, Av. Belgrano 1746, C1093AAS, Buenos Aires, Argentina
| | - Carolina Perez-Castro
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET, Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
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22
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TIM-4 orchestrates mitochondrial homeostasis to promote lung cancer progression via ANXA2/PI3K/AKT/OPA1 axis. Cell Death Dis 2023; 14:141. [PMID: 36806050 PMCID: PMC9941510 DOI: 10.1038/s41419-023-05678-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 02/09/2023] [Accepted: 02/13/2023] [Indexed: 02/22/2023]
Abstract
Mitochondrial function and homeostasis are critical to the proliferation of lung cancer cells. T-cell immunoglobulin and mucin domain-containing molecule 4 (TIM-4) promotes the development and progression of lung cancer. However, the role of TIM-4 in mitochondria homeostasis in tumor cells remains completely unknown. In this study, we found that TIM-4 promoted growth and proliferation of lung cancer cells by the oxidative phosphorylation (OXPHOS) pathway. Consistently, inhibition of OXPHOS reversed TIM-4-induced proliferation of lung cancer cells. Notably, TIM-4 promoted mitochondrial fusion via enhancing L-OPA1 protein expression. Mechanistically, TIM-4 regulated protein of L-OPA1 through the PI3K/AKT pathway, and TIM-4 interacted with ANXA2 to promote the activation of PI3K/AKT signaling. Collectively, TIM-4 promotes oxidative phosphorylation of lung cancer cells to accelerate tumor progress via ANXA2/PI3K/AKT/OPA1 axis, which sheds significant new lights on the potential role of TIM-4 in regulating tumor cell metabolism.
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23
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Xie C, Liang C, Wang R, Yi K, Zhou X, Li X, Chen Y, Miao D, Zhong C, Zhu J. Resveratrol suppresses lung cancer by targeting cancer stem-like cells and regulating tumor microenvironment. J Nutr Biochem 2023; 112:109211. [PMID: 36370924 DOI: 10.1016/j.jnutbio.2022.109211] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 06/30/2022] [Accepted: 09/23/2022] [Indexed: 11/11/2022]
Abstract
Increasing evidence indicate that cancer stem cells (CSCs) are the key driver of tumor initiation and recurrence. The cellular and soluble components of the tumor microenvironment (TME) impact on cancer initiation and progression, such as cytokines and chemokines. Thus, targeting CSCs and TME is a novel anti-cancer approach. Resveratrol (RES), a bioactive phytochemical extracted from various plants, exhibits tumor-suppressing activities in lung cancer, yet the mechanism remains poorly understood. Our data showed that the expression level of IL-6 was positively correlated with the presence of lung cancer stem-like cells (LCSCs) in human lung cancer tissues. In vitro results showed that IL-6 was highly elevated in lung cancer sphere-forming cells and could enhance the stemness of LCSCs, including tumor sphere formation ability, the percentage of CD133 positive cells, and the expression of LCSC specific markers (CD133, ALDH1A1 and Nanog). Simultaneously, our results confirmed that RES effectively inhibited LCSC properties, downregulated Wnt/β-catenin signaling and reduced IL-6 level in vitro and in vivo. Furthermore, we found RES treatment attenuated the activation of Wnt/β-catenin signaling by LiCl (GSK3β agonist). IL-6-promoted LCSC properties and Wnt/β-catenin signaling was also reversed by RES. Taken together, these data illustrated that RES inhibited lung cancer by targeting LCSCs and IL-6 in TME. The novel findings from this study provided evidence that RES exhibited multi-target effects on suppression of lung cancer and could be a novel potent cancer-preventive compound.
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Affiliation(s)
- Chunfeng Xie
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chunhua Liang
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Rong Wang
- State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Kefan Yi
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xu Zhou
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaoting Li
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yue Chen
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Dengshun Miao
- Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Key Laboratory for Aging & Disease, Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Caiyun Zhong
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China; Cancer Research Division, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Jianyun Zhu
- Department of Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China.
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24
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Pan Z, Zhang M, Zhang F, Pan H, Li Y, Shao Y, Yuan X, Wang J, Chen J. Single-Cell Transcriptomics Unveils the Dedifferentiation Mechanism of Lung Adenocarcinoma Stem Cells. Int J Mol Sci 2022; 24:ijms24010482. [PMID: 36613925 PMCID: PMC9820263 DOI: 10.3390/ijms24010482] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/14/2022] [Accepted: 12/17/2022] [Indexed: 12/30/2022] Open
Abstract
Lung adenocarcinoma (LUAD) is a major subtype of lung cancer, and its prognosis is still poor due to therapy resistance, metastasis, and recurrence. In recent years, increasing evidence has shown that the existence of lung cancer stem cells is responsible for the propagation, metastasis, therapy resistance, and recurrence of the tumor. During their transition to cancer stem cells, tumor cells need to inhibit cell differentiation and acquire invasive characteristics. However, our understanding of the property and role of such lung cancer stem cells is still limited. In this study, lung adenocarcinoma cancer stem cells (LCSCs) were enriched from the PC-9 cell line in a serum-free condition. PC-9 cells grew into spheres and showed higher survival rates when exposed to gefitinib: the drug used for the treatment of LUAD. Additionally, we found that the canonical stemness marker protein CD44 was significantly increased in the enriched LCSCs. Then, LCSCs were inoculated into the groin of nude mice for 1.5 months, and tumors were detected in the animals, indicating the strong stemness of the cells. After that, we performed single-cell RNA sequencing (scRNA-seq) on 7320 LCSCs and explored the changes in their transcriptomic signatures. We identified cell populations with a heterogeneous expression of cancer stem marker genes in LCSCs and subsets with different degrees of differentiation. Further analyses revealed that the activation of the FOXM1 (oncoprotein) transcription factor is a key factor in cell dedifferentiation, which enables tumor cells to acquire an epithelial-mesenchymal transition phenotype and increases the LCSC surface marker CD44. Moreover, we found that the combination of CD44, ABCG2, and ALCAM was a specific marker for LCSCs. In summary, this study identified the potential factors and molecular mechanisms underlying the stemness properties of LUAD cancer cells; it could also provide insight into developing novel and effective therapeutic approaches.
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Affiliation(s)
- Zhenhua Pan
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Meidi Zhang
- School of Biomedical Engineering, Tianjin Medical University, Tianjin 300070, China
| | - Fengyu Zhang
- School of Biomedical Engineering, Tianjin Medical University, Tianjin 300070, China
| | - Hongli Pan
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Yongwen Li
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Yi Shao
- Department of Lung Cancer Surgery, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Xin Yuan
- School of Biomedical Engineering, Tianjin Medical University, Tianjin 300070, China
| | - Ju Wang
- School of Biomedical Engineering, Tianjin Medical University, Tianjin 300070, China
- Correspondence: (J.W.); (J.C.)
| | - Jun Chen
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
- Department of Lung Cancer Surgery, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
- Correspondence: (J.W.); (J.C.)
