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Mallick S, Narayana VK, Rai AB, Upadhyay SS, Prasad TSK, P SS, Bose B. Hematopoietic stem cell conditioned media induces apoptosis in colorectal cancer stem cells via dysregulation of HSP90 and 26S proteasome system. Int J Biochem Cell Biol 2025; 184:106773. [PMID: 40210089 DOI: 10.1016/j.biocel.2025.106773] [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: 11/23/2024] [Revised: 02/25/2025] [Accepted: 03/23/2025] [Indexed: 04/12/2025]
Abstract
Cancer stem cells (CSCs) hold a significant role in cancer metastasis, high mortality and severity responsible for therapy resistance and tumour recurrence. The 26S proteasome system plays a major role in protein degradation in normal cells. As most cancers have upregulated 26S proteasome machinery, cancer cells use the 26S proteasome system in their favour for growth support by degrading unwanted proteins, but dysfunction of the 26S proteasome system induces apoptosis in cells. Here, we used hematopoietic stem cells (HSCs) and HSCs-derived conditioned media (CM) to target colorectal cancer stem cells (CRC-CSCs). HSCs are otherwise used extensively to save the lives of patients suffering from hematological malignancies and inherited blood disorders. HSCs-derived conditioned media contains various cytokines, chemokines, and secretory small molecules, which can also target the CRC-CSCs. Moreover, HSCs have exhibited CRC-CSC tropism in vitro in our pilot studies. As therapeutic uses of HSCs for targeting colorectal cancer (CRC) have never been reported, we hypothesized the CRC-CSC targeting properties of HSCs. Our results indicated altered protein function of CRC-CSCs upon co-culture with HSCs. Proteomics approaches showed that HSCs-CM disrupted 26S proteasomal complex and altered the mitochondrial bioenergetics, thereby activating apoptosis in CRC-CSCs. Furthermore, we observed that HSCs-CM significantly induced double-stranded DNA damage and proteasomal degradation, leading to apoptosis and upregulating the autophagy system. This study, hence, provides the prospective targeting of cancer stem cells using HSCs-CM, indicating a possible therapeutic approach.
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Affiliation(s)
- Sumit Mallick
- Stem Cells and Regenerative Medicine Centre, Yenepoya Research Centre, Yenepoya (Deemed to be University), University Road, Deralakatte, Mangalore, Karnataka 575018, India
| | - Vanya Kadla Narayana
- Center for Systems Biology and Molecular Medicine [An ICMR Collaborating Centre of Excellence 2024 (ICMR-CCoE 2024)] , Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore 575018, India
| | - Akhila Balakrishna Rai
- Center for Systems Biology and Molecular Medicine [An ICMR Collaborating Centre of Excellence 2024 (ICMR-CCoE 2024)] , Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore 575018, India
| | - Shubham Sukerndeo Upadhyay
- Center for Systems Biology and Molecular Medicine [An ICMR Collaborating Centre of Excellence 2024 (ICMR-CCoE 2024)] , Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore 575018, India
| | - Thottethodi Subrahmanya Keshava Prasad
- Center for Systems Biology and Molecular Medicine [An ICMR Collaborating Centre of Excellence 2024 (ICMR-CCoE 2024)] , Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore 575018, India
| | - Sudheer Shenoy P
- Stem Cells and Regenerative Medicine Centre, Yenepoya Research Centre, Yenepoya (Deemed to be University), University Road, Deralakatte, Mangalore, Karnataka 575018, India; Specialised Research Unit, Yenepoya Medical College, Yenepoya (Deemed to be University), University Road, Deralakatte, Mangalore, Karnataka 575018, India.
| | - Bipasha Bose
- Stem Cells and Regenerative Medicine Centre, Yenepoya Research Centre, Yenepoya (Deemed to be University), University Road, Deralakatte, Mangalore, Karnataka 575018, India; Specialised Research Unit, Yenepoya Medical College, Yenepoya (Deemed to be University), University Road, Deralakatte, Mangalore, Karnataka 575018, India.
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Parvizi M, Vaezi M, Jeddi F, Bakhshandeh M, Eghdam-Zamiri R, Mobaraki-Asl N, Esmati E, Karimi A. The role and diagnostic value of deregulated miRNAs in cervical cancer. Discov Oncol 2025; 16:922. [PMID: 40413660 DOI: 10.1007/s12672-025-02744-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Accepted: 05/17/2025] [Indexed: 05/27/2025] Open
Abstract
Cervical cancer (CC) remains a significant global health concern, particularly affecting women in low-income countries. Despite advancements in screening programs, CC continues to pose a substantial mortality risk, highlighting the need to explore diagnostic and treatment modalities. This review focuses on the role of deregulated microRNAs (miRNAs) in CC development, emphasizing their potential as biomarkers for early detection and prognosis in body fluids. miRNAs have emerged as critical regulators of key cellular processes, including proliferation, migration, invasion, and apoptosis, and their dysregulation is closely linked to CC progression. Upregulated miRNAs such as miR-146b-3p, miR-1908, and miR-21 promote CC progression by targeting tumor suppressor genes, while downregulated miRNAs like miR-23-3p and miR-4262 are associated with reduced tumor aggressiveness. miRNAs also hold significant promise as non-invasive prognostic biomarkers. Their expression levels correlate with clinical outcomes, including tumor stage, metastasis, and overall survival, making them valuable tools for risk stratification and personalized treatment strategies. Liquid biopsies, which detect circulating miRNAs in bodily fluids, offer a minimally invasive approach to monitor tumor dynamics and predict patient outcomes. Furthermore, exosomal miRNAs are emerging as promising diagnostic and prognostic tools for CC. Advanced diagnostic technologies and bioinformatics tools are anticipated to enhance the identification of evident miRNA biomarkers in the clinical settings. Standardized protocols for sample collection and analysis will improve the reproducibility of miRNA studies, while a deeper understanding of miRNA biology may unlock their potential as therapeutic targets. In conclusion, this review consolidates current research on deregulated miRNAs in CC, highlighting their diagnostic and prognostic significance. The findings underscore the potential of miRNAs to revolutionize CC management through innovative diagnostic and therapeutic strategies.
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Affiliation(s)
- Masoumeh Parvizi
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Vaezi
- Obstetric and Oncology Department, School of Medicine, Women's Reproductive Health Research Center, Clinical Research Institute, Alzahra Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Jeddi
- Department of Genetics and Pathology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Masoumeh Bakhshandeh
- Obstetric and Oncology Department, School of Medicine, Women's Reproductive Health Research Center, Clinical Research Institute, Alzahra Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Eghdam-Zamiri
- Department of Radiation Oncology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Noushin Mobaraki-Asl
- Department of Obstetrics and Gynecology, School of Medicine, Alavi Hospital, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Ebrahim Esmati
- Department of Radiation Oncology, Cancer Institute, IKHC, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Karimi
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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Poudineh M, Darweesh O, Mokhtari M, Zolfaghari O, Khaledi A, Piroozmand A. Expression of microRNAs in the detection and therapeutic roles of viral infections: Mechanisms and applications. J Virus Erad 2025; 11:100586. [PMID: 40296890 PMCID: PMC12034616 DOI: 10.1016/j.jve.2025.100586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 04/30/2025] Open
Abstract
In recent years, microRNAs (miRNAs) are potential diagnostic and therapeutic agents for viral infections. Here, we aimed to investigate the expression of microRNAs in the identification and treatment of viral infections. MiRNAs are non-coding molecules that control gene expression and participate in numerous biological processes, including host immunity and pathogen duplication. MiRNAs have played a role in the pathogenesis of various viral infections, such as HIV and HCV. Their presence in the tissues and serum of infected patients has been demonstrated to help predict disease progression, identify disease subtypes, and evaluate treatment responses. Research has shown that miRNAs can detect viral infections by identifying specific miRNAs in serum. For example, miRNA expression profiling was recently used to distinguish between hepatitis C and hepatitis B viral infections precisely. Furthermore, miRNAs can be used to detect the presence of multiple viral infections simultaneously by assessing the expression levels of these miRNAs. Also, miRNAs can differentiate between different genetic variants of the same virus, which is useful for identifying emerging viral strains or drug-resistant ones. MiRNAs have been identified as being a factor in treating viral infections. For example, miRNA mimics have decreased gene expression and halted viral replication in HIV, HCV, and EBV. Moreover, microRNA antagonists have been utilized to inhibit pro-inflammatory cytokines, thereby modulating the immune response and the severity of infections.
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Affiliation(s)
- Mohsen Poudineh
- Infectious Diseases Research Center, Kashan University of Medical Sciences, Kashan, Iran
- Department of Microbiology and Immunology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Omeed Darweesh
- College of Pharmacy, Al-Kitab University, Kirkuk, 36015, Iraq
| | - Mohsen Mokhtari
- Laboratory Department, Paramedical School, Kashan University of Medical Sciences, Kashan, Iran
| | - Omid Zolfaghari
- Laboratory Department, Paramedical School, Kashan University of Medical Sciences, Kashan, Iran
| | - Azad Khaledi
- Infectious Diseases Research Center, Kashan University of Medical Sciences, Kashan, Iran
- Department of Microbiology and Immunology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Ahmad Piroozmand
- Autoimmune Diseases Research Center, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
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Wang A, Zhang C, Wang Y, Diao P, Cheng J. Leveraging programmed cell death patterns to predict prognosis and therapeutic sensitivity in OSCC. Oral Dis 2025; 31:452-467. [PMID: 39315471 DOI: 10.1111/odi.15139] [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: 05/19/2024] [Revised: 07/13/2024] [Accepted: 09/06/2024] [Indexed: 09/25/2024]
Abstract
OBJECTIVES Intricate associations between programmed cell death (PCD) and cancer development and treatment outcomes have been increasingly appreciated. Here, we integrated 12 PCD patterns to construct a novel biomarker, cell death index (CDI), for oral squamous cell carcinoma (OSCC) prognostication and therapeutic prediction. MATERIALS AND METHODS Univariate Cox regression, Kaplan-Meier survival, and LASSO analyses were performed to construct the CDI. A nomogram combining CDI and selected clinicopathological parameters was established by multivariate Cox regression. The associations between CDI and immune landscape and therapeutic sensitivity were estimated. Single-cell RNA-seq data of OSCC was used to infer CDI genes in selected cell types and determine their expression along cell differentiation trajectory. RESULTS Ten selected PCD genes derived a novel prognostic signature for OSCC. The predictive prognostic performance of CDI and nomogram was robust and superior across multiple independent patient cohorts. CDI was negatively associated with tumor-infiltrating immune cell abundance and immunotherapeutic outcomes. Moreover, scRNA-seq data reanalysis revealed that GSDMB, IL-1A, PRKAA2, and SFRP1 from this signature were primarily expressed in cancer cells and involved in cell differentiation. CONCLUSIONS Our findings established CDI as a novel powerful predictor for prognosis and therapeutic response for OSCC and suggested its potential involvement in cancer cell differentiation.
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Affiliation(s)
- An Wang
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chi Zhang
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yuhan Wang
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Pengfei Diao
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jie Cheng
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
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Patel B, Patel S, Modi F, Patel A, Gelat B, Tanavde V, Vasavada A, Johar K. Combination of paclitaxel with rosiglitazone induces synergistic cytotoxic effects in ovarian cancer cells. Sci Rep 2024; 14:30672. [PMID: 39730440 DOI: 10.1038/s41598-024-74277-9] [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: 05/13/2024] [Accepted: 09/24/2024] [Indexed: 12/29/2024] Open
Abstract
Ovarian cancer is known to be a challenging disease to detect at an early stage and is a major cause of death among women. The current treatment for ovarian cancer typically involves a combination of surgery and the use of drugs such as platinum-based cytotoxic agents, anti-angiogenic drugs, etc. However, current treatment methods are not always effective in preventing the recurrence of ovarian cancer. As a result, the treatments administered after a relapse need to be more aggressive, leading to increased toxicity and drug resistance. To address this issue, researchers are exploring the potential of combining existing anticancer agents with novel or repurposed drugs to reduce the side effects and improve the effectiveness of treatment. In this study, we have investigated the use of rosiglitazone, a well-known anti-diabetic drug, in combination with the chemotherapeutic drug, paclitaxel for the prevention of ovarian cancer. The study utilized the SKOV-3 ovarian cancer cell line to assess the effects of this combination treatment. The results of the study showed that the combination of paclitaxel with rosiglitazone inhibited cell proliferation at much lower concentrations of paclitaxel as compared to paclitaxel alone. The combined treatment also induced cell cycle arrest at the G2/M phase and increased apoptosis by altering the mitochondrial membrane potential of the cells. Additionally, the combination treatment activated the PPAR-γ pathway and downregulated expression of genes associated with cancer stemness, such as NANOG, OCT4, and EHF. Furthermore, the CAM assay substantiated the anti-angiogenic potential of the synergistic treatment of paclitaxel and rosiglitazone. The findings of the study suggest that repurposing rosiglitazone as an anticancer agent in combination with paclitaxel has immense potential to target cancer cell cycle progression and apoptosis, making it a promising therapeutic approach for sensitizing chemo-resistant population of ovarian cancer cells.
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Affiliation(s)
- Binita Patel
- Department of Life Sciences, School of Sciences, Gujarat University, Ahmedabad, 380009, Gujarat, India
| | - Shanaya Patel
- Division of Biological and Life Sciences, School of Arts and Sciences, Ahmedabad University, Central Campus, Ahmedabad, 380009, Gujarat, India
| | - Foram Modi
- Department of Zoology, Biomedical Technology, Human Genetics, and WBC, School of Sciences, Gujarat University, Ahmedabad, 380009, Gujarat, India
| | - Aditi Patel
- Division of Biological and Life Sciences, School of Arts and Sciences, Ahmedabad University, Central Campus, Ahmedabad, 380009, Gujarat, India
| | - Brijesh Gelat
- Department of Zoology, Biomedical Technology, Human Genetics, and WBC, School of Sciences, Gujarat University, Ahmedabad, 380009, Gujarat, India
| | - Vivek Tanavde
- Division of Biological and Life Sciences, School of Arts and Sciences, Ahmedabad University, Central Campus, Ahmedabad, 380009, Gujarat, India
| | - Abhay Vasavada
- Iladevi Cataract and IOL Research Centre, Memnagar, Ahmedabad, 380052, Gujarat, India
| | - Kaid Johar
- Department of Zoology, Biomedical Technology, Human Genetics, and WBC, School of Sciences, Gujarat University, Ahmedabad, 380009, Gujarat, India.
