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Fares M, Alsherbiny M, Elkelesh IA, Said MA, Maklad RM, Lewis W, Li CG, Eldehna WM, Groundwater PW, Gale PA, Keller PA. Investigating the multi-mechanistic anticancer effects of 4-bisarylurea thiouracil derivatives in breast cancer cells. Bioorg Chem 2025; 162:108581. [PMID: 40412224 DOI: 10.1016/j.bioorg.2025.108581] [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: 02/08/2025] [Revised: 04/21/2025] [Accepted: 05/10/2025] [Indexed: 05/27/2025]
Abstract
The study reports the synthesis of a series of 4-bisarylureathiouracil derivatives (6a-e) for potential use in breast cancer treatment. In vitro cytotoxicity was assessed in MCF-7 and MDA-MB-231 human breast cancer cell lines, revealing significant anti-cancer activity. Compound 6e exhibited the highest cytotoxicity, with IC50 values of 7.94 μM for MCF-7 and 6.67 μM for MDA-MB-231, although it was also the most toxic to RAW 264.7 macrophage cells. In contrast, compound 6c demonstrated strong efficacy against both cancer cell lines (IC50 = 9.23 ± 0.6 μM for MCF-7 and 7.72 ± 0.6 μM for MDA-MB-231) while maintaining selectivity (SI values >10.8 and > 12.9, respectively). Flow cytometry and caspase-3 assays indicated that compounds 6a-c induced apoptosis in MCF-7 cells. In anti-inflammatory assays, compounds 6a and 6d showed significant effects, while 6c demonstrated the weakest, suggesting its cytotoxicity is not linked to anti-inflammatory properties. Compound 6c was prioritised for further investigation because of its preferential targeting of cancer cells. Proteomic analysis of 6c-treated cells revealed significant dysregulation of apoptosis, angiogenesis and VEGF signalling, Rho signal transduction, and pi3k-akt signalling pathways. These findings highlighted the potential of compounds 6a-e as effective anticancer agents, warranting further investigation and optimization for therapeutic applications.
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Affiliation(s)
- Mohamed Fares
- Sydney Pharmacy School, The University of Sydney, NSW 2006, Australia; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr city 11829, Egypt.
| | - Muhammad Alsherbiny
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; Metabolomics Facility, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia
| | - Islam A Elkelesh
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr city 11829, Egypt
| | - Mohamed A Said
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr city 11829, Egypt
| | - Raed M Maklad
- School of Chemistry, The University of Sydney, NSW 2006, Australia; School of Mathematical and Physical Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - William Lewis
- School of Chemistry, The University of Sydney, NSW 2006, Australia; Sydney Analytical, The University of Sydney, NSW 2006, Australia
| | - Chun Guang Li
- NICM Health Research Institute, Western Sydney University, Westmead 2145, NSW, Australia
| | - Wagdy M Eldehna
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria 21648, Egypt
| | | | - Philip A Gale
- School of Mathematical and Physical Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Paul A Keller
- School of Science, Molecular Horizons, University of Wollongong, Wollongong, NSW 2522, Australia
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Frey Y, Lungu C, Olayioye MA. Regulation and functions of the DLC family of RhoGAP proteins: Implications for development and cancer. Cell Signal 2025; 125:111505. [PMID: 39549821 DOI: 10.1016/j.cellsig.2024.111505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 10/18/2024] [Accepted: 11/05/2024] [Indexed: 11/18/2024]
Abstract
The DLC (Deleted in Liver Cancer) family of RhoGAP (Rho GTPase-activating) proteins has been extensively studied since the identification of the first family member nearly 30 years ago. Rho GTPase signaling is essential for various cellular processes, including cytoskeletal dynamics, cell migration, and proliferation. Members of the DLC family are key regulators of this signaling pathway, with well-established roles in development and carcinogenesis. Here, we provide a comprehensive review of research into DLC regulation and cellular functions over the last three decades. In particular, we summarize control mechanisms of DLC gene expression at both the transcriptional and post-transcriptional level. Additionally, recent advances in understanding the post-translational regulation of DLC proteins that allow for tuning of protein activity and localization are highlighted. This detailed overview will serve as resource for future studies aimed at further elucidating the complex regulatory mechanisms of DLC family proteins and exploring their potential as targets for therapeutic applications.