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25
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Rawangkan A, Wongsirisin P, Pook-In G, Siriphap A, Yosboonruang A, Kiddee A, Chuerduangphui J, Reukngam N, Duangjai A, Saokaew S, Praphasawat R. Dinactin: A New Antitumor Antibiotic with Cell Cycle Progression and Cancer Stemness Inhibiting Activities in Lung Cancer. Antibiotics (Basel) 2022; 11:antibiotics11121845. [PMID: 36551502 PMCID: PMC9774622 DOI: 10.3390/antibiotics11121845] [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: 11/30/2022] [Revised: 12/13/2022] [Accepted: 12/16/2022] [Indexed: 12/23/2022] Open
Abstract
Lung cancer, especially non-small cell lung cancer (NSCLC), is one of the most complex diseases, despite the existence of effective treatments such as chemotherapy and immunotherapy. Since cancer stem cells (CSCs) are responsible for chemo- and radio-resistance, metastasis, and cancer recurrence, finding new therapeutic targets for CSCs is critical. Dinactin is a natural secondary metabolite produced by microorganisms. Recently, dinactin has been revealed as a promising antitumor antibiotic via various mechanisms. However, the evidence relating to cell cycle progression regulation is constrained, and effects on cancer stemness have not been elucidated. Therefore, the aim of this study is to evaluate the new function of dinactin in anti-NSCLC proliferation, focusing on cell cycle progression and cancer stemness properties in Lu99 and A549 cells. Flow cytometry and immunoblotting analyses revealed that 0.1-1 µM of dinactin suppresses cell growth through induction of the G0/G1 phase associated with down-regulation of cyclins A, B, and D3, and cdk2 protein expression. The tumor-sphere forming capacity was used to assess the effect of dinactin on the cancer stemness potential in NSCLC cells. At a concentration of 1 nM, dinactin reduced both the number and size of the tumor-spheres. The quantitative RT-PCR analyses indicated that dinactin suppressed sphere formation by significantly reducing expression of CSC markers (i.e., ALDH1A1, Nanog, Oct4, and Sox2) in Lu99 cells. Consequently, dinactin could be a promising strategy for NSCLC therapy targeting CSCs.
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Affiliation(s)
- Anchalee Rawangkan
- Division of Microbiology and Parasitology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
- UNIt of Excellence on Clinical Outcomes Research and IntegratioN (UNICORN), School of Pharmaceutical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Pattama Wongsirisin
- Department of Medical Services, National Cancer Institute, Bangkok 10400, Thailand
| | - Grissana Pook-In
- Division of Microbiology and Parasitology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Achiraya Siriphap
- Division of Microbiology and Parasitology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Atchariya Yosboonruang
- Division of Microbiology and Parasitology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Anong Kiddee
- Division of Microbiology and Parasitology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| | | | - Nanthawan Reukngam
- Laboratory of Organic Synthesis, Chulabhorn Research Institute, Bangkok 10210, Thailand
| | - Acharaporn Duangjai
- Division of Physiology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Surasak Saokaew
- UNIt of Excellence on Clinical Outcomes Research and IntegratioN (UNICORN), School of Pharmaceutical Sciences, University of Phayao, Phayao 56000, Thailand
- Division of Social and Administrative Pharmacy, Department of Pharmaceutical Care, School of Pharmaceutical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Ratsada Praphasawat
- Department of Pathology, School of Medicine, University of Phayao, Phayao 56000, Thailand
- Correspondence: ; Tel.: +66-54466666 (ext. 3824) or +66-86-926-2448
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26
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Li Y, Hu J, Guo D, Ma W, Zhang X, Zhang Z, Lu G, He S. LncRNA SNHG5 promotes the proliferation and cancer stem cell-like properties of HCC by regulating UPF1 and Wnt-signaling pathway. Cancer Gene Ther 2022; 29:1373-1383. [PMID: 35338348 PMCID: PMC9576592 DOI: 10.1038/s41417-022-00456-3] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 02/10/2022] [Accepted: 03/04/2022] [Indexed: 12/22/2022]
Abstract
The role of long noncoding RNA (lncRNAs) had been demonstrated in different types of cancer, including hepatocellular carcinoma. This study was intended to investigate the role of lncRNA small nucleolar RNA host gene 5 (SNHG5) in HCC proliferation and the liver CSC-like properties. Through functional experiments, we determined that knockdown of SNHG5 repressed HCC cell proliferation and CSC-like properties, while over-expression of SNHG5 promoted cell growth. At the same time, CSC markers (CD44, CD133, and ALDH1) and related transcription factors (OCT4, SOX2, and NANOG) were downregulated when SNHG5 was knocked down. Mechanically, RNA immunoprecipitation (RIP) and RNA pulldown assay showed that SNHG5 regulated the proliferation and CSC-like properties of HCC by binding UPF1. Further investigations showed that expression of critical components of Wnt/β-catenin pathway (β-catenin, TCF4, c-myc, cyclinD1, and c-Jun) were upregulated with depletion of UPF1 in liver CSCs, which were downregulated with depletion of SNHG5. After use of the inhibitor of Wnt/β-catenin pathway, the formation of liver CSCs sphere decreased. Taken together, SNHG5 plays a critical role to promote HCC cell proliferation and cancer stem cell-like properties via UPF1 and Wnt/β-catenin pathway.
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Affiliation(s)
- Yarui Li
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China
| | - Junbi Hu
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China
| | - Dan Guo
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China
| | - Wenhui Ma
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China
| | - Xu Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China
| | - Zhiyong Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China
| | - Guifang Lu
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China
| | - Shuixiang He
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China.
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Dzul Keflee R, Hoong Leong K, Ogawa S, Bignon J, Chiang Chan M, Weng Kong K. Overview of the multifaceted resistances toward EGFR-TKIs and new chemotherapeutic strategies in non-small cell lung cancer. Biochem Pharmacol 2022; 205:115262. [PMID: 36191627 DOI: 10.1016/j.bcp.2022.115262] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 09/19/2022] [Accepted: 09/20/2022] [Indexed: 11/02/2022]
Abstract
The role of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) has been vastly studied over the last decade. This has led to the rapid development of many generations of EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, patients treated with third-generation TKIs (osimertinib, avitinib and rociletinib) targeting the EGFR T790M mutation have shown emerging resistances and relapses. Therefore, further molecular understanding of NSCLC mutations, bypass signalling, tumour microenvironment and the existence of cancer stem cells to overcome such resistances is warranted. This will pave the way for designing novel and effective chemotherapies to improve patients' overall survival. In this review, we provide an overview of the multifaceted mechanism of resistances towards EGFR-TKIs, as well as the challenges and perspectives that should be addressed in strategising chemotherapeutic treatments to overcome the ever evolving and adaptive nature of NSCLC.
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Affiliation(s)
- Rashidi Dzul Keflee
- Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - Kok Hoong Leong
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.
| | - Satoshi Ogawa
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, 47500 Bandar Sunway, Selangor, Malaysia
| | - Jerome Bignon
- Institut de Chimie des Substances Naturelles CNRS UPR 2301, Université Paris Saclay, Gif-sur-Yvette, France
| | - Mun Chiang Chan
- Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - Kin Weng Kong
- Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.