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Rozek W, Kwasnik M, Socha W, Czech B, Rola J. Profiling of snoRNAs in Exosomes Secreted from Cells Infected with Influenza A Virus. Int J Mol Sci 2024; 26:12. [PMID: 39795871 PMCID: PMC11720657 DOI: 10.3390/ijms26010012] [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: 11/28/2024] [Revised: 12/18/2024] [Accepted: 12/21/2024] [Indexed: 01/13/2025] Open
Abstract
Small nucleolar RNAs (snoRNAs) are non-coding RNAs (ncRNAs) that regulate many cellular processes. Changes in the profiles of cellular ncRNAs and those secreted in exosomes are observed during viral infection. In our study, we analysed differences in expression profiles of snoRNAs isolated from exosomes of influenza (IAV)-infected and non-infected MDCK cells using high-throughput sequencing. The analysis revealed 133 significantly differentially regulated snoRNAs (131 upregulated and 2 downregulated), including 93 SNORD, 38 SNORA, and 2 SCARNA. The most upregulated was SNORD58 (log2FoldChange = 9.61), while the only downregulated snoRNAs were SNORD3 (log2FC = -2.98) and SNORA74 (log2FC = -2.67). Several snoRNAs previously described as involved in viral infections were upregulated, including SNORD27, SNORD28, SNORD29, SNORD58, and SNORD44. In total, 533 interactors of dysregulated snoRNAs were identified using the RNAinter database with an assigned confidence score ≥ 0.25. The main groups of predicted interactors were transcription factors (TFs, 169 interactors) and RNA-binding proteins (RBPs, 130 interactors). Among the most important were pioneer TFs such as POU5F1, SOX2, CEBPB, and MYC, while in the RBP category, notable interactors included Polr2a, TNRC6A, IGF2BP3, and FMRP. Our results suggest that snoRNAs are involved in pro-viral activity, although follow-up studies including experimental validation would be beneficial.
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Affiliation(s)
- Wojciech Rozek
- Department of Virology, National Veterinary Research Institute, 24-100 Pulawy, Poland; (M.K.); (W.S.); (J.R.)
| | - Malgorzata Kwasnik
- Department of Virology, National Veterinary Research Institute, 24-100 Pulawy, Poland; (M.K.); (W.S.); (J.R.)
| | - Wojciech Socha
- Department of Virology, National Veterinary Research Institute, 24-100 Pulawy, Poland; (M.K.); (W.S.); (J.R.)
| | | | - Jerzy Rola
- Department of Virology, National Veterinary Research Institute, 24-100 Pulawy, Poland; (M.K.); (W.S.); (J.R.)
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Kainulainen K, Niskanen EA, Kinnunen J, Mäki-Mantila K, Hartikainen K, Paakinaho V, Malinen M, Ketola K, Pasonen-Seppänen S. Secreted factors from M1 macrophages drive prostate cancer stem cell plasticity by upregulating NANOG, SOX2, and CD44 through NFκB-signaling. Oncoimmunology 2024; 13:2393442. [PMID: 39175947 PMCID: PMC11340773 DOI: 10.1080/2162402x.2024.2393442] [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: 04/29/2024] [Revised: 06/27/2024] [Accepted: 08/13/2024] [Indexed: 08/24/2024] Open
Abstract
The inflammatory tumor microenvironment (TME) is a key driver for tumor-promoting processes. Tumor-associated macrophages are one of the main immune cell types in the TME and their increased density is related to poor prognosis in prostate cancer. Here, we investigated the influence of pro-inflammatory (M1) and immunosuppressive (M2) macrophages on prostate cancer lineage plasticity. Our findings reveal that M1 macrophage secreted factors upregulate genes related to stemness while downregulating genes associated with androgen response in prostate cancer cells. The expression of cancer stem cell (CSC) plasticity markers NANOG, KLF4, SOX2, OCT4, and CD44 was stimulated by the secreted factors from M1 macrophages. Moreover, AR and its target gene PSA were observed to be suppressed in LNCaP cells treated with secreted factors from M1 macrophages. Inhibition of NFκB signaling using the IKK16 inhibitor resulted in downregulation of NANOG, SOX2, and CD44 and CSC plasticity. Our study highlights that the secreted factors from M1 macrophages drive prostate cancer cell plasticity by upregulating the expression of CSC plasticity markers through NFκB signaling pathway.
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Affiliation(s)
- Kirsi Kainulainen
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland
| | - Einari A. Niskanen
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland
| | - Johanna Kinnunen
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland
| | - Kaisa Mäki-Mantila
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland
| | - Kiia Hartikainen
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland
| | - Ville Paakinaho
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland
| | - Marjo Malinen
- Department of Forestry and Environmental Engineering, South-Eastern Finland University of Applied Sciences, Kouvola, Finland
| | - Kirsi Ketola
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland
| | - Sanna Pasonen-Seppänen
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland
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Sánchez-Meza LV, Bello-Rios C, Eloy JO, Gómez-Gómez Y, Leyva-Vázquez MA, Petrilli R, Bernad-Bernad MJ, Lagunas-Martínez A, Medina LA, Serrano-Bello J, Organista-Nava J, Illades-Aguiar B. Cationic Liposomes Carrying HPV16 E6-siRNA Inhibit the Proliferation, Migration, and Invasion of Cervical Cancer Cells. Pharmaceutics 2024; 16:880. [PMID: 39065577 PMCID: PMC11279637 DOI: 10.3390/pharmaceutics16070880] [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: 06/03/2024] [Revised: 06/26/2024] [Accepted: 06/27/2024] [Indexed: 07/28/2024] Open
Abstract
The E6 and E7 oncoproteins of high-risk types of human papillomavirus (HR-HPV) are crucial for the development of cervical cancer (CC). Small interfering RNAs (siRNAs) are explored as novel therapies that silence these oncogenes, but their clinical use is hampered by inefficient delivery systems. Modification (pegylation) with polyethylene glycol (PEG) of liposomal siRNA complexes (siRNA lipoplexes) may improve systemic stability. We studied the effect of siRNA targeting HPV16 E6, delivered via cationic liposomes (lipoplexes), on cellular processes in a cervical carcinoma cell line (CaSki) and its potential therapeutic use. Lipoplexes-PEG-HPV16 E6, composed of DOTAP, Chol, DOPE, and DSPE-PEG2000 were prepared. The results showed that pegylation (5% DSPE-PEG2000) provided stable siRNA protection, with a particle size of 86.42 ± 3.19 nm and a complexation efficiency of over 80%; the siRNA remained stable for 30 days. These lipoplexes significantly reduced HPV16 E6 protein levels and restored p53 protein expression, inhibiting carcinogenic processes such as proliferation by 25.74%, migration (95.7%), and cell invasion (97.8%) at concentrations of 20 nM, 200 nM, and 80 nM, respectively. In conclusion, cationic lipoplexes-PEG-HPV16 E6 show promise as siRNA carriers for silencing HPV16 E6 in CC.
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Affiliation(s)
- Luz Victoria Sánchez-Meza
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Chilpancingo 39090, Guerrero, Mexico; (L.V.S.-M.); (C.B.-R.); (Y.G.-G.); (M.A.L.-V.)
| | - Ciresthel Bello-Rios
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Chilpancingo 39090, Guerrero, Mexico; (L.V.S.-M.); (C.B.-R.); (Y.G.-G.); (M.A.L.-V.)
| | - Josimar O. Eloy
- Department of Pharmacy, Dentistry and Nursing, Faculty of Pharmacy, Federal University of Ceará, 1210 Pastor Samuel Munguba Street, Fortaleza 60430-160, CE, Brazil;
| | - Yazmín Gómez-Gómez
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Chilpancingo 39090, Guerrero, Mexico; (L.V.S.-M.); (C.B.-R.); (Y.G.-G.); (M.A.L.-V.)
| | - Marco Antonio Leyva-Vázquez
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Chilpancingo 39090, Guerrero, Mexico; (L.V.S.-M.); (C.B.-R.); (Y.G.-G.); (M.A.L.-V.)
| | - Raquel Petrilli
- Institute of Health Sciences, University of International Integration of the Afro-Brazilian Lusophony, Redenção 62790-000, CE, Brazil;
| | | | - Alfredo Lagunas-Martínez
- Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, Cuernavaca 62100, Morelos, Mexico;
| | - Luis Alberto Medina
- Instituto de Física, Universidad Nacional Autónoma de Mexico, Ciudad de Mexico 04510, Mexico;
- Unidad de Investigación Biomédica en Cáncer INCan/UNAM, Instituto Nacional de Cancerología, Actualmente Hospital Ángeles Puebla, Ciudad de Mexico 14080, Mexico
| | - Janeth Serrano-Bello
- Facultad de Odontología, Universidad Nacional Autónoma de Mexico, Ciudad de Mexico 04360, Mexico;
| | - Jorge Organista-Nava
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Chilpancingo 39090, Guerrero, Mexico; (L.V.S.-M.); (C.B.-R.); (Y.G.-G.); (M.A.L.-V.)
| | - Berenice Illades-Aguiar
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Chilpancingo 39090, Guerrero, Mexico; (L.V.S.-M.); (C.B.-R.); (Y.G.-G.); (M.A.L.-V.)
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Farhangnia P, Ghods R, Falak R, Zarnani AH, Delbandi AA. Identification of placenta-specific protein 1 (PLAC-1) expression on human PC-3 cell line-derived prostate cancer stem cells compared to the tumor parental cells. Discov Oncol 2024; 15:251. [PMID: 38943028 PMCID: PMC11213845 DOI: 10.1007/s12672-024-01121-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 06/25/2024] [Indexed: 06/30/2024] Open
Abstract
Placenta-specific protein 1 (PLAC-1) is a gene primarily expressed in the placenta and the testis. Interestingly, it is also found to be expressed in many solid tumors, and it is involved in malignant cell features. However, no evidence has been reported regarding the relationship between PLAC-1 and cancer stem cells (CSCs). In the current research, we explored the expression of the PLAC-1 molecule in prostate cancer stem cells (PCSCs) derived from the human PC-3 cell line. The enrichment of PCSCs was achieved using a three-dimensional cell culture technique known as the sphere-formation assay. To confirm the identity of PCSCs, we examined the expression of genes associated with stemness and pluripotency, such as SOX2, OCT4, Nanog, C-Myc, and KLF-4, as well as stem cell differentiation molecules like CD44 and CD133. These evaluations were conducted in both the PCSCs and the original tumor cells (parental cells) using real-time PCR and flow cytometry. Subsequently, we assessed the expression of the PLAC-1 molecule in both enriched cells and parental tumor cells at the gene and protein levels using the same techniques. The tumor cells from the PC-3 cell line formed spheroids with CSC characteristics in a non-adherent medium. The expression of SOX2, OCT4, Nanog, and C-Myc genes (p < 0.01), and the molecules CD44 and CD133 (p < 0.05) were significantly elevated in PCSCs compared to the parental cells. The expression of the PLAC-1 molecule in PCSCs showed a significant increase compared to the parental cells at both gene (p < 0.01) and protein (p < 0.001) levels. In conclusion, it was indicated for the first time that PLAC-1 is up-regulated in PCSCs derived from human PC-3 cell line. This study may propose PLAC-1 as a potential target in targeted therapies, which should be confirmed through further studies.
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Affiliation(s)
- Pooya Farhangnia
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Roya Ghods
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Reza Falak
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Amir-Hassan Zarnani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali-Akbar Delbandi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
- Reproductive Sciences and Technology Research Center, Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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10
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Christofidou ED, Tomazou M, Voutouri C, Michael C, Stylianopoulos T, Spyrou GM, Strati K. Oct4 is a gatekeeper of epithelial identity by regulating cytoskeletal organization in skin keratinocytes. Cell Rep 2024; 43:113859. [PMID: 38421873 DOI: 10.1016/j.celrep.2024.113859] [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: 05/08/2023] [Revised: 12/05/2023] [Accepted: 02/08/2024] [Indexed: 03/02/2024] Open
Abstract
Oct4 is a pioneer transcription factor regulating pluripotency. However, it is not well known whether Oct4 has an impact on epidermal cells. We generated OCT4 knockout clonal cell lines using immortalized human skin keratinocytes to identify a functional role for the protein. Here, we report that Oct4-deficient cells transitioned into a mesenchymal-like phenotype with enlarged size and shape, exhibited accelerated migratory behavior, decreased adhesion, and appeared arrested at the G2/M cell cycle checkpoint. Oct4 absence had a profound impact on cortical actin organization, with loss of microfilaments from the cell membrane, increased puncta deposition in the cytoplasm, and stress fiber formation. E-cadherin, β-catenin, and ZO1 were almost absent from cell-cell contacts, while fibronectin deposition was markedly increased in the extracellular matrix (ECM). Mapping of the transcriptional and chromatin profiles of Oct4-deficient cells revealed that Oct4 controls the levels of cytoskeletal, ECM, and differentiation-related genes, whereas epithelial identity is preserved through transcriptional and non-transcriptional mechanisms.
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Affiliation(s)
| | - Marios Tomazou
- Department of Bioinformatics, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus
| | - Chrysovalantis Voutouri
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia 2109, Cyprus
| | - Christina Michael
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia 2109, Cyprus
| | - Triantafyllos Stylianopoulos
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia 2109, Cyprus
| | - George M Spyrou
- Department of Bioinformatics, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus
| | - Katerina Strati
- Department of Biological Sciences, University of Cyprus, Nicosia 2109, Cyprus.
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11
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Bian Z, Wu X, Chen Q, Gao Q, Xue X, Wang Y. Oct4 activates IL-17A to orchestrate M2 macrophage polarization and cervical cancer metastasis. Cancer Immunol Immunother 2024; 73:73. [PMID: 38430256 PMCID: PMC10908604 DOI: 10.1007/s00262-023-03596-z] [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: 06/29/2023] [Accepted: 12/10/2023] [Indexed: 03/03/2024]
Abstract
BACKGROUND Cervical cancer is a common malignant tumor in the female. Interleukin (IL)-17A is a proinflammatory factor and exerts a vital function in inflammatory diseases and cancers. M2 macrophage has been confirmed to promote tumor development. Nevertheless, it is not yet known whether IL-17A facilitates cervical cancer development by inducing M2 macrophage polarization. Therefore, this study was conducted to investigate the regulatory effect of IL-17A on M2 macrophage polarization and the underlying mechanism in cervical cancer development. METHODS RT-qPCR was utilized for testing IL-17A expression in cancer tissues and cells. Flow cytometry was applied to evaluate the M1 or M2 macrophage polarization. Cell proliferative, migratory, and invasive capabilities were measured through colony formation and transwell assays. ChIP and luciferase reporter assays were applied to determine the interaction between IL-17A and octamer-binding transcription factor 4 (OCT4). RESULTS IL-17A expression and concentration were high in metastatic tissues and cells of cervical cancer. IL-17A was found to facilitate M2 macrophage polarization in cervical cancer. Furthermore, IL-17A facilitated the macrophage-mediated promotion of cervical cancer cell proliferative, migratory, and invasive capabilities. Mechanistic assays manifested that Oct4 binds to and transcriptionally activated IL-17A in cervical cancer cells. Furthermore, Oct4 promoted cervical cancer cell malignant phenotype and M2 macrophage polarization by activating the p38 pathway that, in turn, upregulated IL-17A. Additionally, in vivo experiments confirmed that Oct4 knockdown reduced tumor growth and metastasis. CONCLUSION Oct4 triggers IL-17A to facilitate the polarization of M2 macrophages, which promotes cervical cancer cell metastasis.