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Identification of Prognostic Markers and Potential Therapeutic Targets in Gastric Adenocarcinoma by Machine Learning Based on mRNAsi Index. JOURNAL OF ONCOLOGY 2022; 2022:8926127. [PMID: 36213825 PMCID: PMC9546691 DOI: 10.1155/2022/8926127] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/11/2022] [Accepted: 09/14/2022] [Indexed: 11/23/2022]
Abstract
Background Cancer stem cells (CSCs), characterized by self-renewal and therapeutic resistance, play important roles in stomach adenocarcinoma (STAD). However, the molecular mechanism of STAD stem cells is still unclear. In this study, our purpose is to explore the expression of stem cell-related genes in STAD. Methods The stemness index based on mRNA expression (mRNAsi) was used to analyze STAD cases in The Cancer Genome Atlas (TCGA). Firstly, mRNAsi was used and analyzed by differential expression, survival analysis, clinical stage, and gender in STAD. Then, weighted gene coexpression network analysis (WGCNA) was used to discover the fascinating modules and key genes. Enrichment analysis was carried out to annotate the functions and pathways of key genes. The gene expression comprehensive database (GEO) in STAD was used to verify the expression levels of key genes in all cancers. Protein-protein interaction networks is used to determine the relationships between key genes. Results The mRNAsi was obviously upregulated in tumor cases. With the increase of tumor stage and T stage, the mRNAsi score decreased, and the overall survival rate of high score group patients was better. According to the degree of association with mRNAsi, different modules and key genes were screened out. A total of 6,740 differential genes were found, of which 1,147 genes were downregulated and 5,593 genes were upregulated. 19 key genes (BUB1, BUB1B, KIF14, NCAPH, RACGAP, KIF15, CENPF, TPX2, RAD54L, KIF18B, KIF4A, TTK, SGO2, PLK4, ARHGAP11A, XRCC2, Clorf112, NCAPG, and ORC6) were screened due to significant upregulation in STAD. And they had been proven that enriched from the cell cycle Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, relating to cell proliferation Gene Ontology (GO) terms, as well. Among them, 9 genes have been extensively associated to OS, and 3 genes had been associated to receive chemotherapy resistance. PPI protein network suggests that there is a sturdy correlation between these key genes. Conclusion A total of 19 key genes were found to play an essential position in retaining the traits of STAD stem cells. These genes can be used to evaluate the prognosis of STAD patients or become specific therapeutic targets.
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Skurikhin EG, Ermakova N, Zhukova M, Pershina O, Pan E, Pakhomova A, Kogai L, Goldberg V, Simolina E, Skurikhina V, Widera D, Kubatiev A, Morozov SG, Kushlinskii N, Dygai A. Analysis of Circulating Tumor and Cancer Stem Cells Provides New Opportunities in Diagnosis and Treatment of Small Cell Lung Cancer. Int J Mol Sci 2022; 23:ijms231810853. [PMID: 36142766 PMCID: PMC9503899 DOI: 10.3390/ijms231810853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/12/2022] [Accepted: 09/14/2022] [Indexed: 11/16/2022] Open
Abstract
Current methods for diagnosis and treatment of small cell lung cancer (SCLC) have only a modest efficacy. In this pilot study, we analyzed circulating tumor cells (CTCs) and cancer stem cells (CSCs) in patients with SCLC to search for new diagnostic and prognostic markers and novel approaches to improve the treatment of the disease. In other forms of lung cancer, we showed a heterogeneity of blood CTCs and CSCs populations, as well as changes in other cell populations (ALDH+, CD87+CD276+, and EGF+Axl+) in smokers. A number of CTCs and CSCs in patients with SCLC have been shown to be resistant to chemotherapy (CT). High cytotoxic activity and resistance to apoptosis of reprogrammed CD3+CD8+ T-lymphocytes (rTcells) in relation to naive CD3+CD8+ T-lymphocytes was demonstrated in a smoking patient with SCLC (Patient G) in vitro. The target for rTcells was patient G’s blood CSCs. Reprogramming of CD3+CD8+ T-lymphocytes was carried out with the MEK1/2 inhibitor and PD-1/PD-L1 pathway blocker nivolumab. The training procedure was performed with a suspension of dead CTCs and CSCs obtained from patient’s G blood. The presented data show a new avenue for personalized SCLC diagnosis and targeted improvement of chemotherapy based on the use of both CTCs and CSCs.
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Affiliation(s)
- Evgenii G. Skurikhin
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Lenin, 3, 634028 Tomsk, Russia
- Correspondence: ; Tel.: +7-3822-418-375
| | - Natalia Ermakova
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Lenin, 3, 634028 Tomsk, Russia
| | - Mariia Zhukova
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Lenin, 3, 634028 Tomsk, Russia
- Ministry of Health of the Russian Federation, Siberian State Medical University, Moskovski, 2, 634050 Tomsk, Russia
| | - Olga Pershina
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Lenin, 3, 634028 Tomsk, Russia
| | - Edgar Pan
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Lenin, 3, 634028 Tomsk, Russia
| | - Angelina Pakhomova
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Lenin, 3, 634028 Tomsk, Russia
| | - Lena Kogai
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Lenin, 3, 634028 Tomsk, Russia
- Ministry of Health of the Russian Federation, Siberian State Medical University, Moskovski, 2, 634050 Tomsk, Russia
| | - Victor Goldberg
- Cancer Research Institute, Tomsk National Research Medical Center, Kooperativny, 5, 634009 Tomsk, Russia
| | - Elena Simolina
- Cancer Research Institute, Tomsk National Research Medical Center, Kooperativny, 5, 634009 Tomsk, Russia
| | - Victoria Skurikhina
- Ministry of Health of the Russian Federation, Siberian State Medical University, Moskovski, 2, 634050 Tomsk, Russia
| | - Darius Widera
- Stem Cell Biology and Regenerative Medicine Group, School of Pharmacy, Whiteknights Campus, Reading RG6 6AP, UK
| | - Aslan Kubatiev
- Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia
| | - Sergey G. Morozov
- Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia
| | | | - Alexander Dygai
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Lenin, 3, 634028 Tomsk, Russia
- Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia
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PFKFB3 regulates cancer stemness through the hippo pathway in small cell lung carcinoma. Oncogene 2022; 41:4003-4017. [PMID: 35804016 PMCID: PMC9374593 DOI: 10.1038/s41388-022-02391-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 06/13/2022] [Accepted: 06/15/2022] [Indexed: 12/16/2022]
Abstract
PFKFB3 (6-phosphofructo-2-kinase) is the rate-limiting enzyme of glycolysis and is overexpressed in several human cancers that are associated with poor prognosis. High PFKFB3 expression in cancer stem cells promotes glycolysis and survival in the tumor microenvironment. Inhibition of PFKFB3 by the glycolytic inhibitor PFK158 and by shRNA stable knockdown in small cell lung carcinoma (SCLC) cell lines inhibited glycolysis, proliferation, spheroid formation, and the expression of cancer stem cell markers CD133, Aldh1, CD44, Sox2, and ABCG2. These factors are also associated with chemotherapy resistance. We found that PFK158 treatment and PFKFB3 knockdown enhanced the ABCG2-interacting drugs doxorubicin, etoposide, and 5-fluorouracil in reducing cell viability under conditions of enriched cancer stem cells (CSC). Additionally, PFKFB3 inhibition attenuated the invasion/migration of SCLC cells by downregulating YAP/TAZ signaling while increasing pLATS1 via activation of pMST1 and NF2 and by reducing the mesenchymal protein expression. PFKFB3 knockdown and PFK158 treatment in a H1048 SCLC cancer stem cell-enriched mouse xenograft model showed significant reduction in tumor growth and weight with reduced expression of cancer stem cell markers, ABCG2, and YAP/TAZ. Our findings identify that PFKFB3 is a novel target to regulate cancer stem cells and its associated therapeutic resistance markers YAP/TAZ and ABCG2 in SCLC models.
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Cisplatin-Resistant CD44+ Lung Cancer Cells Are Sensitive to Auger Electrons. Int J Mol Sci 2022; 23:ijms23137131. [PMID: 35806135 PMCID: PMC9266901 DOI: 10.3390/ijms23137131] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/20/2022] [Accepted: 06/23/2022] [Indexed: 02/01/2023] Open
Abstract
Cancer stem cells (CSCs) are resistant to conventional therapy and present a major clinical challenge since they are responsible for the relapse of many cancers, including non-small cell lung cancer (NSCLC). Hence, future successful therapy should also eradicate CSCs. Auger electrons have demonstrated promising therapeutic potential and can induce DNA damage while sparing surrounding cells. Here, we sort primary patient-derived NSCLC cells based on their expression of the CSC-marker CD44 and investigate the effects of cisplatin and a thymidine analog (deoxyuridine) labeled with an Auger electron emitter (125I). We show that the CD44+ populations are more resistant to cisplatin than the CD44− populations. Interestingly, incubation with the thymidine analog 5-[125I]iodo-2′-deoxyuridine ([125I]I-UdR) induces equal DNA damage, G2/M cell cycle arrest, and apoptosis in the CD44− and CD44+ populations. Our results suggest that Auger electron emitters can also eradicate resistant lung cancer CD44+ populations.
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Chen M, Wang X, Wang W, Gui X, Li Z. Immune- and Stemness-Related Genes Revealed by Comprehensive Analysis and Validation for Cancer Immunity and Prognosis and Its Nomogram in Lung Adenocarcinoma. Front Immunol 2022; 13:829057. [PMID: 35833114 PMCID: PMC9271778 DOI: 10.3389/fimmu.2022.829057] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 05/20/2022] [Indexed: 12/24/2022] Open
Abstract
Objective Lung adenocarcinoma (LUAD) is a familiar lung cancer with a very poor prognosis. This study investigated the immune- and stemness-related genes to develop model related with cancer immunity and prognosis in LUAD. Method The Cancer Genome Atlas (TCGA) was utilized for obtaining original transcriptome data and clinical information. Differential expression, prognostic value, and correlation with clinic parameter of mRNA stemness index (mRNAsi) were conducted in LUAD. Significant mRNAsi-related module and hub genes were screened using weighted gene coexpression network analysis (WGCNA). Meanwhile, immune-related differential genes (IRGs) were screened in LUAD. Stem cell index and immune-related differential genes (SC-IRGs) were screened and further developed to construct prognosis-related model and nomogram. Comprehensive analysis of hub genes and subgroups, involving enrichment in the subgroup [gene set enrichment analysis (GSEA)], gene mutation, genetic correlation, gene expression, immune, tumor mutation burden (TMB), and drug sensitivity, used bioinformatics and reverse transcription polymerase chain reaction (RT-PCR) for verification. Results Through difference analysis, mRNAsi of LUAD group was markedly higher than that of normal group. Clinical parameters (age, gender, and T staging) were ascertained to be highly relevant to mRNAsi. MEturquoise and MEblue were found to be the most significant modules (including positive and negative correlations) related to mRNAsi via WGCNA. The functions and pathways of the two mRNAsi-related modules were mainly enriched in tumorigenesis, development, and metastasis. Combining stem cell index-related differential genes and immune-related differential genes, 30 prognosis-related SC-IRGs were screened via Cox regression analysis. Then, 16 prognosis-related SC-IRGs were screened to construct a LASSO regression model at last. In addition, the model was successfully validated by using TCGA-LUAD and GSE68465, whereas c-index and the calibration curves were utilized to demonstrate the clinical value of our nomogram. Following the validation of the model, GSEA, immune cell correlation, TMB, clinical relevance, etc., have found significant difference in high- and low-risk groups, and 16-gene expression of the SC-IRG model also was tested by RT-PCR. ADRB2, ANGPTL4, BDNF, CBLC, CX3CR1, and IL3RA were found markedly different expression between the tumor and normal group. Conclusion The SC-IRG model and the prognostic nomogram could accurately predict LUAD survival. Our study used mRNAsi combined with immunity that may lay a foundation for the future research studies in LUAD.
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Affiliation(s)
- Mengqing Chen
- Department of Respiratory and Critical Care Medicine, the Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xue Wang
- Department of Respiratory and Critical Care Medicine, the Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Wenjun Wang
- Department of Respiratory and Critical Care Medicine, the Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xuemei Gui
- Department of Respiratory and Critical Care Medicine, the Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Zhan Li
- Department of Stem Cell and Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China
- Central Laboratory, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China
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Multifunctional Nanoplatforms as a Novel Effective Approach in Photodynamic Therapy and Chemotherapy, to Overcome Multidrug Resistance in Cancer. Pharmaceutics 2022; 14:pharmaceutics14051075. [PMID: 35631660 PMCID: PMC9143284 DOI: 10.3390/pharmaceutics14051075] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/02/2022] [Accepted: 05/14/2022] [Indexed: 12/24/2022] Open
Abstract
It is more than sixty years since the era of modern photodynamic therapy (PDT) for cancer began. Enhanced selectivity for malignant cells with a reduced selectivity for non-malignant cells and good biocompatibility along with the limited occurrence of side effects are considered to be the most significant advantages of PDT in comparison with conventional therapeutic approaches, e.g., chemotherapy. The phenomenon of multidrug resistance, which is associated with drug efflux transporters, was originally identified in relation to the application of chemotherapy. Unfortunately, over the last thirty years, numerous papers have shown that many photosensitizers are the substrates of efflux transporters, significantly restricting the effectiveness of PDT. The concept of a dynamic nanoplatform offers a possible solution to minimize the multidrug resistance effect in cells affected by PDT. Indeed, recent findings have shown that the utilization of nanoparticles could significantly enhance the therapeutic efficacy of PDT. Additionally, multifunctional nanoplatforms could induce the synergistic effect of combined treatment regimens, such as PDT with chemotherapy. Moreover, the surface modifications that are associated with nanoparticle functionalization significantly improve the target potential of PDT or chemo-PDT in multidrug resistant and cancer stem cells.
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Fan Y, Wang Q, Shi M, Ju G, Lu H, Zheng L, Chen J, Zhou X, Xiao T, Chen S. Circ_0020123 promotes NSCLC tumorigenesis via up-regulating KIAA1522 expression through miR-940. Cell Cycle 2022; 21:894-907. [PMID: 35196193 PMCID: PMC9037485 DOI: 10.1080/15384101.2022.2034093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Circ_0020123 was highly expressed in NSCLC tissues and cell lines, and knockdown of circ_0020123 abolished cell growth, migration and invasion in vitro and hindered tumor growth in nude mice. Mechanically, circ_0020123 directly targeted miR-940, and KIAA1522 was a target of miR-940. Thereafter, a series of rescue experiments showed that circ_0020123 served its biological functions by miR-940/KIAA1522 axis. In all, circ_0020123 acted as an oncogene to promote the tumorigenesis of NSCLC via miR-940/KIAA1522 axis, suggesting a potential therapeutic target for NSCLC treatment.