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Affiliation(s)
- Zhuoqiong Bian
- Department of the Fifth Rheumatology, The Fifth Hospital of Xi'an City, Xi'an, 710000, Shaanxi, China
| | - Xiaoling Wu
- Department of Obstetrics and Gynecology, Second Affiliated Hospital, Xi'an Jiao Tong University, 157 West Fifth Road, Xincheng District, Xi'an, 710000, Shaanxi, China
| | - Qing Chen
- Department of Obstetrics and Gynecology, Second Affiliated Hospital, Xi'an Jiao Tong University, 157 West Fifth Road, Xincheng District, Xi'an, 710000, Shaanxi, China
| | - Qing Gao
- Department of Obstetrics and Gynecology, Second Affiliated Hospital, Xi'an Jiao Tong University, 157 West Fifth Road, Xincheng District, Xi'an, 710000, Shaanxi, China
| | - Xiang Xue
- Department of Obstetrics and Gynecology, Second Affiliated Hospital, Xi'an Jiao Tong University, 157 West Fifth Road, Xincheng District, Xi'an, 710000, Shaanxi, China
| | - Yidong Wang
- Department of Obstetrics and Gynecology, Second Affiliated Hospital, Xi'an Jiao Tong University, 157 West Fifth Road, Xincheng District, Xi'an, 710000, Shaanxi, China.
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12
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Aref S, Khaled O, Menshawy NE, Azmy E, Aref M, Salama O, Khaled N. Significance of OCT3/4 and SOX2 antigens expression by leukemic blast cells in adult acute leukemia. J Egypt Natl Canc Inst 2024; 36:5. [PMID: 38342816 DOI: 10.1186/s43046-024-00209-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 01/13/2024] [Indexed: 02/13/2024] Open
Abstract
OBJECTIVE This study aimed to address the prognostic impact of SOX2 and OCT3/4 expression on adult acute leukemia patients' outcomes. METHODS SOX2 and OCT3/4 expression by blast cells were evaluated by flow cytometry in 80 acute leukemia patients and 8 healthy controls. RESULTS Baseline SOX2 and OCT3/4 expression were significantly higher in both ALL (P = < 0.001, P = 0.005 respectively) and AML patients (P < 0.001, P = 0.003 respectively) as compared to control, and decline at complete remission (CR) and elevated again at relapse. High SOX2 and OCT3/4 levels were significantly correlated with the presence of adverse risk stratification parameters. CONCLUSION Our findings indicated that both SOX2 and OCT3/4 could serve as biomarkers that could improve risk stratification of acute leukemia patients. Also, both SOX2 and OCT3/4 might be a therapeutic target, especially in resistant acute leukemia.
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Affiliation(s)
- Salah Aref
- Hematology Unit, Mansoura University Oncology Center, Mansoura University, Mansoura, Egypt.
| | - Omnyia Khaled
- Hematology Unit, Mansoura University Oncology Center, Mansoura University, Mansoura, Egypt
| | - Nadia El Menshawy
- Hematology Unit, Mansoura University Oncology Center, Mansoura University, Mansoura, Egypt
| | - Emad Azmy
- Hematology Unit, Internal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Mohamed Aref
- Internal Medicine Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Osama Salama
- Hematology Unit, Mansoura University Oncology Center, Mansoura University, Mansoura, Egypt
| | - Nada Khaled
- Hematology Unit, Mansoura University Oncology Center, Mansoura University, Mansoura, Egypt
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13
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Yoo JS, Kang MK. Clinical significance of exosomal noncoding RNAs in hepatocellular carcinoma: a narrative review. JOURNAL OF YEUNGNAM MEDICAL SCIENCE 2024; 42:4. [PMID: 38325815 PMCID: PMC11812098 DOI: 10.12701/jyms.2023.01186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/20/2023] [Accepted: 12/30/2023] [Indexed: 02/09/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide, with poor prognosis owing to its high frequency of recurrence and metastasis. Moreover, most patients are diagnosed at an advanced stage owing to a lack of early detection markers. Exosomes, which are characterized by their cargos of stable intracellular messengers, such as DNA, RNA, proteins, and lipids, play a crucial role in regulating cell differentiation and HCC development. Recently, exosomal noncoding RNAs (ncRNAs), including microRNAs, long ncRNAs, and circular RNAs, have become increasingly important diagnostic, prognostic, and predictive markers of HCC. Herein, we discuss the clinical implications of exosomal ncRNAs, specifically those within the HCC regulatory network.
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Affiliation(s)
- Jae Sung Yoo
- Department of Gastroenterology and Hepatology, The Catholic University of Korea, Seoul St Mary’s Hospital, Seoul, Korea
| | - Min Kyu Kang
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
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14
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Tripathi T, Yadav J, Janjua D, Chaudhary A, Joshi U, Senrung A, Chhokar A, Aggarwal N, Bharti AC. Targeting Cervical Cancer Stem Cells by Phytochemicals. Curr Med Chem 2024; 31:5222-5254. [PMID: 38288813 DOI: 10.2174/0109298673281823231222065616] [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: 09/12/2023] [Revised: 11/25/2023] [Accepted: 11/30/2023] [Indexed: 09/06/2024]
Abstract
Cervical cancer (CaCx) poses a significant global health challenge, ranking as the fourth most common cancer among women worldwide. Despite the emergence of advanced treatment strategies, recurrence remains a bottleneck in favorable treatment outcomes and contributes to poor prognosis. The chemo- or radio-therapy resistance coupled with frequent relapse of more aggressive tumors are some key components that contribute to CaCx-related mortality. The onset of therapy resistance and relapse are attributed to a small subset of, slow-proliferating Cancer Stem Cells (CSC). These CSCs possess the properties of tumorigenesis, self-renewal, and multi-lineage differentiation potential. Because of slow cycling, these cells maintain themselves in a semi-quiescent stage and protect themselves from different anti-proliferative anti-cancer drugs. Keeping in view recent advances in their phenotypic and functional characterization, the feasibility of targeting CSC and associated stem cell signaling bears a strong translational value. The presence of CSC has been reported in CaCx (CCSC) which remains a forefront area of research. However, we have yet to identify clinically useful leads that can target CCSC. There is compelling evidence that phytochemicals, because of their advantages over synthetic anticancer drugs, could emerge as potential therapeutic leads to target these CCSCs. The present article examined the potential of phytochemicals with reported anti-CSC properties and evaluated their future in preclinical and clinical applications against CaCx.
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Affiliation(s)
- Tanya Tripathi
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
| | - Joni Yadav
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
| | - Divya Janjua
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
| | - Apoorva Chaudhary
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
| | - Udit Joshi
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
| | - Anna Senrung
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
- Neuropharmacology and Drug Delivery Laboratory, Department of Zoology, Daulat Ram College, University of Delhi (North Campus), Delhi, 110007, India
| | - Arun Chhokar
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
- Deshbandhu College, University of Delhi, New Delhi, 110019, India
| | - Nikita Aggarwal
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
| | - Alok Chandra Bharti
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
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15
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Luo J, Huang R, Xiao P, Xu A, Dong Z, Zhang L, Wu R, Qiu Y, Zhu L, Zhang R, Tang L. Construction of hub transcription factor-microRNAs-messenger RNA regulatory network in recurrent implantation failure. J Assist Reprod Genet 2024; 41:3-13. [PMID: 37878219 PMCID: PMC10789703 DOI: 10.1007/s10815-023-02947-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 09/14/2023] [Indexed: 10/26/2023] Open
Abstract
PURPOSE Recurrent implantation failure (RIF) affects up to 10% of in vitro fertilization (IVF) patients worldwide. However, the pathogenesis of RIF remains unclear. This study was aimed at identifying hub transcription factors (TFs) of RIF in bioinformatics approaches. METHODS The GSE111974 (mRNA), GSE71332 (miRNA), and GSE103465 (mRNA) datasets were downloaded from the Gene Expression Omnibus database from human endometrial tissue using R version 4.2.1 and used to identify differentially expressed TFs (DETFs), differentially expressed miRNAs, and differentially expressed genes for RIF, respectively. DETFs were subjected to functional enrichment analysis and the protein-protein interaction network analysis using the Search Tool for the Retrieval of Interacting Genes (version 11.5) database. Hub TFs were identified using the cytoHubb plug-in, after which a hub TF-miRNA-mRNA network was constructed using Cytoscape v3.8.2. RESULTS Fifty-seven DETFs were identified, in which Gene Ontology analysis revealed to be mainly involved in the regulation of transcription. Kyoto Encyclopedia of Genes and Genomes pathway analysis suggested that DETFs were enriched in transcriptional misregulation in cancer, aldosterone synthesis and secretion, AMPK signaling pathway, and cGMP-PKG signaling pathway. EOMES, NKX2-1, and POU5F1 were identified as hub TFs, and a hub TF-miRNA-mRNA regulatory network was constructed using these three hub TFs, four miRNAs, and four genes. CONCLUSION Collectively, we identified three promising molecular biomarkers for the diagnosis of RIF, which may further be potential therapeutic targets. This study provides novel insights into the molecular mechanisms underlying RIF. However, further experiments are required to verify these results.
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Affiliation(s)
- Jiahuan Luo
- Department of Reproductive Genetics, The First Affiliated Hospital of Kunming Medical University, No. 295, Xichang Road, Wuhua District, Kunming, China
- Department of Reproductive Medicine, The First Affiliated Hospital of Dali University, Dali, China
- Innovation Team in Reproductive Medicine, Dali University, No. 32, Carlsberg Avenue, Dali, Yunnan, China
- First Clinical Medical College, Kunming Medical University, Kunming, China
| | - Rongxia Huang
- Department of Gynecology, Kunming Maternal and Child Health Hospital, Kunming, China
| | - Pengying Xiao
- Reproductive Medicine Center, Dongguan Songshan Lake Central Hospital, Dongguan, 523429, China
| | - Anli Xu
- Department of Reproductive Medicine, The First Affiliated Hospital of Dali University, Dali, China
- Innovation Team in Reproductive Medicine, Dali University, No. 32, Carlsberg Avenue, Dali, Yunnan, China
- Reproductive Medicine Center, Kunming Maternal and Child Health Hospital, No. 43, Huashan West Road, Huashan Street, Wuhua District, Kunming, China
| | - Zhaomei Dong
- Department of Reproductive Medicine, The First Affiliated Hospital of Dali University, Dali, China
- Innovation Team in Reproductive Medicine, Dali University, No. 32, Carlsberg Avenue, Dali, Yunnan, China
- Reproductive Medicine Center, Kunming Maternal and Child Health Hospital, No. 43, Huashan West Road, Huashan Street, Wuhua District, Kunming, China
| | - Lirong Zhang
- Department of Reproductive Medicine, The First Affiliated Hospital of Dali University, Dali, China
- Innovation Team in Reproductive Medicine, Dali University, No. 32, Carlsberg Avenue, Dali, Yunnan, China
- Reproductive Medicine Center, Kunming Maternal and Child Health Hospital, No. 43, Huashan West Road, Huashan Street, Wuhua District, Kunming, China
| | - Rui Wu
- Department of Reproductive Medicine, The First Affiliated Hospital of Dali University, Dali, China
- Reproductive Medicine Center, Kunming Maternal and Child Health Hospital, No. 43, Huashan West Road, Huashan Street, Wuhua District, Kunming, China
| | - Yunlin Qiu
- Department of Reproductive Medicine, The First Affiliated Hospital of Dali University, Dali, China
- Reproductive Medicine Center, Kunming Maternal and Child Health Hospital, No. 43, Huashan West Road, Huashan Street, Wuhua District, Kunming, China
| | - Li Zhu
- Department of Reproductive Medicine, The First Affiliated Hospital of Dali University, Dali, China.
- Innovation Team in Reproductive Medicine, Dali University, No. 32, Carlsberg Avenue, Dali, Yunnan, China.
- Reproductive Medicine Center, Kunming Maternal and Child Health Hospital, No. 43, Huashan West Road, Huashan Street, Wuhua District, Kunming, China.
| | - Ruopeng Zhang
- Reproductive Medicine Center, Dongguan Songshan Lake Central Hospital, Dongguan, 523429, China.
- Reproductive Medicine Center, Kunming Maternal and Child Health Hospital, No. 43, Huashan West Road, Huashan Street, Wuhua District, Kunming, China.
| | - Li Tang
- Department of Reproductive Genetics, The First Affiliated Hospital of Kunming Medical University, No. 295, Xichang Road, Wuhua District, Kunming, China.
- First Clinical Medical College, Kunming Medical University, Kunming, China.
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16
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Hasan A, Khan NA, Uddin S, Khan AQ, Steinhoff M. Deregulated transcription factors in the emerging cancer hallmarks. Semin Cancer Biol 2024; 98:31-50. [PMID: 38123029 DOI: 10.1016/j.semcancer.2023.12.001] [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: 09/28/2023] [Revised: 11/25/2023] [Accepted: 12/14/2023] [Indexed: 12/23/2023]
Abstract
Cancer progression is a multifaceted process that entails several stages and demands the persistent expression or activation of transcription factors (TFs) to facilitate growth and survival. TFs are a cluster of proteins with DNA-binding domains that attach to promoter or enhancer DNA strands to start the transcription of genes by collaborating with RNA polymerase and other supporting proteins. They are generally acknowledged as the major regulatory molecules that coordinate biological homeostasis and the appropriate functioning of cellular components, subsequently contributing to human physiology. TFs proteins are crucial for controlling transcription during the embryonic stage and development, and the stability of different cell types depends on how they function in different cell types. The development and progression of cancer cells and tumors might be triggered by any anomaly in transcription factor function. It has long been acknowledged that cancer development is accompanied by the dysregulated activity of TF alterations which might result in faulty gene expression. Recent studies have suggested that dysregulated transcription factors play a major role in developing various human malignancies by altering and rewiring metabolic processes, modifying the immune response, and triggering oncogenic signaling cascades. This review emphasizes the interplay between TFs involved in metabolic and epigenetic reprogramming, evading immune attacks, cellular senescence, and the maintenance of cancer stemness in cancerous cells. The insights presented herein will facilitate the development of innovative therapeutic modalities to tackle the dysregulated transcription factors underlying cancer.