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Affiliation(s)
- Yihui Fan
- Department of Thoracic Surgery, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China
| | - Qing Wang
- Department of Thoracic Surgery, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China
| | - Minxin Shi
- Department of Thoracic Surgery, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China
| | - Guanjun Ju
- Department of Thoracic Surgery, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China
| | - Haimin Lu
- Department of Thoracic Surgery, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China
| | - Liyun Zheng
- Department of Scientific, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China
| | - Jian Chen
- Department of Clinical Laboratory, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China
| | - Xiaomei Zhou
- Department of Thoracic Surgery, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China
| | - Ting Xiao
- Department of Thoracic Surgery, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China
| | - Saihua Chen
- Department of Thoracic Surgery, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China,CONTACT Saihua Chen Department of Thoracic Surgery, Tumor Hospital Affiliated to Nantong University, No. 30, Tongyang North Road, Pingchao Town, Tongzhou District, Nantong City, Jiangsu Province, China
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Ring finger protein 6 enhances chemo-resistance by transcriptionally activating proliferating cell nuclear antigen expression and attenuating DNA damage in lung adenocarcinoma. Cancer Lett 2022; 534:215609. [DOI: 10.1016/j.canlet.2022.215609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/15/2022] [Accepted: 02/24/2022] [Indexed: 11/20/2022]
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Serum Level of CEACAM1 in Patients with Nonsmall Cell Lung Cancer and Its Clinical Significance in Cancer Tissue. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:7948010. [PMID: 35449849 PMCID: PMC9018175 DOI: 10.1155/2022/7948010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/16/2022] [Accepted: 03/18/2022] [Indexed: 12/23/2022]
Abstract
Objective To analyze the expression of CEACAM1 in serum of patients with nonsmall cell lung cancer (NSCLC) and to explore the correlation and clinical significance between the expression of CEACAM1 and pathological parameters of NSCLC tissue. Methods A total of 100 patients with NSCLC who underwent tumor resection were screened. Another 100 healthy patients in physical examination department were selected as control group. Venous blood and cancer tissue samples were collected. The expression of CEACAM1, TGF-β, VEGF-A, and IL-8 was detected. Results The results of various indicators in the lung cancer group were much higher than those in the healthy group; CEACAM1 was significantly positively correlated with TGF-β expression. The later the clinical stage and the higher the degree of differentiation of cancer tissue specimens, the more the expression of CEACAM1 in serum samples. Conclusions The expression level of CEACAM1 in the serum of NSCLC patients is strongly correlated with TGF-β, VEGF-A, and IL-8, indicating that serum CEACAM1 and TGF-β levels can predict the occurrence, progression, and prognosis of lung cancer and provide a target for future targeted therapy of lung cancer.
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Nicoś M, Krawczyk P. Genetic Clonality as the Hallmark Driving Evolution of Non-Small Cell Lung Cancer. Cancers (Basel) 2022; 14:1813. [PMID: 35406585 PMCID: PMC8998004 DOI: 10.3390/cancers14071813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/28/2022] [Accepted: 03/29/2022] [Indexed: 12/12/2022] Open
Abstract
Data indicate that many driver alterations from the primary tumor of non-small cell lung cancer (NSCLC) are predominantly shared across all metastases; however, disseminating cells may also acquire a new genetic landscape across their journey. By comparing the constituent subclonal mutations between pairs of primary and metastatic samples, it is possible to derive the ancestral relationships between tumor clones, rather than between tumor samples. Current treatment strategies mostly rely on the theory that metastases are genetically similar to the primary lesions from which they arise. However, intratumor heterogeneity (ITH) affects accurate diagnosis and treatment decisions and it is considered the main hallmark of anticancer therapy failure. Understanding the genetic changes that drive the metastatic process is critical for improving the treatment strategies of this deadly condition. Application of next generation sequencing (NGS) techniques has already created knowledge about tumorigenesis and cancer evolution; however, further NGS implementation may also allow to reconstruct phylogenetic clonal lineages and clonal expansion. In this review, we discuss how the clonality of genetic alterations influence the seeding of primary and metastatic lesions of NSCLC. We highlight that wide genetic analyses may reveal the phylogenetic trajectories of NSCLC evolution, and may pave the way to better management of follow-up and treatment.
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Affiliation(s)
- Marcin Nicoś
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-954 Lublin, Poland;
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Cortes-Dericks L, Galetta D. Impact of Cancer Stem Cells and Cancer Stem Cell-Driven Drug Resiliency in Lung Tumor: Options in Sight. Cancers (Basel) 2022; 14:267. [PMID: 35053430 PMCID: PMC8773978 DOI: 10.3390/cancers14020267] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 12/20/2021] [Accepted: 01/04/2022] [Indexed: 12/12/2022] Open
Abstract
Causing a high mortality rate worldwide, lung cancer remains an incurable malignancy resistant to conventional therapy. Despite the discovery of specific molecular targets and new treatment strategies, there remains a pressing need to develop more efficient therapy to further improve the management of this disease. Cancer stem cells (CSCs) are considered the root of sustained tumor growth. This consensus corroborates the CSC model asserting that a distinct subpopulation of malignant cells within a tumor drives and maintains tumor progression with high heterogeneity. Besides being highly tumorigenic, CSCs are highly refractory to standard drugs; therefore, cancer treatment should be focused on eliminating these cells. Herein, we present the current knowledge of the existence of CSCs, CSC-associated mechanisms of chemoresistance, the ability of CSCs to evade immune surveillance, and potential CSC inhibitors in lung cancer, to provide a wider insight to drive a more efficient elimination of this pro-oncogenic and treatment-resistant cell fraction.
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Affiliation(s)
| | - Domenico Galetta
- Division of Thoracic Surgery, European Institute of Oncology, IRCCS, 20141 Milan, Italy;
- Department of Oncology and Hematology-Oncology-DIPO, University of Milan, 20122 Milan, Italy
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Yu J, Zhang L, Peng J, Ward R, Hao P, Wang J, Zhang N, Yang Y, Guo X, Xiang C, An S, Xu TR. Dictamnine, a novel c-Met inhibitor, suppresses the proliferation of lung cancer cells by downregulating the PI3K/AKT/mTOR and MAPK signaling pathways. Biochem Pharmacol 2022; 195:114864. [PMID: 34861243 DOI: 10.1016/j.bcp.2021.114864] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/20/2021] [Accepted: 11/26/2021] [Indexed: 01/19/2023]
Abstract
Dictamnine (Dic), a naturally occurring small-molecule furoquinoline alkaloid isolated from the root bark of Dictamnus dasycarpus Turcz., is reported to display anticancer properties. However, little is known about the direct target proteins and anticancer mechanisms of Dic. In the current study, Dic was found to suppress the growth of lung cancer cells in vitro and in vivo, and to attenuate the activation of PI3K/AKT/mTOR and mitogen-activated protein kinase (MAPK) signaling pathways by inhibiting the phosphorylation and activation of receptor tyrosine kinase c-Met. Moreover, the binding of Dic to c-Met was confirmed by using cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assay. Among all cancer cell lines tested, Dic inhibited the proliferation of c-Met-dependent EBC-1 cells with the greatest potency (IC50 = 2.811 μM). Notably, Dic was shown to synergistically improve the chemo-sensitivity of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-resistant lung cancer cells to gefitinib and osimertinib. These results suggest that Dic is a c-Met inhibitor that can serve as a potential therapeutic agent in the treatment of lung cancer, especially against EGFR TKI-resistant and c-Met-dependent lung cancer.
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Affiliation(s)
- Jiaojiao Yu
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
| | - Lijing Zhang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
| | - Jun Peng
- Department of Thoracic Surgery, the First People's Hospital of Yunnan Province, Kunming 650032, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, China
| | - Richard Ward
- Centre for Translational Pharmacology, Institute of Molecular Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
| | - Peiqi Hao
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
| | - Jiwei Wang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
| | - Na Zhang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
| | - Yang Yang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
| | - Xiaoxi Guo
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
| | - Cheng Xiang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
| | - Su An
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China; State Key Laboratory of Primate Biomedical Research, Kunming University of Science and Technology, Kunming 650500, China.
| | - Tian-Rui Xu
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China; State Key Laboratory of Primate Biomedical Research, Kunming University of Science and Technology, Kunming 650500, China.
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Potential Role of GST- π in Lung Cancer Stem Cell Cisplatin Resistance. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9142364. [PMID: 34840986 PMCID: PMC8626171 DOI: 10.1155/2021/9142364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 10/14/2021] [Accepted: 10/20/2021] [Indexed: 11/18/2022]
Abstract
Background Cancer stem cells (CSCs) are responsible for tumorigenesis, chemoresistance, and metastasis. Chemoresistance is a major challenge in the management of lung cancer. Glutathione-sulphur-transferase-π (GST-π) plays an important role in the origin and development of various types of cancer by regulating the cellular redox balance. Recent investigations have demonstrated that GST-π is associated with the chemoresistance of lung CSCs (LCSCs). However, the mechanism of GST-π in lung cancer, particularly in LCSCs, remains unclear. The present study is aimed at exploring the potential role of GST-π in stemness and cisplatin (DDP) resistance of LCSCs. Materials and methods. In the present study, lung cancer cell spheres were established using the A549 cell line, which according to our previous research, was confirmed to exhibit characteristics of stem cells. Next, GST-π protein expression, apoptosis percentage, and intracellular reactive oxygen species (ROS) concentration in A549 adherent cells and A549 cell spheres were analyzed by western blotting and flow cytometry, respectively. Finally, DDP resistance, ROS concentration, and GST-π expression in LCSCs were analyzed following the interference with GST-π using DL-buthionine-(S,R)-sulphoximine and N-acetylcysteine. Results The results revealed that GST-π was highly expressed in A549 cell spheres compared with A549 adherent cells and was associated with a decreased intracellular ROS concentration (both P < 0.05). Regulating GST-π protein expression could alter DDP resistance of LCSCs by influencing ROS. Conclusion These results suggested that GST-π may be important for LCSC drug resistance by downregulating ROS levels. These findings may contribute to the development of new adjuvant therapeutic strategies for lung cancer.
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Primary Lung Cancer Organoids for Personalized Medicine-Are They Ready for Clinical Use? Cancers (Basel) 2021; 13:cancers13194832. [PMID: 34638316 PMCID: PMC8507762 DOI: 10.3390/cancers13194832] [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: 08/23/2021] [Revised: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Identification of novel therapeutic strategies for the treatment of non-small cell lung cancer (NSCLC) remains an urgent need in the area of lung cancer research. Traditional in vitro cell culture systems form one of the corner stones of cancer research. However, the growth of cancer cells in a two-dimensional pattern on a plastic dish in artificial conditions is not ideal, as the growth pattern significantly differs from that of a complex tumor in a patient. Hence, in recent years, efforts have been undertaken to generate more complex three-dimensional in vitro models, so-called organoid or tumoroid models, that more closely resemble the growth pattern and tumor heterogeneity observed in a patient. In this review, we summarize the efforts thus far undertaken in the area of NSCLC organoid development. Abstract Despite many developments in recent years, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death worldwide. Therefore, additional research, aiming to further elucidate the underlying molecular mechanisms of malignant transformation and development of therapy resistance, as well as the identification of additional novel therapeutic avenues, is crucial. For this purpose, reliable in vitro models are indispensable, as they allow for quick identification of suspected oncogenic drivers or evaluation of novel therapeutic strategies in a timely and cost-effective fashion. However, standard two-dimensional cell culture systems, the most frequently used in vitro model, are usually not truly representative of the situation in a patient as these models lack the tumor heterogeneity, the surrounding tumor microenvironment and the three-dimensional complexity of a tumor in vitro. For this reason, 3D cell culture systems, in particular organoids generated from normal non-malignant cells or tumor cell-based organoids (tumoroids), have in recent years gained much attention as alternative in vitro model systems that more closely resemble the actual primary tumor. In this review, we provide an overview of the available literature in the field of NSCLC organoids, which might still be in its infancy, but is gaining momentum.
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Lu J, Cao LL, Xu Y, Huang XY, Cho SJ, Ashktorab H, Smoot DT, Li P, Zheng CH, Kim JW, Ryeom SW, Yoon SS, Yoon C, Huang CM. WITHDRAWN: FOXC1 modulates stem-like cell properties and chemoresistance through hedgehog and EMT signaling in gastric adenocarcinoma. Mol Ther 2021:S1525-0016(21)00464-0. [PMID: 34534693 DOI: 10.1016/j.ymthe.2021.09.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 03/30/2021] [Accepted: 09/07/2021] [Indexed: 11/21/2022] Open
Abstract
This article has been withdrawn at the request of the editors. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
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Affiliation(s)
- Jun Lu
- Department of Gastric Surgery, Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10013, USA
| | - Long-Long Cao
- Department of Gastric Surgery, Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
| | - Yu Xu
- Department of Pathology, School of Basic Medical Sciences, Fujian Medical, 35001 University, Fuzhou 35001, Fujian Province, China
| | - Xiao-Yan Huang
- Department of Gastric Surgery, Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
| | - Soo-Jeong Cho
- Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul 100-000, South Korea
| | - Hassan Ashktorab
- Department of Medicine, Howard University, Washington, DC 20541, USA
| | - Duane T Smoot
- Department of Medicine, Howard University, Washington, DC 20541, USA
| | - Ping Li
- Department of Gastric Surgery, Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
| | - Chao-Hui Zheng
- Department of Gastric Surgery, Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
| | - Ji-Won Kim
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Gyeonggi-do 100-000, South Korea
| | - Sandra W Ryeom
- Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19019, USA; Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032
| | - Sam S Yoon
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10013, USA; Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032
| | - Changhwan Yoon
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10013, USA; Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032.
| | - Chang-Ming Huang
- Department of Gastric Surgery, Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China.
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Crous A, Abrahamse H. Aluminium (III) phthalocyanine chloride tetrasulphonate is an effective photosensitizer for the eradication of lung cancer stem cells. ROYAL SOCIETY OPEN SCIENCE 2021; 8:210148. [PMID: 34527268 PMCID: PMC8424323 DOI: 10.1098/rsos.210148] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 08/19/2021] [Indexed: 05/04/2023]
Abstract
Cancer stem cells (CSCs) are considered to contribute to the recurrence of lung cancer due to their stem-like nature and the involvement of genetic markers associated with drug efflux, regeneration and metastases. Photodynamic therapy (PDT) is a cost-effective and non-invasive therapeutic application that can act as an alternative therapy for lung cancer when considering CSC involvement. Stem-like cells derived from the A549 lung cancer cell line, positive for CD133, CD56 and CD44 antigen markers, were characterized, intracellular localization of aluminium (III) phthalocyanine chloride tetrasulphonate (AlPcS4Cl) determined and its anti-cancer PDT effects were evaluated. Results confirmed that isolated cells were stem cell-like and subcellular localization of AlPcS4Cl in integral organelles involved in cell homeostasis supported the destruction of CSC. AlPcS4Cl's effectivity was demonstrated with CSC eradication showing a significant increase in cytotoxicity and cell death via apoptosis, caused by a decrease in mitochondrial membrane potential. PDT could serve as a palliative treatment for lung cancer and improve prognosis by elimination of lung CSCs.