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Affiliation(s)
- Adria Hasan
- Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Lucknow 226026, India; Department of Bioengineering, Faculty of Engineering, Integral University, Lucknow 226026, India
| | - Naushad Ahmad Khan
- Department of Surgery, Trauma and Vascular Surgery Clinical Research, Hamad General Hospital, Doha 3050, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Biosciences, Integral University, Lucknow 226026, India; Animal Research Center, Qatar University, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar
| | - Abdul Q Khan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar.
| | - Martin Steinhoff
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Animal Research Center, Qatar University, Doha, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar; Department of Medicine, Weill Cornell Medicine Qatar, Qatar Foundation-Education City, Doha 24144, Qatar; Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; College of Medicine, Qatar University, Doha 2713, Qatar
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Zhang S, Yang R, Ouyang Y, Shen Y, Hu L, Xu C. Cancer stem cells: a target for overcoming therapeutic resistance and relapse. Cancer Biol Med 2023; 20:j.issn.2095-3941.2023.0333. [PMID: 38164743 PMCID: PMC10845928 DOI: 10.20892/j.issn.2095-3941.2023.0333] [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: 09/04/2023] [Accepted: 11/20/2023] [Indexed: 01/03/2024] Open
Abstract
Cancer stem cells (CSCs) are a small subset of cells in cancers that are thought to initiate tumorous transformation and promote metastasis, recurrence, and resistance to treatment. Growing evidence has revealed the existence of CSCs in various types of cancers and suggested that CSCs differentiate into diverse lineage cells that contribute to tumor progression. We may be able to overcome the limitations of cancer treatment with a comprehensive understanding of the biological features and mechanisms underlying therapeutic resistance in CSCs. This review provides an overview of the properties, biomarkers, and mechanisms of resistance shown by CSCs. Recent findings on metabolic features, especially fatty acid metabolism and ferroptosis in CSCs, are highlighted, along with promising targeting strategies. Targeting CSCs is a potential treatment plan to conquer cancer and prevent resistance and relapse in cancer treatment.
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Affiliation(s)
- Shuo Zhang
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610042, China
| | - Rui Yang
- Department of Ultrasound in Medicine, Chengdu Wenjiang District People’s Hospital, Chengdu 611130, China
| | - Yujie Ouyang
- Acupuncture and Massage College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yang Shen
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- School of Pharmacy, Macau University of Science and Technology, Macau SAR 999078, China
| | - Lanlin Hu
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Yu-Yue Pathology Scientific Research Center, Chongqing 400039, China
- Jinfeng Laboratory, Chongqing 401329, China
| | - Chuan Xu
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Yu-Yue Pathology Scientific Research Center, Chongqing 400039, China
- Jinfeng Laboratory, Chongqing 401329, China
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18
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Wang Q, Bode AM, Zhang T. Targeting CDK1 in cancer: mechanisms and implications. NPJ Precis Oncol 2023; 7:58. [PMID: 37311884 DOI: 10.1038/s41698-023-00407-7] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 05/25/2023] [Indexed: 06/15/2023] Open
Abstract
Cyclin dependent kinases (CDKs) are serine/threonine kinases that are proposed as promising candidate targets for cancer treatment. These proteins complexed with cyclins play a critical role in cell cycle progression. Most CDKs demonstrate substantially higher expression in cancer tissues compared with normal tissues and, according to the TCGA database, correlate with survival rate in multiple cancer types. Deregulation of CDK1 has been shown to be closely associated with tumorigenesis. CDK1 activation plays a critical role in a wide range of cancer types; and CDK1 phosphorylation of its many substrates greatly influences their function in tumorigenesis. Enrichment of CDK1 interacting proteins with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was conducted to demonstrate that the associated proteins participate in multiple oncogenic pathways. This abundance of evidence clearly supports CDK1 as a promising target for cancer therapy. A number of small molecules targeting CDK1 or multiple CDKs have been developed and evaluated in preclinical studies. Notably, some of these small molecules have also been subjected to human clinical trials. This review evaluates the mechanisms and implications of targeting CDK1 in tumorigenesis and cancer therapy.
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Affiliation(s)
- Qiushi Wang
- The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN, 55912, USA
| | - Ann M Bode
- The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN, 55912, USA.
| | - Tianshun Zhang
- The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN, 55912, USA.
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19
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Sen U, Shanavas S, Nagendra AH, Nihad M, Chaudhury D, Rachamalla HK, Banerjee R, Shenoy P S, Bose B. Significance of Oct-4 transcription factor as a pivotal therapeutic target for CD44 + /24 - mammary tumor initiating cells: Aiming at the root of the recurrence. Cell Biol Int 2023; 47:742-753. [PMID: 36573403 DOI: 10.1002/cbin.11978] [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: 09/04/2021] [Revised: 11/24/2022] [Accepted: 12/03/2022] [Indexed: 12/28/2022]
Abstract
Breast cancer (BC) remains one of the deadliest and frequently diagnosed metastatic cancers worldwide. Cancer stem cells (CSCs) are the cell population within the tumor niche, having an epithelial to mesenchymal (EMT) transition phenotype, high self-renewal, vigorous metastatic capacity, drug resistance, and tumor relapse. Identification of targets for induction of apoptosis is essential to provide novel therapeutic approaches in BC. Our earlier studies showed that Vitamin C induces apoptotic cell death by losing redox balance in TNBC CSCs. In this study, we have attempted to identify previously unrecognized CSC survival factors that can be used as druggable targets for bCSCs apoptosis regulators isolated from the TNBC line, MDA MB 468. After a thorough literature review, Oct-4 was identified as the most promising marker for its unique abundance in cancer and absence in normal cells and the contribution of Oct-4 to the sustenance of cancer cells. We then validated a very high expression of Oct-4 in the MDA MB 468 bCSCs population using flow-cytometry. The loss of Oct-4 was carried out using small interfering RNA (siRNA)-mediated knockdown in the bCSCs, followed by assessing for cellular apoptosis. Our results indicated that Oct-4 knockdown induced cell death, changes in cellular morphology, inhibited mammosphere formation, and positive for Annexin-V expression, thereby indicating the role of Oct-4 in bCSC survival. Moreover, our findings also suggest the direct interaction between Oct-4 and Vitamin C using in silico docking. This data, hence, contributes towards novel information about Oct-4 highlighting this molecule as a novel survival factor in bCSCs.
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Affiliation(s)
- Utsav Sen
- Stem cells and regenerative medicine centre, Yenepoya Research Centre, Yenepoya (Deemed to be university), Deralakatte, Mangalore, Karnataka, India
| | - Shanooja Shanavas
- Stem cells and regenerative medicine centre, Yenepoya Research Centre, Yenepoya (Deemed to be university), Deralakatte, Mangalore, Karnataka, India
| | - Apoorva H Nagendra
- Stem cells and regenerative medicine centre, Yenepoya Research Centre, Yenepoya (Deemed to be university), Deralakatte, Mangalore, Karnataka, India
| | - Muhammad Nihad
- Stem cells and regenerative medicine centre, Yenepoya Research Centre, Yenepoya (Deemed to be university), Deralakatte, Mangalore, Karnataka, India
| | - Debajit Chaudhury
- Stem cells and regenerative medicine centre, Yenepoya Research Centre, Yenepoya (Deemed to be university), Deralakatte, Mangalore, Karnataka, India
| | - Hari K Rachamalla
- Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana, India.,Academy of Scientific & Innovative Research (AcSIR), CSIR-HRDC Campus, Ghaziabad, Uttar Pradesh, India
| | - Rajkumar Banerjee
- Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana, India.,Academy of Scientific & Innovative Research (AcSIR), CSIR-HRDC Campus, Ghaziabad, Uttar Pradesh, India
| | - Sudheer Shenoy P
- Stem cells and regenerative medicine centre, Yenepoya Research Centre, Yenepoya (Deemed to be university), Deralakatte, Mangalore, Karnataka, India
| | - Bipasha Bose
- Stem cells and regenerative medicine centre, Yenepoya Research Centre, Yenepoya (Deemed to be university), Deralakatte, Mangalore, Karnataka, India
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20
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Gómez-Gómez Y, Organista-Nava J, Clemente-Periván SI, Lagunas-Martínez A, Salmerón-Bárcenas EG, Villanueva-Morales D, Ayala-Reyna DY, Del Carmen Alarcón-Romero L, Ortiz-Ortiz J, Jiménez-López MA, Bello-Rios C, Leyva-Vázquez MA, Illades-Aguiar B. The expression of Oct3/4A mRNA and not its isoforms is upregulated by the HPV16 E7 oncoprotein. Mol Biol Rep 2023; 50:981-991. [PMID: 36378419 DOI: 10.1007/s11033-022-07988-9] [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: 05/06/2022] [Accepted: 09/28/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE Oct3/4 a transcription factor is involved in maintaining the characteristics of cancer stem cells. Oct3/4 can be expressed differentially with respect to the progression of cervical cancer (CC). In addition, Oct3/4 can give rise to three isoforms by alternative splicing of the mRNA Oct3/4A, Oct3/4B and Oct3/4B1. The aim of this study was to evaluate the mRNA expression from Oct3/4A, Oct3/4B and Oct3/4B1 in low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), CC samples, and measure the effect of the HPV16 E7 oncoprotein on the mRNA expression from Oct3/4 isoforms in the C-33A cell line. METHODS The expression levels of Oct3/4A, Oct3/4B and Oct3/4B1 mRNA were analyzed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) in patients with LSILs, HSILs and CC. Additionally, C-33A cells that expressed the HPV16 E7 oncoprotein were established to evaluate the effect of E7 on the expression of Oct3/4 mRNA isoforms. RESULTS Oct3/4A (p = 0.02), Oct3/4B (p = 0. 001) and Oct3/4B1 (p < 0. 0001) expression is significantly higher in patients with LSIL, HSIL and CC than in woman with non-IL. In the C-33A cell line, the expression of Oct3/4A mRNA in the presence of the E7 oncoprotein increased compared to that in nontransfected C-33A cells. CONCLUSION Oct3/4B and Oct3/4B1 mRNA were expressed at similar levels among the different groups. These data indicate that only the mRNA of Oct3/4A is upregulated by the HPV16 E7 oncoprotein.
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Affiliation(s)
- Yazmín Gómez-Gómez
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Edificio C primer piso, Av. Lázaro Cárdenas S/N, Ciudad Universitaria sur, 39090, Chilpancingo, Guerrero, México
| | - Jorge Organista-Nava
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Edificio C primer piso, Av. Lázaro Cárdenas S/N, Ciudad Universitaria sur, 39090, Chilpancingo, Guerrero, México.
| | - Sayuri Itzel Clemente-Periván
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Edificio C primer piso, Av. Lázaro Cárdenas S/N, Ciudad Universitaria sur, 39090, Chilpancingo, Guerrero, México
| | - Alfredo Lagunas-Martínez
- Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, 62100, Cuernavaca, Morelos, México
| | - Eric Genaro Salmerón-Bárcenas
- Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, 07360, Ciudad de México, Mexico
| | - Daniel Villanueva-Morales
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Edificio C primer piso, Av. Lázaro Cárdenas S/N, Ciudad Universitaria sur, 39090, Chilpancingo, Guerrero, México
| | - Dania Yahaira Ayala-Reyna
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Edificio C primer piso, Av. Lázaro Cárdenas S/N, Ciudad Universitaria sur, 39090, Chilpancingo, Guerrero, México
| | - Luz Del Carmen Alarcón-Romero
- Laboratorio de Citopatología, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, 39090, Chilpancingo, Guerrero, México
| | - Julio Ortiz-Ortiz
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Edificio C primer piso, Av. Lázaro Cárdenas S/N, Ciudad Universitaria sur, 39090, Chilpancingo, Guerrero, México
| | | | - Ciresthel Bello-Rios
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Edificio C primer piso, Av. Lázaro Cárdenas S/N, Ciudad Universitaria sur, 39090, Chilpancingo, Guerrero, México
| | - Marco Antonio Leyva-Vázquez
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Edificio C primer piso, Av. Lázaro Cárdenas S/N, Ciudad Universitaria sur, 39090, Chilpancingo, Guerrero, México
| | - Berenice Illades-Aguiar
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Edificio C primer piso, Av. Lázaro Cárdenas S/N, Ciudad Universitaria sur, 39090, Chilpancingo, Guerrero, México.
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21
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Chaudhary A, Raza SS, Haque R. Transcriptional factors targeting in cancer stem cells for tumor modulation. Semin Cancer Biol 2023; 88:123-137. [PMID: 36603792 DOI: 10.1016/j.semcancer.2022.12.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 12/29/2022] [Accepted: 12/30/2022] [Indexed: 01/03/2023]
Abstract
Cancer Stem Cells (CSCs) are now considered the primary "seeds" for the onset, development, metastasis, and recurrence of tumors. Despite therapeutic breakthroughs, cancer remains the leading cause of death worldwide. This is because the tumor microenvironment contains a key population of cells known as CSCs, which promote tumor aggression. CSCs are self-renewing cells that aid tumor recurrence by promoting tumor growth and persisting in patients after many traditional cancer treatments. According to reports, numerous transcription factors (TF) play a key role in maintaining CSC pluripotency and its self-renewal property. The understanding of the functions, structures, and interactional dynamics of these transcription factors with DNA has modified the hypothesis, paving the way for novel transcription factor-targeted therapies. These TFs, which are crucial and are required by cancer cells, play a vital function in the etiology of human cancer. Such CSC TFs will help with gene expression profiling, which provides crucial data for predicting the prognosis of patients. To overcome anti-cancer medication resistance and completely eradicate cancer, a potent therapy combining TFs-based CSC targets with traditional chemotherapy may be developed. In order to develop therapies that could eliminate CSCs, we here concentrated on the effect of TFs and other components of signalling pathways on cancer stemness.
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Affiliation(s)
- Archana Chaudhary
- Department of Biotechnology, School of Earth Biological and Environmental Sciences, Central University of South Bihar, Gaya, Bihar, India
| | - Syed Shadab Raza
- Laboratory for Stem Cell & Restorative Neurology, Era's Lucknow Medical College and Hospital, Era University, Lucknow, India
| | - Rizwanul Haque
- Department of Biotechnology, School of Earth Biological and Environmental Sciences, Central University of South Bihar, Gaya, Bihar, India.
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22
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Ishaq Y, Ikram A, Alzahrani B, Khurshid S. The Role of miRNAs, circRNAs and Their Interactions in Development and Progression of Hepatocellular Carcinoma: An Insilico Approach. Genes (Basel) 2022; 14:genes14010013. [PMID: 36672755 PMCID: PMC9858589 DOI: 10.3390/genes14010013] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/06/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a type of malignant tumor. miRNAs are noncoding RNAs and their differential expression patterns are observed in HCC-induced by alcoholism, HBV and HCV infections. By acting as a competing endogenous RNA (ceRNA), circRNA regulates the miRNA function, indirectly controlling the gene expression and leading to HCC progression. In the present study, data mining was performed to screen out all miRNAs and circRNA involved in alcohol, HBV or HCV-induced HCC with statistically significant (≤0.05%) expression levels reported in various studies. Further, the interaction of miRNAs and circRNA was also investigated to explore their role in HCC due to various causative agents. Together, these study data provide a deeper understanding of the circRNA-miRNA regulatory mechanisms in HCC. These screened circRNA, miRNA and their interactions can be used as prognostic biomarkers or therapeutic targets for the treatment of HCC.
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Affiliation(s)
- Yasmeen Ishaq
- Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore (UOL), Lahore 54000, Pakistan
| | - Aqsa Ikram
- Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore (UOL), Lahore 54000, Pakistan
- Correspondence:
| | - Badr Alzahrani
- Department of Clinical Laboratory Sciences, Jouf University, Sakaka 42421, Saudi Arabia
| | - Sana Khurshid
- Department of Molecular Biology, Virtual University of Pakistan, 1-Davis Road, Lahore 54000, Pakistan
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23
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Larcombe MR, Hsu S, Polo JM, Knaupp AS. Indirect Mechanisms of Transcription Factor-Mediated Gene Regulation during Cell Fate Changes. ADVANCED GENETICS (HOBOKEN, N.J.) 2022; 3:2200015. [PMID: 36911290 PMCID: PMC9993476 DOI: 10.1002/ggn2.202200015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Indexed: 06/18/2023]
Abstract
Transcription factors (TFs) are the master regulators of cellular identity, capable of driving cell fate transitions including differentiations, reprogramming, and transdifferentiations. Pioneer TFs recognize partial motifs exposed on nucleosomal DNA, allowing for TF-mediated activation of repressed chromatin. Moreover, there is evidence suggesting that certain TFs can repress actively expressed genes either directly through interactions with accessible regulatory elements or indirectly through mechanisms that impact the expression, activity, or localization of other regulatory factors. Recent evidence suggests that during reprogramming, the reprogramming TFs initiate opening of chromatin regions rich in somatic TF motifs that are inaccessible in the initial and final cellular states. It is postulated that analogous to a sponge, these transiently accessible regions "soak up" somatic TFs, hence lowering the initial barriers to cell fate changes. This indirect TF-mediated gene regulation event, which is aptly named the "sponge effect," may play an essential role in the silencing of the somatic transcriptional network during different cellular conversions.
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Affiliation(s)
- Michael R. Larcombe
- Department of Anatomy and Developmental BiologyMonash UniversityClaytonVictoria3168Australia
- Development and Stem Cells ProgramMonash Biomedicine Discovery InstituteClaytonVictoria3168Australia
- Australian Regenerative Medicine InstituteMonash UniversityClaytonVictoria3168Australia
| | - Sheng Hsu
- Department of Anatomy and Developmental BiologyMonash UniversityClaytonVictoria3168Australia
- Development and Stem Cells ProgramMonash Biomedicine Discovery InstituteClaytonVictoria3168Australia
- Australian Regenerative Medicine InstituteMonash UniversityClaytonVictoria3168Australia
| | - Jose M. Polo
- Department of Anatomy and Developmental BiologyMonash UniversityClaytonVictoria3168Australia
- Development and Stem Cells ProgramMonash Biomedicine Discovery InstituteClaytonVictoria3168Australia
- Australian Regenerative Medicine InstituteMonash UniversityClaytonVictoria3168Australia
- South Australian Immunogenomics Cancer Institute, Faculty of Health and Medical SciencesUniversity of AdelaideAdelaideSouth Australia5005Australia
- Adelaide Centre for Epigenetics, Faculty of Health and Medical SciencesUniversity of AdelaideAdelaideSouth Australia5005Australia
| | - Anja S. Knaupp
- Department of Anatomy and Developmental BiologyMonash UniversityClaytonVictoria3168Australia
- Development and Stem Cells ProgramMonash Biomedicine Discovery InstituteClaytonVictoria3168Australia
- Australian Regenerative Medicine InstituteMonash UniversityClaytonVictoria3168Australia
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24
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Zhang L, Wu S, Huang J, Shi Y, Yin Y, Cao X. A mitochondria-related signature for predicting immune microenvironment and therapeutic response in osteosarcoma. Front Oncol 2022; 12:1085065. [PMID: 36531021 PMCID: PMC9751795 DOI: 10.3389/fonc.2022.1085065] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 11/15/2022] [Indexed: 11/19/2023] Open
Abstract
BACKGROUND Osteosarcoma remains to be the most devastating malignant tumor in children and teenagers. Mitochondria have also been proven to play critical roles in osteosarcoma. However, a mitochondria-related signature has been established in osteosarcoma to comprehensively evaluate the pathogenic roles and regulatory roles of mitochondria in osteosarcoma. METHODS In this study, osteosarcoma samples' transcriptome data and clinical information were collected from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) databases. A comprehensive bioinformatics analysis was performed on the samples at the bulk RNA sequencing level and single-cell RNA sequencing (scRNA-seq) level. EdU, Transwell, and immunohistochemistry (IHC) were performed on PCCB. RESULTS A mitochondria-related signature was constructed in osteosarcoma patients. The prognostic value of the mitochondria-related signature was explored. The predictive value of the mitochondria-related signature in the immune microenvironment and chemotherapy agents was explored. The association between mitochondria and immunity in the tumor microenvironment of osteosarcoma at the scRNA-seq level was investigated. The tumorigenic role of the critical mitochondria-related gene, PCCB, was verified by in vitro validation. CONCLUSION In conclusion, a mitochondria-related signature was developed in osteosarcoma with solid predictive values in the immune microenvironment, chemotherapy agents, and prognosis.
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Affiliation(s)
| | | | | | | | | | - Xu Cao
- Department of Orthopaedics, The Third Xiangya Hospital, Central South University, Changsha, China
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25
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Vishnubalaji R, Shaath H, Al-Alwan M, Abdelalim EM, Alajez NM. Reciprocal interplays between MicroRNAs and pluripotency transcription factors in dictating stemness features in human cancers. Semin Cancer Biol 2022; 87:1-16. [PMID: 36354097 DOI: 10.1016/j.semcancer.2022.10.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022]
Abstract
The interplay between microRNAs (miRNAs) and pluripotency transcription factors (TFs) orchestrates the acquisition of cancer stem cell (CSC) features during the course of malignant transformation, rendering them essential cancer cell dependencies and therapeutic vulnerabilities. In this review, we discuss emerging themes in tumor heterogeneity, including the clonal evolution and the CSC models and their implications in resistance to cancer therapies, and then provide thorough coverage on the roles played by key TFs in maintaining normal and malignant stem cell pluripotency and plasticity. In addition, we discuss the reciprocal interactions between miRNAs and MYC, OCT4, NANOG, SOX2, and KLF4 pluripotency TFs and their contributions to tumorigenesis. We provide our view on the potential to interfere with key miRNA-TF networks through the use of RNA-based therapeutics as single agents or in combination with other therapeutic strategies, to abrogate the CSC state and render tumor cells more responsive to standard and targeted therapies.
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Affiliation(s)
- Radhakrishnan Vishnubalaji
- Translational Cancer and Immunity Center (TCIC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Hibah Shaath
- Translational Cancer and Immunity Center (TCIC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Monther Al-Alwan
- Stem Cell and Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; College of Medicine, Al-Faisal University, Riyadh 11533, Saudi Arabia
| | - Essam M Abdelalim
- Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, PO Box 34110, Doha, Qatar; College of Health & Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Nehad M Alajez
- Translational Cancer and Immunity Center (TCIC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar; College of Health & Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.
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26
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Zhang J, Zhao J, Wei S, Huang P, Tu X, Su G, Gan Y, Gong W, Xiang B. Developing and Validating an Autophagy Gene-Set-Based Prognostic Signature in Hepatocellular Carcinoma Patients. Int J Gen Med 2022; 15:8399-8415. [DOI: 10.2147/ijgm.s388592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 11/17/2022] [Indexed: 11/29/2022] Open
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27
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Abdou Hassan W, Muqresh MA, Omar M. The Potential Role of CD44 and CD133 in Colorectal Stem Cell Cancer. Cureus 2022; 14:e30509. [DOI: 10.7759/cureus.30509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/20/2022] [Indexed: 11/05/2022] Open
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28
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Xu Z, Yu W, Li L, Wang G. Identification of pyroptosis-related gene signature for predicting prognosis of patients with pancreatic cancer using bioinformatics. Medicine (Baltimore) 2022; 101:e31043. [PMID: 36253973 PMCID: PMC9575720 DOI: 10.1097/md.0000000000031043] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Pancreatic cancer, a common digestive system malignancy, is dubbed the "king of cancers". The role of pyrophosis-related genes (PRGs) in pancreatic cancer prognosis is yet unknown. In pancreatic cancer and normal tissue, we discovered 9 PRGs that are expressed differently in pancreatic cancer and healthy tissue. Based on the differential expression of PRGs, 2 clusters of pancreatic cancer cases could be identified. The 2 groups had significant disparities in total survival time. The prognostic model of a 5-PRGs signature was created using least absolute shrinkage and selection operator (LASSO) method. The median risk score was used to split pancreatic cancer patients in The Cancer Genome Atlas (TCGA) cohort into 2 groups: low risk and high risk. Patients classified as low-risk had significantly higher survival rates than those classified as high-risk (P < .01). The same results were obtained by validating them against the Gene Expression Omnibus database (P = .030). Cox regression statistical analysis showed that risk score was an independent predictor of overall survival in pancreatic cancer patients. Functional enrichment analysis revealed that apoptosis, cell proliferation, and cell cycle-related biological processes and signaling pathways were enriched. Additionally, the immunological status of the high-risk group worsened. In conclusion, a novel pyroptosis-related gene signature can be used to predict pancreatic cancer patient prognosis.
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Affiliation(s)
- Zhongbo Xu
- Emergency Department, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China
| | - Wenyan Yu
- The Research Center for Differentiation and Development of Basic Theories of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China
| | - Lin Li
- Emergency Department, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China
| | - Guojuan Wang
- Department of Oncology, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China
- *Correspondence: Guojuan Wang, Department of Oncology, Affiliated Hospital of Jiangxi University of Chinese Medicine, No.445, Bayi Avenue, Nanchang 330006, Jiangxi, China (e-mail: )
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29
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Wang Y, Zhao J, Chen S, Li D, Yang J, Zhao X, Qin M, Guo M, Chen C, He Z, Zhou Y, Xu L. Let-7 as a Promising Target in Aging and Aging-Related Diseases: A Promise or a Pledge. Biomolecules 2022; 12:1070. [PMID: 36008964 PMCID: PMC9406090 DOI: 10.3390/biom12081070] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/28/2022] [Accepted: 07/29/2022] [Indexed: 12/10/2022] Open
Abstract
The abnormal regulation and expression of microRNA (miRNA) are closely related to the aging process and the occurrence and development of aging-related diseases. Lethal-7 (let-7) was discovered in Caenorhabditis elegans (C. elegans) and plays an important role in development by regulating cell fate regulators. Accumulating evidence has shown that let-7 is elevated in aging tissues and participates in multiple pathways that regulate the aging process, including affecting tissue stem cell function, body metabolism, and various aging-related diseases (ARDs). Moreover, recent studies have found that let-7 plays an important role in the senescence of B cells, suggesting that let-7 may also participate in the aging process by regulating immune function. Therefore, these studies show the diversity and complexity of let-7 expression and regulatory functions during aging. In this review, we provide a detailed overview of let-7 expression regulation as well as its role in different tissue aging and aging-related diseases, which may provide new ideas for enriching the complex expression regulation mechanism and pathobiological function of let-7 in aging and related diseases and ultimately provide help for the development of new therapeutic strategies.
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Affiliation(s)
- Ya Wang
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China; (Y.W.); (J.Z.); (S.C.); (D.L.); (J.Y.); (X.Z.); (M.Q.); (M.G.); (C.C.)
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Juanjuan Zhao
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China; (Y.W.); (J.Z.); (S.C.); (D.L.); (J.Y.); (X.Z.); (M.Q.); (M.G.); (C.C.)
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Shipeng Chen
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China; (Y.W.); (J.Z.); (S.C.); (D.L.); (J.Y.); (X.Z.); (M.Q.); (M.G.); (C.C.)
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Dongmei Li
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China; (Y.W.); (J.Z.); (S.C.); (D.L.); (J.Y.); (X.Z.); (M.Q.); (M.G.); (C.C.)
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Jing Yang
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China; (Y.W.); (J.Z.); (S.C.); (D.L.); (J.Y.); (X.Z.); (M.Q.); (M.G.); (C.C.)
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Xu Zhao
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China; (Y.W.); (J.Z.); (S.C.); (D.L.); (J.Y.); (X.Z.); (M.Q.); (M.G.); (C.C.)
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Ming Qin
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China; (Y.W.); (J.Z.); (S.C.); (D.L.); (J.Y.); (X.Z.); (M.Q.); (M.G.); (C.C.)
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Mengmeng Guo
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China; (Y.W.); (J.Z.); (S.C.); (D.L.); (J.Y.); (X.Z.); (M.Q.); (M.G.); (C.C.)
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Chao Chen
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China; (Y.W.); (J.Z.); (S.C.); (D.L.); (J.Y.); (X.Z.); (M.Q.); (M.G.); (C.C.)
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Zhixu He
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi 563000, China;
| | - Ya Zhou
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China; (Y.W.); (J.Z.); (S.C.); (D.L.); (J.Y.); (X.Z.); (M.Q.); (M.G.); (C.C.)
- Department of Medical Physics, Zunyi Medical University, Zunyi 563000, China
| | - Lin Xu
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China; (Y.W.); (J.Z.); (S.C.); (D.L.); (J.Y.); (X.Z.); (M.Q.); (M.G.); (C.C.)
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
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The emerging landscape of exosomal CircRNAs in solid cancers and hematological malignancies. Biomark Res 2022; 10:28. [PMID: 35505392 PMCID: PMC9066734 DOI: 10.1186/s40364-022-00375-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 04/05/2022] [Indexed: 12/24/2022] Open
Abstract
Circular RNAs (circRNAs) are a type of recently discovered noncoding RNA. They exert their biological functions by competitively binding to microRNAs (miRNAs) as miRNA sponges, promoting gene transcription and participating in the regulation of selective splicing, interacting with proteins and being translated into proteins. Exosomes are derived from intracavitary vesicles (ILVs), which are formed by the inward budding of multivesicular bodies (MVBs), and exosome release plays a pivotal role in intercellular communication. Accumulating evidence indicates that circRNAs in exosomes are associated with solid tumor invasion and metastasis. Additionally, emerging studies in the last 1 ~ 2 years have revealed that exosomal circRNA also have effect on hematological malignancies. In this review, we outline the properties and biological functions of circRNAs and exosomes. In particular, we summarize in detail the mechanism and roles of exosomal circRNAs and highlight their application as novel biomarkers in malignant tumors.