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Affiliation(s)
- Anine Crous
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, PO Box 17011, Johannesburg 2028, South Africa
| | - Heidi Abrahamse
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, PO Box 17011, Johannesburg 2028, South Africa
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Wu Q, Siddharth S, Sharma D. Triple Negative Breast Cancer: A Mountain Yet to Be Scaled Despite the Triumphs. Cancers (Basel) 2021; 13:3697. [PMID: 34359598 PMCID: PMC8345029 DOI: 10.3390/cancers13153697] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/13/2021] [Accepted: 07/18/2021] [Indexed: 12/12/2022] Open
Abstract
Metastatic progression and tumor recurrence pertaining to TNBC are certainly the leading cause of breast cancer-related mortality; however, the mechanisms underlying TNBC chemoresistance, metastasis, and tumor relapse remain somewhat ambiguous. TNBCs show 77% of the overall 4-year survival rate compared to other breast cancer subtypes (82.7 to 92.5%). TNBC is the most aggressive subtype of breast cancer, with chemotherapy being the major approved treatment strategy. Activation of ABC transporters and DNA damage response genes alongside an enrichment of cancer stem cells and metabolic reprogramming upon chemotherapy contribute to the selection of chemoresistant cells, majorly responsible for the failure of anti-chemotherapeutic regime. These selected chemoresistant cells further lead to distant metastasis and tumor relapse. The present review discusses the approved standard of care and targetable molecular mechanisms in chemoresistance and provides a comprehensive update regarding the recent advances in TNBC management.
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Affiliation(s)
| | - Sumit Siddharth
- Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA;
| | - Dipali Sharma
- Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA;
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Fu W, Zhao J, Hu W, Dai L, Jiang Z, Zhong S, Deng B, Huang Y, Wu W, Yin J. LINC01224/ZNF91 Promote Stem Cell-Like Properties and Drive Radioresistance in Non-Small Cell Lung Cancer. Cancer Manag Res 2021; 13:5671-5681. [PMID: 34285587 PMCID: PMC8286114 DOI: 10.2147/cmar.s313744] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 06/13/2021] [Indexed: 12/22/2022] Open
Abstract
Background Radioresistance is the main reason for the failure of radiotherapy in non-small-cell lung cancer (NSCLC); however, the molecular mechanism of radioresistance is still unclear. Methods An RNA-Seq assay was used to screen differentially expressed long non-coding RNAs (lncRNAs) and genes in irradiation-resistant NSCLC cells. RT-PCR and Western blotting assays were performed to analyze the expressions of lncRNAs and genes. The chromosome conformation capture (3C) assay was performed to measure chromatin interactions. Cell cytotoxicity, cell apoptosis, sphere formation and Transwell assays were performed to assess cellular function. Results In this study, it was found that LINC01224 increased during the induction of radioresistance in NSCLC cells. LINC01224 was located within the enhancer of ZNF91, and LINC01224 could affect the transcription of ZNF91 by regulating the long-range interactions between the ZNF91 enhancer and promoter. Moreover, upregulation of LINC01224 and ZNF91 could promote irradiation resistance by regulating the stem cell-like properties of NSCLC cells. In addition, high expression levels of LINC01224 and ZNF91 in tissue samples were associated with radioresistance in NSCLC patients. Conclusion Our findings demonstrated that LINC01224/ZNF91 drove radioresistance regulation by promoting the stem cell-like properties in NSCLC.
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Affiliation(s)
- Wenfan Fu
- Departments of Chest Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, People's Republic of China
| | - Jian Zhao
- Departments of Chest Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, People's Republic of China
| | - Weimin Hu
- Departments of Chest Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, People's Republic of China
| | - Lu Dai
- Departments of Chest Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, People's Republic of China
| | - Zeyong Jiang
- Departments of Chest Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, People's Republic of China
| | - Shengpeng Zhong
- Departments of Chest Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, People's Republic of China
| | - Boyun Deng
- Departments of Chest Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, People's Republic of China
| | - Yun Huang
- Departments of Chest Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, People's Republic of China
| | - Wenjie Wu
- Departments of Chest Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, People's Republic of China
| | - Jun Yin
- Departments of Chest Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, People's Republic of China
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Jiang X, Renkema H, Smeitink J, Beyrath J. Sonlicromanol's active metabolite KH176m normalizes prostate cancer stem cell mPGES-1 overexpression and inhibits cancer spheroid growth. PLoS One 2021; 16:e0254315. [PMID: 34242345 PMCID: PMC8270194 DOI: 10.1371/journal.pone.0254315] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Accepted: 06/24/2021] [Indexed: 12/12/2022] Open
Abstract
Aggressiveness of cancers, like prostate cancer, has been found to be associated with elevated expression of the microsomal prostaglandin E synthase-1 (mPGES-1). Here, we investigated whether KH176m (the active metabolite of sonlicromanol), a recently discovered selective mPGES-1 inhibitor, could affect prostate cancer cells-derived spheroid growth. We demonstrated that KH176m suppressed mPGES-1 expression and growth of DU145 (high mPGES-1 expression)-derived spheroids, while it had no effect on the LNCaP cell line, which has low mPGES-1 expression. By addition of exogenous PGE2, we found that the effect of KH176m on mPGES-1 expression and spheroid growth is due to the inhibition of a PGE2-driven positive feedback control-loop of mPGES-1 transcriptional regulation. Cancer stem cells (CSCs) are a subset of cancer cells exhibiting the ability of self-renewal, plasticity, and initiating and maintaining tumor growth. Our data shows that mPGES-1 is specifically expressed in this CSCs subpopulation (CD44+CD24-). KH176m inhibited the expression of mPGES-1 and reduced the growth of spheroids derived from the CSC. Based on the results obtained we propose selective mPGES-1 targeting by the sonlicromanol metabolite KH176m as a potential novel treatment approach for cancer patients with high mPGES-1 expression.
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Affiliation(s)
- Xiaolan Jiang
- Khondrion BV, Nijmegen, The Netherlands
- Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
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Zhang R, Liu P, Zhang X, Ye Y, Yu J. Lin28A promotes the proliferation and stemness of lung cancer cells via the activation of mitogen-activated protein kinase pathway dependent on microRNA let-7c. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:982. [PMID: 34277782 PMCID: PMC8267304 DOI: 10.21037/atm-21-2124] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 06/04/2021] [Indexed: 12/20/2022]
Abstract
Background Among patients with lung cancer, metastatic and relapsed cases account for the largest proportion of disease-associated deaths. Tumor metastasis and relapse are believed to originate from cancer stem cells (CSCs), which have the capacity to be highly proliferative and invasive. In our previous studies, we established a conditional basement membrane extract-based (BME-based) 3-dimensional (3D) culture system to mimic the tumor growth environment in vivo and further amplified lung cancer stem cells (LCSCs) in our system. However, the molecular mechanisms of LCSC amplification and development in our 3D culture system have not been fully uncovered. Method We established the conditional 3D culture system to amplify LCSCs in other lung cancer cell lines, followed by examining the expression of Lin28A and let-7 microRNAs in them. We also explored the expression of Lin28A and let-7 microRNAs in LCSCs from clinical lung cancer tissue samples and even analyzed the correlation of Lin28A/let-7c and patients’ survival outcomes. We further constructed A549 cells either knockdown of Lin28A or overexpression of let-7c, followed by investigating stemness marker gene expression, and stemness phenotypes including mammosphere culture, cell migration and invasion in vitro, as well as tumorigenicity in vivo. Results Here, we observed that Lin28A/let-7c was dysregulated in LCSCs in both the 3D culture system and lung cancer tissues. Further, the abnormal expression of Lin28A/let-7c was correlated with poor survival outcomes. Via the construction of A549 cells with let-7c over-expression, we found that let-7c inhibited the maintenance of LCSC properties, while the results of Lin28A knockdown showed that Lin28A played a critical role in the enrichment and proliferation of LCSCs via mitogen-activated protein kinase (MAPK) signaling pathway. Importantly, we found that LCSCs with knockdown of Lin28A or over-expression of let-7c exhibited inhibited carcinogenesis and disrupted expansion in vivo. Conclusions Our study uncovered the functions and mechanisms of the Lin28A/let-7c/MAPK signaling pathway in promoting the proliferation and cancer stemness of LCSCs, which might be a potential therapeutic target for reducing and even eliminating LCSCs in the future.