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Routila J, Qiao X, Weltner J, Rantala JK, Carpén T, Hagström J, Mäkitie A, Leivo I, Ruuskanen M, Söderlund J, Rintala M, Hietanen S, Irjala H, Minn H, Westermarck J, Ventelä S. Cisplatin overcomes radiotherapy resistance in OCT4-expressing head and neck squamous cell carcinoma. Oral Oncol 2022; 127:105772. [PMID: 35245886 DOI: 10.1016/j.oraloncology.2022.105772] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 02/11/2022] [Accepted: 02/12/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Cisplatin is combined with radiotherapy for advanced head and neck squamous cell carcinoma (HNSCC). While providing a beneficial effect on survival, it also causes side effects and thus is an important target when considering treatment de-escalation. Currently, there are no biomarkers to predict its patient-selective therapeutic utility. In this study, we examined the role of the stem cell factor OCT4 as a potential biomarker to help clinicians stratify HNSCC patients between radiotherapy and chemoradiotherapy. MATERIALS AND METHODS OCT4 immunohistochemical staining of a population-validated tissue microarray (PV-TMA) (n = 166) representative of a standard HNSCC patients was carried out, and 5-year survival was analyzed. The results were validated using ex vivo drug sensitivity analysis of HNSCC tumor samples, and further cross-validated in independent oropharyngeal (n = 118), nasopharyngeal (n = 170), and vulvar carcinoma (n = 95) clinical datasets. In vitro, genetically modified, patient-derived HNSCC cells were used. RESULTS OCT4 expression in HNSCC tumors was associated with radioresistance. However, combination therapy with cisplatin was found to overcome thisradioresistance in OCT4-expressing HNSCC tumors. The results were validated by using several independent patient cohorts. Furthermore, CRISPRa-based OCT4 overexpression in the HNSCC cell line resulted in apoptosis resistance, and cisplatin was found to downregulate OCT4 protein expression in vitro. Ex vivo drug sensitivity analysis of HNSCC tumors confirmed the association between OCT4 expression and cisplatin sensitivity. CONCLUSION This study introduces OCT4 immunohistochemistry as a simple and cost-effective diagnostic approach for clinical practice to identify HNSCC patients benefitting from radiosensitization by cisplatin using either full or reduced dosing.
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Affiliation(s)
- Johannes Routila
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; Department for Otorhinolaryngology - Head and Neck Surgery, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, 20521 Turku, Finland
| | - Xi Qiao
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Jere Weltner
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, SE-14186 Stockholm, Sweden and Division of Obstetrics and Gynecology, Karolinska Universitetssjukhuset, SE-14186 Stockholm, Sweden
| | - Juha K Rantala
- MISVIK Biology Ltd, Karjakatu 35 B, 20520 Turku, Finland
| | - Timo Carpén
- Department for Otorhinolaryngology - Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, P.O.Box 263, FI-00029 HUS Helsinki, Finland
| | - Jaana Hagström
- Department of Oral Pathology and Radiology, University of Turku, Turku, Finland
| | - Antti Mäkitie
- Department for Otorhinolaryngology - Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, P.O.Box 263, FI-00029 HUS Helsinki, Finland
| | - Ilmo Leivo
- Department of Oral Pathology and Radiology, University of Turku, Turku, Finland; Institute of Biomedicine, Pathology, University of Turku, Kiinamyllynkatu 10 D, 20520 Turku, Finland
| | - Miia Ruuskanen
- Department for Otorhinolaryngology - Head and Neck Surgery, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, 20521 Turku, Finland
| | - Jenni Söderlund
- Department of Obstetrics and Gynecology, Turku University Hospital and University of Turku, Turku, Finland
| | - Marjut Rintala
- Department of Obstetrics and Gynecology, Turku University Hospital and University of Turku, Turku, Finland
| | - Sakari Hietanen
- Department of Obstetrics and Gynecology, Turku University Hospital and University of Turku, Turku, Finland; FICAN West Cancer Centre, Turku, Finland
| | - Heikki Irjala
- Department for Otorhinolaryngology - Head and Neck Surgery, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, 20521 Turku, Finland
| | - Heikki Minn
- FICAN West Cancer Centre, Turku, Finland; Department of Oncology and Radiotherapy, University of Turku and Turku University Hospital, Turku, Finland
| | - Jukka Westermarck
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; Biomedical Institute, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland; FICAN West Cancer Centre, Turku, Finland
| | - Sami Ventelä
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; Department for Otorhinolaryngology - Head and Neck Surgery, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, 20521 Turku, Finland; FICAN West Cancer Centre, Turku, Finland.
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HNF4A Regulates the Proliferation and Tumor Formation of Cervical Cancer Cells through the Wnt/β-Catenin Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8168988. [PMID: 35132353 PMCID: PMC8817108 DOI: 10.1155/2022/8168988] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 12/22/2021] [Indexed: 12/25/2022]
Abstract
Hepatocyte nuclear factor 4 alpha (HNF4A) is a transcriptional factor which plays an important role in the development of the liver, kidney, and intestines. Nevertheless, its role in cervical cancer and the underlying mechanism remain unknown. In this study, both immunohistochemistry and western blotting revealed that the expression of HNF4A was downregulated in cervical cancer. Xenograft assays suggested that HN4A could inhibit tumorigenic potential of cervical cancer in vivo. Functional studies illustrated that HNF4A also inhibited the proliferation and viability of cervical cancer cells in vitro. In addition, FACS analysis implied that HNF4A could induce cell cycle arrest from the G0/G1 phase to S phase. Further studies suggested that HNF4A downregulated the activity of the Wnt/β-catenin pathway. Altogether, our data demonstrated that HNF4A inhibited tumor formation and proliferation of cervical cancer cells through suppressing the activity of the Wnt/β-catenin pathway.
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Zhang S, Li X, Zhang X, Zhang S, Tang C, Kuang W. The Pyroptosis-Related Gene Signature Predicts the Prognosis of Hepatocellular Carcinoma. Front Mol Biosci 2022; 8:781427. [PMID: 35047554 PMCID: PMC8762168 DOI: 10.3389/fmolb.2021.781427] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/13/2021] [Indexed: 12/20/2022] Open
Abstract
Objective: Hepatocellular carcinoma (HCC) is a genetically and phenotypically heterogeneous tumor, and the prediction of its prognosis remains a challenge. In the past decade, studies elucidating the mechanisms that induce tumor cell pyroptosis has rapidly increased. The elucidation of their mechanisms is essential for the clinical development optimal application of anti-hepatocellular carcinoma therapeutics. Methods: Based on the different expression profiles of pyroptosis-related genes in HCC, we constructed a LASSO Cox regression pyroptosis-related genes signature that could more accurately predict the prognosis of HCC patients. Results: We identified seven pyroptosis-related genes signature (BAK1, CHMP4B, GSDMC, NLRP6, NOD2, PLCG1, SCAF11) in predicting the prognosis of HCC patients. Kaplan Meier survival analysis showed that the pyroptosis-related high-risk gene signature was associated with poor prognosis HCC patients. Moreover, the pyroptosis-related genes signature performed well in the survival analysis and ICGC validation group. The hybrid nomogram and calibration curve further demonstrated their feasibility and accuracy for predicting the prognosis of HCC patients. Meanwhile, the evaluation revealed that our novel signature predicted the prognosis of HCC patients more accurately than traditional clinicopathological features. GSEA analysis further revealed the novel signature associated mechanisms of immunity response in high-risk groups. Moreover, analysis of immune cell subsets with relevant functions revealed significant differences in aDCs, APC co-stimulation, CCR, check-point, iDCs, Macrophages, MHC class-I, Treg, and type II INF response between high- and low-risk groups. Finally, the expression of Immune checkpoints was enhanced in high-risk group, and m6A-related modifications were expressed differently between low- and high-risk groups. Conclusion: The novel pyroptosis-related genes signature can predict the prognosis of patients with HCC and insight into new cell death targeted therapies.
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Affiliation(s)
- Shuqiao Zhang
- First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xinyu Li
- Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiang Zhang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Shijun Zhang
- Department of Traditional Chinese Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chunzhi Tang
- Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Weihong Kuang
- Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
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Feng J. The p53 Pathway Related Genes Predict the Prognosis of Colon Cancer. Int J Gen Med 2022; 15:169-177. [PMID: 35023955 PMCID: PMC8747760 DOI: 10.2147/ijgm.s346280] [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: 11/04/2021] [Accepted: 12/22/2021] [Indexed: 12/14/2022] Open
Abstract
Background Colon cancer is a common gastrointestinal malignancy. This study aimed to explore the relationship between p53 pathway-related genes and prognosis of colon cancer. Methods The mRNA datasets of colon cancer and adjacent tissues were downloaded from The Cancer Genome Atlas (TCGA) database, and the differential expression of genes in two groups was analyzed. Then, P53 pathway-related genes were intersected with differentially expressed genes (DEGs) to obtain P53 pathway-related differentially expressed genes. Then, overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS) in clusters were compared by consistent cluster analysis. Univariate and multivariate Cox regression analysis of DEGs was performed to obtain survival-related DEGs. Risk scores were calculated for each sample based on survival-related DEGs, and patients were divided into high/low risk scores. Prognostic differences, tumor immune cell infiltration levels, and immune pathway activation status were compared between the two groups. Results We identified 28 DEGs and two clusters. There are significant differences in PFS between the two clusters (P=0.011), and no significant difference between OS and DSS. We obtained 3 DEGs (CDKN2A, BAK1, BTG1) that were significantly related to PFS, and CDKN2A was considered an independent prognostic factor. PFS showed statistically significant difference between high/low risk score groups (P=0.015). There were significant differences in immune cell infiltration level and immune pathway activity between two groups. Conclusion The p53 pathway-related genes are significantly related to PFS in colon cancer patients and play an important role in regulating the tumor immune microenvironment.
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Affiliation(s)
- Jinggao Feng
- Department of Gastrointestinal and Anorectal Surgery, The Central Hospital of Yongzhou, Yongzhou City, Hunan Province, 425100, People's Republic of China
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Silva CTX, Saddi VA, Silva KSFE, Sugita DM, Guillo LA. Expression of the cancer stem cell marker OCT4 is associated with worse prognosis and survival in cutaneous melanoma. Melanoma Res 2021; 31:439-448. [PMID: 34433195 DOI: 10.1097/cmr.0000000000000767] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cutaneous melanoma has an aggressive clinical presentation, showing rapid rate of growth and metastatic dissemination due to the permanence of cancer stem cells. The present study was to evaluate the expression of the self-renewal regulatory factor and the clinical significance of the transcription factor OCT4 in melanoma. Melanoma tissues were stained by immunohistochemistry and the correlation between the expression of this marker was determined through clinical-pathological variables and survival outcomes. Positive expression of nuclear and cytoplasmic OCT4 was observed in 49% and 41.2% of cases, respectively. The positive expression of nuclear OCT4 in melanoma was significantly associated with prognostic factors, such as Breslow depth, Clark's level, ulceration and metastasis. Survival of patients was 56% compared to positive nuclear OCT4 expression and 94.2% when compared to the low expression of the gene. Nuclear OCT4 positive genotype indicated aggressive tumor behavior with a worse clinical outcome, which indicates OCT4 as a useful biomarker in the prognosis of melanoma.
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Affiliation(s)
| | - Vera Aparecida Saddi
- Laboratory of Genetics and Biodiversity, Department of Environmental and Health Science, Pontifical Catholic University of Goiás
| | | | | | - Lidia Andreu Guillo
- Cell Biochemistry Laboratory, Department of Biochemistry and Molecular Biology, Institute of Biological Sciences, Federal University of Goiás, Goiânia, Goiás, Brazil
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Song Z, Zhang G, Yu Y, Li S. A Prognostic Autophagy-Related Gene Pair Signature and Small-Molecule Drugs for Hepatocellular Carcinoma. Front Genet 2021; 12:689801. [PMID: 34497633 PMCID: PMC8419440 DOI: 10.3389/fgene.2021.689801] [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: 04/01/2021] [Accepted: 07/28/2021] [Indexed: 02/02/2023] Open
Abstract
Dysregulation of autophagy-related genes (ARGs) is related to the prognosis of cancers. However, the aberrant expression of ARGs signature in the prognosis of hepatocellular carcinoma (HCC) remain unclear. Using The Cancer Genome Atlas and the International Cancer Genome Consortium database, 188 common autophagy-related gene pairs (ARGPs) were identified. Through univariate, least absolute shrinkage and selection operator analysis, and multivariate Cox regression analysis, a prognostic signature of the training set was constructed on the basis of 6 ARGPs. Further analysis revealed that the ARGP based signature performed more accurately in overall survival (OS) prediction compared to other published gene signatures. In addition, a high risk of HCC was closely related to CTLA4 upregulation, LC3 downregulation, low-response to axitinib, rapamycin, temsirolimus, docetaxel, metformin, and high-response to bleomycin. Univariate Cox and multivariate Cox analysis revealed that the risk score was an independent prognostic factor for HCC. These results were internally validated in the test and TCGA sets and externally validated in the ICGC set. A nomogram, consisting of the risk score and the TNM stage, performed well when compared to an ideal nomogram. In conclusion, a 6-ARGP-based prognostic signature was identified and validated as an effective predictor of OS of patients with HCC. Furthermore, we recognized six small-molecule drugs, which may be potentially effective in treating HCC.
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Affiliation(s)
- ZeBing Song
- Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - GuoPei Zhang
- Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yang Yu
- Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - ShaoQiang Li
- Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Qi W, Yan Q, Lv M, Song D, Wang X, Tian K. Prognostic Signature of Osteosarcoma Based on 14 Autophagy-Related Genes. Pathol Oncol Res 2021; 27:1609782. [PMID: 34335109 PMCID: PMC8322075 DOI: 10.3389/pore.2021.1609782] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 06/04/2021] [Indexed: 12/14/2022]
Abstract
Background: Osteosarcoma is a common malignancy of bone with inferior survival outcome. Autophagy can exert multifactorial influence on tumorigenesis and tumor progression. However, the specific function of genes related to autophagy in the prognosis of osteosarcoma patients remains unclear. Herein, we aimed to explore the association of genes related to autophagy with the survival outcome of osteosarcoma patients. Methods: The autophagy-associated genes that were related to the prognosis of osteosarcoma were optimized by LASSO Cox regression analysis. The survival of osteosarcoma patients was forecasted by multivariate Cox regression analysis. The immune infiltration status of 22 immune cell types in osteosarcoma patients with high and low risk scores was compared by using the CIBERSORT tool. Results: The risk score model constructed according to 14 autophagy-related genes (ATG4A, BAK1, BNIP3, CALCOCO2, CCL2, DAPK1, EGFR, FAS, GRID2, ITGA3, MYC, RAB33B, USP10, and WIPI1) could effectively predict the prognosis of patients with osteosarcoma. A nomogram model was established based on risk score and metastasis. Conclusion: Autophagy-related genes were identified as pivotal prognostic signatures, which could guide the clinical decision making in the treatment of osteosarcoma.
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Affiliation(s)
- Wei Qi
- Department of West Hospital Orthopaedic Trauma, Zibo Central Hospital, Zibo, China
| | - Qian Yan
- Department of Information Section, Zibo Central Hospital, Zibo, China
| | - Ming Lv
- Department of West Hospital Orthopaedic Trauma, Zibo Central Hospital, Zibo, China
| | - Delei Song
- Department of West Hospital Orthopaedic Trauma, Zibo Central Hospital, Zibo, China
| | - Xianbin Wang
- Department of Eastern Hospital Orthopaedic Trauma, Zibo Central Hospital, Zibo, China
| | - Kangsong Tian
- Department of West Hospital Orthopaedic Trauma, Zibo Central Hospital, Zibo, China
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Zhang B, Mao S, Liu X, Li S, Zhou H, Gu Y, Liu W, Fu L, Liao C, Wang P. MiR-125b inhibits cardiomyocyte apoptosis by targeting BAK1 in heart failure. Mol Med 2021; 27:72. [PMID: 34238204 PMCID: PMC8268255 DOI: 10.1186/s10020-021-00328-w] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 06/10/2021] [Indexed: 01/27/2023] Open
Abstract
Background Although miR-125b plays a crucial role in many human cancers. However, its function in heart failure (HF) remains unclear. Our study aimed to investigate its involvement in heart failure. Methods In this study, the mouse HF model was successfully constructed through transverse aortic constriction (TAC) operation. Changes in mRNA and protein levels in isolated myocytes and heart tissues were examined using qRT-PCR, Western blot and Immunohistochemical staining and immunofluorescent staining. Changes in cardiac functions were examined using ultrasound. Interactions between miR-125b and BAK1 was analyzed using the luciferase reporter assay. Cardiomyocyte apoptosis was evaluated using the TUNEL staining. Results We found that miR-125b expression was significantly downregulated in myocardial tissues of HF mice. Moreover, miR-125b upregulation in HF mice injected with agomir-125b efficiently ameliorated cardiac function. Further, miR-125b upregulation significantly decreased the protein levels of apoptosis-related makers c-caspase 3 and Bax, while increased Bcl-2 expression. In addition, BAK1 was identified as a direct target of miR-125b. As expected, BAK1 overexpression observably reversed the effect of agomir-125b on cardiac function and on the expression of apoptosis-related makers in the heart tissues of HF mice. Conclusions Taken together, miR-125b overexpression efficiently attenuated cardiac function injury of HF mice by targeting BAK1 through inhibiting cardiomyocyte apoptosis, suggesting that miR-125b/BAK1 axis might be a potential target for the diagnosis or treatment of HF. Supplementary Information The online version contains supplementary material available at 10.1186/s10020-021-00328-w.
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Affiliation(s)
- Bei Zhang
- Guizhou Medical University, No. 9 Beijing Road, Yunyan District, Guiyang, Guizhou, 550004, People's Republic of China.,Department of Ultrasound Medicine, The Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Yunyan District, Guiyang, Guizhou, 550004, People's Republic of China
| | - Shanyong Mao
- Guizhou Medical University, No. 9 Beijing Road, Yunyan District, Guiyang, Guizhou, 550004, People's Republic of China.,Department of Ultrasound Medicine, The Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Yunyan District, Guiyang, Guizhou, 550004, People's Republic of China
| | - Xingde Liu
- Guizhou Medical University, No. 9 Beijing Road, Yunyan District, Guiyang, Guizhou, 550004, People's Republic of China. .,Department of Cardiology, The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, 550004, People's Republic of China.
| | - Sha Li
- Department of Ultrasound Medicine, The Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Yunyan District, Guiyang, Guizhou, 550004, People's Republic of China.
| | - Haiyan Zhou
- Departmentof Clinical Research Centre, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550004, People's Republic of China
| | - Ying Gu
- Department of Ultrasound Medicine, The Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Yunyan District, Guiyang, Guizhou, 550004, People's Republic of China
| | - Wupeng Liu
- Department of Cardiology, The Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang City, Guizhou, 550014, People's Republic of China
| | - Lei Fu
- Department of Ultrasound Medicine, The Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Yunyan District, Guiyang, Guizhou, 550004, People's Republic of China
| | - Chunyan Liao
- Department of Ultrasound Medicine, The Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Yunyan District, Guiyang, Guizhou, 550004, People's Republic of China
| | - Pengzhen Wang
- Department of Ultrasound Medicine, The Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Yunyan District, Guiyang, Guizhou, 550004, People's Republic of China
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Liu X, Zhang Z, Kan S, Lv Z, Zhou S, Liu X, Jing P, Xu W. PHF20 inhibition promotes apoptosis and cisplatin chemosensitivity via the OCT4‑p‑STAT3‑MCL1 signaling pathway in hypopharyngeal squamous cell carcinoma. Int J Oncol 2021; 59:38. [PMID: 33982773 PMCID: PMC8121096 DOI: 10.3892/ijo.2021.5218] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 04/12/2021] [Indexed: 12/13/2022] Open
Abstract
Cisplatin is a widely used platinum‑based chemotherapeutic agent for hypopharyngeal squamous cell carcinoma (HSCC). However, resistance to cisplatin limits its use for the treatment of HSCC, and the underlying molecular mechanism requires further investigation. The present study performed functional assays to determine whether the expression of plant homeodomain finger protein 20 (PHF20) may be involved in the apoptosis and cisplatin resistance of HSCC. The expression levels of PHF20 were higher in cisplatin‑resistant HSCC cells compared with those in cisplatin‑sensitive cells. The inhibition of PHF20 suppressed cell viability but did not affect the migratory and invasive abilities of HSCC cells compared with those of negative control‑transfected cells. Furthermore, PHF20 inhibition reduced cell viability by enhancing apoptosis compared with those in the control cells in vitro. Notably, the inhibition of PHF20 sensitized HSCC cells to cisplatin, thus increasing apoptosis via the signal transducer and activator of transcription 3 (STAT3)‑myeloid cell leukemia‑1 (MCL1) pathway. Octamer‑binding transcription factor 4 (OCT4) overexpression restored phosphorylated STAT3‑MCL1‑mediated apoptosis induced by PHF20 inhibition. In vivo experiments confirmed that PHF20 silencing induced tumor growth and increased apoptosis in HSCC cells compared with those in the control cells. Thus, PHF20 inhibition may promote apoptosis and improve cisplatin chemosensitivity via the OCT4‑p‑STAT3‑MCL1 signaling pathway in HSCC.
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Affiliation(s)
- Xiuxiu Liu
- Department of Otorhinolaryngology, Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
- Shandong Provincial Key Laboratory of Otology, Jinan, Shandong 250022, P.R. China
| | - Zhancheng Zhang
- Department of Otorhinolaryngology, Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
- Department of Otorhinolaryngology, The Fourth Hospital of Jinan, Jinan, Shandong 250031, P.R. China
| | - Shifeng Kan
- Department of Otorhinolaryngology, Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
- Shandong Provincial Key Laboratory of Otology, Jinan, Shandong 250022, P.R. China
| | - Zhenghua Lv
- Department of Otorhinolaryngology, Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
- Shandong Provincial Key Laboratory of Otology, Jinan, Shandong 250022, P.R. China
| | - Shengli Zhou
- Department of Otorhinolaryngology, Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
- Shandong Provincial Key Laboratory of Otology, Jinan, Shandong 250022, P.R. China
| | - Xianfang Liu
- Department of Otorhinolaryngology, Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
- Shandong Provincial Key Laboratory of Otology, Jinan, Shandong 250022, P.R. China
| | - Peihang Jing
- Department of Otorhinolaryngology, Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Wei Xu
- Department of Otorhinolaryngology, Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
- Shandong Provincial Key Laboratory of Otology, Jinan, Shandong 250022, P.R. China
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40
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AlAbdi L, Saha D, He M, Dar MS, Utturkar SM, Sudyanti PA, McCune S, Spears BH, Breedlove JA, Lanman NA, Gowher H. Oct4-Mediated Inhibition of Lsd1 Activity Promotes the Active and Primed State of Pluripotency Enhancers. Cell Rep 2021; 30:1478-1490.e6. [PMID: 32023463 DOI: 10.1016/j.celrep.2019.11.040] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 07/30/2019] [Accepted: 12/19/2019] [Indexed: 12/16/2022] Open
Abstract
An aberrant increase in pluripotency gene (PpG) expression due to enhancer reactivation could induce stemness and enhance the tumorigenicity of cancer stem cells. Silencing of PpG enhancers (PpGe) during embryonic stem cell differentiation involves Lsd1-mediated H3K4me1 demethylation and DNA methylation. Here, we observed retention of H3K4me1 and DNA hypomethylation at PpGe associated with a partial repression of PpGs in F9 embryonal carcinoma cells (ECCs) post-differentiation. H3K4me1 demethylation in F9 ECCs could not be rescued by Lsd1 overexpression. Given our observation that H3K4me1 demethylation is accompanied by strong Oct4 repression in P19 ECCs, we tested if Oct4 interaction with Lsd1 affects its catalytic activity. Our data show a dose-dependent inhibition of Lsd1 activity by Oct4 and retention of H3K4me1 at PpGe in Oct4-overexpressing P19 ECCs. These data suggest that Lsd1-Oct4 interaction in cancer stem cells could establish a "primed" enhancer state that is susceptible to reactivation, leading to aberrant PpG expression.
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Affiliation(s)
- Lama AlAbdi
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
| | - Debapriya Saha
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
| | - Ming He
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
| | - Mohd Saleem Dar
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
| | - Sagar M Utturkar
- Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA
| | - Putu Ayu Sudyanti
- Department of Statistics, Purdue University, West Lafayette, IN 47907, USA
| | - Stephen McCune
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
| | - Brice H Spears
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
| | - James A Breedlove
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
| | - Nadia A Lanman
- Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA; Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA
| | - Humaira Gowher
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA; Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
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41
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Liu X, Zhang Y, Zheng P, Cui N. Msi1 inhibits cervical cancer cell apoptosis by downregulating BAK through AKT signaling. J Cancer 2021; 12:2422-2429. [PMID: 33758618 PMCID: PMC7974892 DOI: 10.7150/jca.52950] [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: 09/07/2020] [Accepted: 01/13/2021] [Indexed: 12/11/2022] Open
Abstract
Musashi-1 (Msi1) is an RNA binding protein that functions as a regulator in multiple carcinomas. Our previous study demonstrated that Msi1 could promote the proliferation of cervical cancer cells by targeting the cell cycle proteins P21, P27 and P53. However, the mechanisms by which Msi1 affects the survival of cervical cancer cells, such as apoptosis, are still unclear. In this study, we found that the expression of Msi1 inhibited cervical cancer cell apoptosis in vitro and in vivo. Furthermore, the expression of Msi1 downregulated the expression of PTEN, while AKT signaling was activated, which resulted in a reduction in the proapoptotic protein BAK. In addition, rescue the expression of BAK in Msi1 expressing cervical cancer cells induced the increase of apoptosis cells. These findings indicate that Msi1 regulates cervical cancer cell apoptosis by inhibiting PTEN and activating AKT signaling, which leads to the downregulation of BAK.
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Affiliation(s)
- Xian Liu
- Department of Reproductive Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 710061 Xi'an, Shaanxi, PR China.,Section of Cancer Stem Cell Research, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of the People's Republic of China, 710061 Xi'an, Shaanxi, PR China
| | - Yanru Zhang
- Department of Reproductive Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 710061 Xi'an, Shaanxi, PR China.,Section of Cancer Stem Cell Research, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of the People's Republic of China, 710061 Xi'an, Shaanxi, PR China
| | - PengSheng Zheng
- Department of Reproductive Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 710061 Xi'an, Shaanxi, PR China.,Section of Cancer Stem Cell Research, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of the People's Republic of China, 710061 Xi'an, Shaanxi, PR China
| | - Nan Cui
- Department of Reproductive Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 710061 Xi'an, Shaanxi, PR China.,Section of Cancer Stem Cell Research, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of the People's Republic of China, 710061 Xi'an, Shaanxi, PR China
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42
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Li G, Chen Y, Jin W, Zhai B, Li Y, Sun G, Li H, Kang X, Tian Y. Effects of miR-125b-5p on Preadipocyte Proliferation and Differentiation in Chicken. Mol Biol Rep 2021; 48:491-502. [PMID: 33398680 DOI: 10.1007/s11033-020-06080-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Accepted: 12/10/2020] [Indexed: 12/21/2022]
Abstract
Our previous studies have shown that miR-125b-5p was highly expressed and significantly upregulated during abdominal fat deposition in chickens. However, the role of miR-125b in the regulation of adipogenesis is not clear in chickens. Therefore, we evaluated the effects of miR-125b-5p on preadipocyte proliferation and differentiation and the interaction between miR-125b-5p and the acyl-CoA synthetase bubblegum family member 2 (ACSBG2) gene in adipogenesis in chicken abdominal adipose tissue. Here, transfection tests of miR-125b-5p mimic/inhibitor were performed in preadipocytes, and the effects of miR-125b-5p on preadipocytes proliferation and differentiation were analyzed. The target site of miR-125b-5p in the 3'UTR (untranslated region) of ACSBG2 were verified by a luciferase reporter assay. Our results showed that miR-125b-5p overexpression inhibited proliferation and reduced the number of cells in S phase and G2/M phase in preadipocytes; conversely, miR-125b-5p inhibition promoted the proliferation and increased the number of cells in S phase and G2/M phase. In adipocytes after induction, miR-125b-5p overexpression led to a notable increase in the accumulation of lipid droplets as well as in the concentration of triglycerides, while miR-125b-5p inhibition had the opposite effect. Furthermore, miR-125b-5p could directly bind to the 3'UTR of ACSBG2, and its overexpression could significantly repress the mRNA and protein expression of ACSBG2. These results indicate that miR-125b-5p can inhibit preadipocyte proliferation and can promote preadipocyte differentiation to affect adipogenesis in chicken abdominal adipose tissues, at least partially by downregulating ACSBG2.
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Affiliation(s)
- Guoxi Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, 450002, P. R. China.
| | - Yi Chen
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, 450002, P. R. China
| | - Wenjiao Jin
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, 450002, P. R. China
| | - Bin Zhai
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, 450002, P. R. China
| | - Yuanfang Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, 450002, P. R. China
| | - Guirong Sun
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, 450002, P. R. China
| | - Hong Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, 450002, P. R. China
| | - Xiangtao Kang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, 450002, P. R. China
| | - Yadong Tian
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, 450002, P. R. China.
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43
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LGR6 activates the Wnt/β-catenin signaling pathway and forms a β-catenin/TCF7L2/LGR6 feedback loop in LGR6 high cervical cancer stem cells. Oncogene 2021; 40:6103-6114. [PMID: 34489551 PMCID: PMC8530990 DOI: 10.1038/s41388-021-02002-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 08/11/2021] [Accepted: 08/24/2021] [Indexed: 02/08/2023]
Abstract
The leucine-rich repeat-containing G-protein-coupled receptor 6 (LGR6) is considered to be a stem cell marker in many normal tissues and promotes tissue development, regeneration, and repair. LGR6 is also related to the initiation and progression of some malignant tumors. However, the role of LGR6 in cervical cancer has not been reported. Here, immunohistochemistry and western blotting showed that LGR6 was significantly upregulated in cervical cancer, compared with the normal cervix. By analyzing The Cancer Genome Atlas database, LGR6 was found to be correlated with a poor prognosis of cervical cancer. Then, a small population of LGR6high cells isolated by using the fluorescence-activated cell sorting exhibited enhanced properties of cancer stem cells including self-renewal, differentiation, and tumorigenicity. Moreover, RNA sequencing revealed that LGR6 was correlated with the Wnt signaling pathway and TOP/FOP, reverse transcription-PCR, and western blotting further proved that LGR6 could activate the Wnt/β-catenin signaling pathway. Interestingly, LGR6 upregulated the expression of TCF7L2 by activating the Wnt/β-catenin pathway. Then, TCF7L2 combining with β-catenin in the nucleus enhanced LGR6 transcription by binding the promoter of LGR6, which further activated the Wnt signaling to form a positive feedback loop. Thus, our study demonstrated that LGR6 activated a novel β-catenin/TCF7L2/LGR6-positive feedback loop in LGR6high cervical cancer stem cells (CSCs), which provided a new therapeutic strategy for targeting cervical CSCs to improve the prognosis of cervical cancer patients.