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Affiliation(s)
- Rui Zhang
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Pengpeng Liu
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Xiao Zhang
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yingnan Ye
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jinpu Yu
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
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Heng WS, Kruyt FAE, Cheah SC. Understanding Lung Carcinogenesis from a Morphostatic Perspective: Prevention and Therapeutic Potential of Phytochemicals for Targeting Cancer Stem Cells. Int J Mol Sci 2021; 22:ijms22115697. [PMID: 34071790 PMCID: PMC8198077 DOI: 10.3390/ijms22115697] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/06/2021] [Accepted: 05/07/2021] [Indexed: 12/24/2022] Open
Abstract
Lung cancer is still one of the deadliest cancers, with over two million incidences annually. Prevention is regarded as the most efficient way to reduce both the incidence and death figures. Nevertheless, treatment should still be improved, particularly in addressing therapeutic resistance due to cancer stem cells—the assumed drivers of tumor initiation and progression. Phytochemicals in plant-based diets are thought to contribute substantially to lung cancer prevention and may be efficacious for targeting lung cancer stem cells. In this review, we collect recent literature on lung homeostasis, carcinogenesis, and phytochemicals studied in lung cancers. We provide a comprehensive overview of how normal lung tissue operates and relate it with lung carcinogenesis to redefine better targets for lung cancer stem cells. Nine well-studied phytochemical compounds, namely curcumin, resveratrol, quercetin, epigallocatechin-3-gallate, luteolin, sulforaphane, berberine, genistein, and capsaicin, are discussed in terms of their chemopreventive and anticancer mechanisms in lung cancer and potential use in the clinic. How the use of phytochemicals can be improved by structural manipulations, targeted delivery, concentration adjustments, and combinatorial treatments is also highlighted. We propose that lung carcinomas should be treated differently based on their respective cellular origins. Targeting quiescence-inducing, inflammation-dampening, or reactive oxygen species-balancing pathways appears particularly interesting.
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Affiliation(s)
- Win Sen Heng
- Faculty of Medical Sciences, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (W.S.H.); (F.A.E.K.)
- Faculty of Medicine and Health Sciences, UCSI University, Kuala Lumpur 56000, Malaysia
| | - Frank A. E. Kruyt
- Faculty of Medical Sciences, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (W.S.H.); (F.A.E.K.)
| | - Shiau-Chuen Cheah
- Faculty of Medicine and Health Sciences, UCSI University, Kuala Lumpur 56000, Malaysia
- Correspondence: ; Tel.: +60-3-91018880
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Apatinib suppresses lung cancer stem-like cells by complex interplay between β-catenin signaling and mitochondrial ROS accumulation. Cell Death Discov 2021; 7:102. [PMID: 33980809 PMCID: PMC8115647 DOI: 10.1038/s41420-021-00480-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/21/2021] [Accepted: 04/13/2021] [Indexed: 02/07/2023] Open
Abstract
The abnormal activation of Wnt/β-catenin signaling plays a critical role in the development of lung cancer, which is also important in the generation and maintenance of lung cancer stem cell (CSC). CSCs have unique capabilities to resist anticancer therapy, seed recurrent tumors, and disseminate to and colonize distant tissues. Apatinib, a small-molecule VEGFR2-tyrosine kinase inhibitor, shows highly efficient antitumor activity in heavily treated, chemoresistant, and metastatic lung cancer. We speculated that inhibition of Wnt/β-catenin signaling and targeting lung CSCs could be one of the anti-tumor mechanisms of apatinib. In the present study we demonstrated that apatinib repressed lung CSC-like traits by hindering sphere formation ability, lung CSC-related marker expression and decreasing chemoresistance derived stemness. Mechanistically, apatinib exerted its anti-CSC effects by inhibiting β-catenin and its downstream targets. Moreover, apatinib induced the production of reactive oxyen species (ROS), which participated in the inhibitory effects of apatinib on lung CSCs. It was found that β-catenin regulated apatinib-induced production of ROS. Inhibition or promotion of ROS production with N-acetyl-L-cysteine or H2O2 not only upregulated or downregulated β-catenin expression, but also prevented or promoted DNA damage, rescued or impeded sphere formation, respectively. Collectively, our findings reveal that apatinib directly inhibits β-catenin signaling and promotes ROS generation to suppress lung CSC-like characteristics. A clearer understanding of the anti-cancer mechanisms of apatinib is required for its better application in combating advanced and refractory/recurrent lung cancer when combined with conventional chemotherapy.
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Nawara HM, Afify SM, Hassan G, Zahra MH, Seno A, Seno M. Paclitaxel-Based Chemotherapy Targeting Cancer Stem Cells from Mono- to Combination Therapy. Biomedicines 2021; 9:biomedicines9050500. [PMID: 34063205 PMCID: PMC8147479 DOI: 10.3390/biomedicines9050500] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/25/2021] [Accepted: 04/29/2021] [Indexed: 12/12/2022] Open
Abstract
Paclitaxel (PTX) is a chemotherapeutical agent commonly used to treat several kinds of cancer. PTX is known as a microtubule-targeting agent with a primary molecular mechanism that disrupts the dynamics of microtubules and induces mitotic arrest and cell death. Simultaneously, other mechanisms have been evaluated in many studies. Since the anticancer activity of PTX was discovered, it has been used to treat many cancer patients and has become one of the most extensively used anticancer drugs. Regrettably, the resistance of cancer to PTX is considered an extensive obstacle in clinical applications and is one of the major causes of death correlated with treatment failure. Therefore, the combination of PTX with other drugs could lead to efficient therapeutic strategies. Here, we summarize the mechanisms of PTX, and the current studies focusing on PTX and review promising combinations.
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Affiliation(s)
- Hend M. Nawara
- Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan; (H.M.N.); (S.M.A.); (G.H.); (M.H.Z.); (A.S.)
| | - Said M. Afify
- Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan; (H.M.N.); (S.M.A.); (G.H.); (M.H.Z.); (A.S.)
- Division of Biochemistry, Chemistry Department, Faculty of Science, Menoufia University, Menoufia 32511, Egypt
| | - Ghmkin Hassan
- Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan; (H.M.N.); (S.M.A.); (G.H.); (M.H.Z.); (A.S.)
- Department of Microbiology and Biochemistry, Faculty of Pharmacy, Damascus University, Damascus 10769, Syria
| | - Maram H. Zahra
- Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan; (H.M.N.); (S.M.A.); (G.H.); (M.H.Z.); (A.S.)
| | - Akimasa Seno
- Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan; (H.M.N.); (S.M.A.); (G.H.); (M.H.Z.); (A.S.)
| | - Masaharu Seno
- Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan; (H.M.N.); (S.M.A.); (G.H.); (M.H.Z.); (A.S.)
- Correspondence: ; Tel.: +81-86-251-8216
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