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Adiga D, Eswaran S, Pandey D, Sharan K, Kabekkodu SP. Molecular landscape of recurrent cervical cancer. Crit Rev Oncol Hematol 2021; 157:103178. [PMID: 33279812 DOI: 10.1016/j.critrevonc.2020.103178] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 11/06/2020] [Accepted: 11/11/2020] [Indexed: 02/07/2023] Open
Abstract
Cervical cancer (CC) is a major gynecological problem in developing and underdeveloped countries. Despite the significant advancement in early detection and treatment modalities, several patients recur. Moreover, the molecular mechanisms responsible for CC recurrence remains obscure. The patients with CC recurrence often show poor prognosis and significantly high mortality rates. The clinical management of recurrent CC depends on treatment history, site, and extent of the recurrence. Owing to poor prognosis and limited treatment options, recurrent CC often presents a challenge to the clinicians. Several in vitro, in vivo, and patient studies have led to the identification of the critical molecular changes responsible for CC recurrence. Both aberrant genetic and epigenetic modifications leading to altered cell signaling pathways have been reported to impact CC recurrence. Researchers are currently trying to dissect the molecular pathways in CC and translate these findings for better management of disease. This article attempts to review the existing knowledge of disease relapse, accompanying challenges, and associated molecular players in CC.
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Affiliation(s)
- Divya Adiga
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Sangavi Eswaran
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Deeksha Pandey
- Department of OBGYN, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Krishna Sharan
- Department of Radiotherapy and Oncology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
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45
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Kumagai K, Takanashi M, Ohno SI, Harada Y, Fujita K, Oikawa K, Sudo K, Ikeda SI, Nishi H, Oikawa K, Kuroda M. WAPL induces cervical intraepithelial neoplasia modulated with estrogen signaling without HPV E6/E7. Oncogene 2021; 40:3695-3706. [PMID: 33947962 PMCID: PMC8154587 DOI: 10.1038/s41388-021-01787-5] [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: 08/21/2020] [Revised: 03/30/2021] [Accepted: 04/12/2021] [Indexed: 02/03/2023]
Abstract
Since cervical cancer still afflicts women around the world, it is necessary to understand the underlying mechanism of cervical cancer development. Infection with HPV is essential for the development of cervical intraepithelial neoplasia (CIN). In addition, estrogen receptor signaling is implicated in the development of cervical cancer. Previously, we have isolated human wings apart-like (WAPL), which is expected to cause chromosomal instability in the process of HPV-infected precancerous lesions to cervical cancer. However, the role of WAPL in the development of CIN is still unknown. In this study, in order to elucidate the role of WAPL in the early lesion, we established WAPL overexpressing mice (WAPL Tg mice) and HPV E6/E7 knock-in (KI) mice. WAPL Tg mice developed CIN lesion without HPV E6/E7. Interestingly, in WAPL Tg mice estrogen receptor 1 (ESR1) showed reduction as compared with the wild type, but cell growth factors MYC and Cyclin D1 controlled by ESR1 expressed at high levels. These results suggested that WAPL facilitates sensitivity of ESR1 mediated by some kind of molecule, and as a result, affects the expression of MYC and Cyclin D1 in cervical cancer cells. To detect such molecules, we performed microarray analysis of the uterine cervix in WAPL Tg mice, and focused MACROD1, a co-activator of ESR1. MACROD1 expression was increased in WAPL Tg mice compared with the wild type. In addition, knockdown of WAPL induced the downregulation of MACROD1, MYC, and Cyclin D1 but not ESR1 expression. Furthermore, ESR1 sensitivity assay showed lower activity in WAPL or MACROD1 downregulated cells than control cells. These data suggested that WAPL increases ESR1 sensitivity by activating MACROD1, and induces the expression of MYC and Cyclin D1. Therefore, we concluded that WAPL not only induces chromosomal instability in cervical cancer tumorigenesis, but also plays a key role in activating estrogen receptor signaling in early tumorigenesis.
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Affiliation(s)
- Katsuyoshi Kumagai
- grid.410793.80000 0001 0663 3325Pre-clinical Research Center, Tokyo Medical University, Tokyo, Japan
| | - Masakatsu Takanashi
- grid.410793.80000 0001 0663 3325Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
| | - Shin-ichiro Ohno
- grid.410793.80000 0001 0663 3325Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
| | - Yuichirou Harada
- grid.410793.80000 0001 0663 3325Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
| | - Koji Fujita
- grid.410793.80000 0001 0663 3325Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
| | - Keiki Oikawa
- grid.410793.80000 0001 0663 3325Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
| | - Katsuko Sudo
- grid.410793.80000 0001 0663 3325Pre-clinical Research Center, Tokyo Medical University, Tokyo, Japan
| | - Shun-ichi Ikeda
- Department of Obstetrics and Gynecology, Kohseichuo General Hospital, Tokyo, Japan
| | - Hirotaka Nishi
- grid.410793.80000 0001 0663 3325Department of Obstetrics and Gynecology, Tokyo Medical University, Tokyo, Japan
| | - Kosuke Oikawa
- grid.412857.d0000 0004 1763 1087Department of Pathology, Wakayama Medical University, Wakayama, Japan
| | - Masahiko Kuroda
- grid.410793.80000 0001 0663 3325Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
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46
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Peng B, Theng PY, Le MTN. Essential functions of miR-125b in cancer. Cell Prolif 2020; 54:e12913. [PMID: 33332677 PMCID: PMC7848968 DOI: 10.1111/cpr.12913] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 08/20/2020] [Accepted: 09/07/2020] [Indexed: 12/14/2022] Open
Abstract
MicroRNAs (miRNAs) are small and highly conserved non-coding RNAs that silence target mRNAs, and compelling evidence suggests that they play an essential role in the pathogenesis of human diseases, especially cancer. miR-125b, which is the mammalian orthologue of the first discovered miRNA lin-4 in Caenorhabditis elegans, is one of the most important miRNAs that regulate various physiological and pathological processes. The role of miR-125b in many types of cancer has been well established, and so here we review the current knowledge of how miR-125b is deregulated in different types of cancer; its oncogenic and/or tumour-suppressive roles in tumourigenesis and cancer progression; and its regulation with regard to treatment response, all of which are underlined in multiple studies. The emerging information that elucidates the essential functions of miR-125b might help support its potentiality as a diagnostic and prognostic biomarker as well as an effective therapeutic tool against cancer.
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Affiliation(s)
- Boya Peng
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Department of Biomedical Sciences, School of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong.,N.1 Institute for Health, National University of Singapore, Singapore, Singapore
| | - Poh Ying Theng
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Minh T N Le
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Department of Biomedical Sciences, School of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong.,N.1 Institute for Health, National University of Singapore, Singapore, Singapore.,City University of Hong Kong Shenzhen Research Institute, Shenzhen, China
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47
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Choi YS, Han JM, Kang YJ, Jung HJ. Chloroform extract of Citrus unshiu Markovich peel induces apoptosis and inhibits stemness in HeLa human cervical cancer cells. Mol Med Rep 2020; 23:86. [PMID: 33236129 PMCID: PMC7716394 DOI: 10.3892/mmr.2020.11727] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 11/11/2020] [Indexed: 12/13/2022] Open
Abstract
Cervical cancer is the second most common cancer among women worldwide. However, chemotherapies for this cancer often cause many side effects and chemoresistance. Citrus unshiu Markovich peel (CECU) has been used as a traditional medicine for the treatment of various diseases in East Asia. Recently, the anticancer activities and mechanisms of action of CECU extract have been reported in a number of different cancer cell types, but no study has evaluated the therapeutic effect of this natural product on cervical cancer cells. In the current study, the anticancer activity and the underlying molecular mechanism of the chloroform extract of CECU was investigated on HeLa human cervical cancer cells. The results showed that CECU effectively inhibited the proliferation and migration of HeLa cells. Treatment of cells with CECU led to cell cycle arrest at the G2/M phase and activation of extrinsic and intrinsic apoptotic pathways. Furthermore, the proliferation inhibitory effect of CECU was due to the inactivation of AKT and ERK signaling, upregulation of p53 and p21, and downregulation of cyclin B1 and cyclin D1, but not reactive oxygen species (ROS) generation. Furthermore, CECU inhibited the stem‑like features of HeLa cells by downregulating key cancer stemness biomarkers. Therefore, CECU may be an effective complementary and alternative medicine for the prevention and treatment of cervical cancer.
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Affiliation(s)
- Ye Seul Choi
- Department of Life Science and Biochemical Engineering, Sun Moon University, Asan, South Chungcheong 31460, Republic of Korea
| | - Jang Mi Han
- Department of Life Science and Biochemical Engineering, Sun Moon University, Asan, South Chungcheong 31460, Republic of Korea
| | - Yue Jai Kang
- Department of Aquatic Life and Medical Sciences, Sun Moon University, Asan, South Chungcheong 31460, Republic of Korea
| | - Hye Jin Jung
- Department of Life Science and Biochemical Engineering, Sun Moon University, Asan, South Chungcheong 31460, Republic of Korea
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48
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Induced Pluripotency: A Powerful Tool for In Vitro Modeling. Int J Mol Sci 2020; 21:ijms21238910. [PMID: 33255453 PMCID: PMC7727808 DOI: 10.3390/ijms21238910] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 11/13/2020] [Accepted: 11/17/2020] [Indexed: 12/11/2022] Open
Abstract
One of the greatest breakthroughs of regenerative medicine in this century was the discovery of induced pluripotent stem cell (iPSC) technology in 2006 by Shinya Yamanaka. iPSCs originate from terminally differentiated somatic cells that have newly acquired the developmental capacity of self-renewal and differentiation into any cells of three germ layers. Before iPSCs can be used routinely in clinical practice, their efficacy and safety need to be rigorously tested; however, iPSCs have already become effective and fully-fledged tools for application under in vitro conditions. They are currently routinely used for disease modeling, preparation of difficult-to-access cell lines, monitoring of cellular mechanisms in micro- or macroscopic scales, drug testing and screening, genetic engineering, and many other applications. This review is a brief summary of the reprogramming process and subsequent differentiation and culture of reprogrammed cells into neural precursor cells (NPCs) in two-dimensional (2D) and three-dimensional (3D) conditions. NPCs can be used as biomedical models for neurodegenerative diseases (NDs), which are currently considered to be one of the major health problems in the human population.
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49
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Yang WT, Feng Q, Ma HM, Lei D, Zheng PS. NF-YA promotes the cell proliferation and tumorigenic properties by transcriptional activation of SOX2 in cervical cancer. J Cell Mol Med 2020; 24:12464-12475. [PMID: 32954681 PMCID: PMC7686972 DOI: 10.1111/jcmm.15777] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 08/03/2020] [Accepted: 08/05/2020] [Indexed: 12/24/2022] Open
Abstract
NF‐YA is considered as a crucial regulator for the maintenance of cancer stem cell (CSC) and involved in various types of malignant tumours. However, the exact function and molecular mechanisms of NF‐YA in the progression of cervical cancer remains poorly understood. Here, the expression of NF‐YA detected by immunohistochemistry was gradually increased from normal cervical tissues, to the high‐grade squamous intraepithelial lesions, and then to cervical cancer tissues. NF‐YA promoted the cell proliferation and tumorigenic properties of cervical cancer cells as well as tumorsphere formation and chemoresistance in vitro. The luciferase reporter assay combined with mutagenesis analyses and Western blotting showed that NF‐YA trans‐activated the expression of SOX2 in cervical cancer. Furthermore, quantitative chromatin immunoprecipitation (qChIP) and electrophoretic mobility shift assay (EMSA) confirmed that NF‐YA protein directly bound to the CCAAT box region located upstream of the SOX2 promoter. Together, our data demonstrated that NF‐YA was highly expressed in cervical cancer and promoted the cell proliferation, tumorigenicity and CSC characteristic by trans‐activating the expression of SOX2.
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Affiliation(s)
- Wen-Ting Yang
- Department of Reproductive Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, Xi'an, China
| | - Qian Feng
- Department of Reproductive Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, Xi'an, China
| | - Hong-Mei Ma
- Department of Reproductive Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, Xi'an, China
| | - Dan Lei
- Department of Reproductive Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, Xi'an, China
| | - Peng-Sheng Zheng
- Department of Reproductive Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of the People's Republic of China, Shaanxi, Xi'an, China
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50
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Qiao Y, Agboola OS, Hu X, Wu Y, Lei L. Tumorigenic and Immunogenic Properties of Induced Pluripotent Stem Cells: a Promising Cancer Vaccine. Stem Cell Rev Rep 2020; 16:1049-1061. [PMID: 32939647 PMCID: PMC7494249 DOI: 10.1007/s12015-020-10042-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/09/2020] [Indexed: 02/06/2023]
Abstract
Induced pluripotent stem cells (iPSCs) are mainly characterized by their unlimited proliferation abilities and potential to develop into almost any cell type. The creation of this technology has been of great interest to many scientific fields, especially regenerative biology. However, concerns about the safety of iPSC application in transplantation have arisen due to the tumorigenic and immunogenic properties of iPSCs. This review will briefly introduce the developing history of somatic reprogramming and applications of iPSC technology in regenerative medicine. In addition, the review will highlight two challenges to the efficient usage of iPSCs and the underlying mechanisms of these challenges. Finally, the review will discuss the expanding application of iPSC technology in cancer immunotherapy as a potential cancer vaccine and its advantages in auxiliary treatment compared with oncofetal antigen-based and embryonic stem cell (ESC)-based vaccines.
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Affiliation(s)
- Yu Qiao
- Department of Histology and Embryology, Basic Medical Science College, Harbin Medical University, 194 Xuefu Rd, Nangang District, Harbin, Heilongjiang Province, 150081, People's Republic of China
| | - Oluwafemi Solomon Agboola
- Department of Histology and Embryology, Basic Medical Science College, Harbin Medical University, 194 Xuefu Rd, Nangang District, Harbin, Heilongjiang Province, 150081, People's Republic of China
| | - Xinglin Hu
- Department of Histology and Embryology, Basic Medical Science College, Harbin Medical University, 194 Xuefu Rd, Nangang District, Harbin, Heilongjiang Province, 150081, People's Republic of China
| | - Yanshuang Wu
- Department of Histology and Embryology, Basic Medical Science College, Harbin Medical University, 194 Xuefu Rd, Nangang District, Harbin, Heilongjiang Province, 150081, People's Republic of China
| | - Lei Lei
- Department of Histology and Embryology, Basic Medical Science College, Harbin Medical University, 194 Xuefu Rd, Nangang District, Harbin, Heilongjiang Province, 150081, People's Republic of China.
- Key laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Ministry of Education, Harbin, China.
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