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Affiliation(s)
- Yannick Frey
- University of Stuttgart, Institute of Cell Biology and Immunology, Stuttgart, Germany; Medical University of Innsbruck, Institute of Pathophysiology, Innsbruck, Austria
| | - Cristiana Lungu
- University of Stuttgart, Institute of Cell Biology and Immunology, Stuttgart, Germany; University of Stuttgart, Stuttgart Research Center Systems Biology, Stuttgart, Germany
| | - Monilola A Olayioye
- University of Stuttgart, Institute of Cell Biology and Immunology, Stuttgart, Germany; University of Stuttgart, Stuttgart Research Center Systems Biology, Stuttgart, Germany.
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Poliseno L, Lanza M, Pandolfi PP. Coding, or non-coding, that is the question. Cell Res 2024; 34:609-629. [PMID: 39054345 PMCID: PMC11369213 DOI: 10.1038/s41422-024-00975-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 04/30/2024] [Indexed: 07/27/2024] Open
Abstract
The advent of high-throughput sequencing uncovered that our genome is pervasively transcribed into RNAs that are seemingly not translated into proteins. It was also found that non-coding RNA transcripts outnumber canonical protein-coding genes. This mindboggling discovery prompted a surge in non-coding RNA research that started unraveling the functional relevance of these new genetic units, shaking the classic definition of "gene". While the non-coding RNA revolution was still taking place, polysome/ribosome profiling and mass spectrometry analyses revealed that peptides can be translated from non-canonical open reading frames. Therefore, it is becoming evident that the coding vs non-coding dichotomy is way blurrier than anticipated. In this review, we focus on several examples in which the binary classification of coding vs non-coding genes is outdated, since the same bifunctional gene expresses both coding and non-coding products. We discuss the implications of this intricate usage of transcripts in terms of molecular mechanisms of gene expression and biological outputs, which are often concordant, but can also surprisingly be discordant. Finally, we discuss the methodological caveats that are associated with the study of bifunctional genes, and we highlight the opportunities and challenges of therapeutic exploitation of this intricacy towards the development of anticancer therapies.
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Affiliation(s)
- Laura Poliseno
- Oncogenomics Unit, Core Research Laboratory, ISPRO, Pisa, Italy.
- Institute of Clinical Physiology, CNR, Pisa, Italy.
| | - Martina Lanza
- Oncogenomics Unit, Core Research Laboratory, ISPRO, Pisa, Italy
- Institute of Clinical Physiology, CNR, Pisa, Italy
- University of Siena, Siena, Italy
| | - Pier Paolo Pandolfi
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Torino, Italy.
- Renown Institute for Cancer, Nevada System of Higher Education, Reno, NV, USA.
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Qattan A, Al-Tweigeri T, Suleman K, Alkhayal W, Tulbah A. Advanced Insights into Competitive Endogenous RNAs (ceRNAs) Regulated Pathogenic Mechanisms in Metastatic Triple-Negative Breast Cancer (mTNBC). Cancers (Basel) 2024; 16:3057. [PMID: 39272915 PMCID: PMC11394539 DOI: 10.3390/cancers16173057] [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: 08/01/2024] [Revised: 08/28/2024] [Accepted: 08/28/2024] [Indexed: 09/15/2024] Open
Abstract
Triple-negative breast cancer is aggressive and challenging to treat because of a lack of targets and heterogeneity among tumors. A paramount factor in the mortality from breast cancer is metastasis, which is driven by genetic and phenotypic alterations that drive epithelial-mesenchymal transition, stemness, survival, migration and invasion. Many genetic and epigenetic mechanisms have been identified in triple-negative breast cancer that drive these metastatic phenotypes; however, this knowledge has not yet led to the development of effective drugs for metastatic triple-negative breast cancer (mTNBC). One that may not have received enough attention in the literature is post-translational regulation of broad sets of cancer-related genes through inhibitory microRNAs and the complex competitive endogenous RNA (ceRNA) regulatory networks they are influenced by. This field of study and the resulting knowledge regarding alterations in these networks is coming of age, enabling translation into clinical benefit for patients. Herein, we review metastatic triple-negative breast cancer (mTNBC), the role of ceRNA network regulation in metastasis (and therefore clinical outcomes), potential approaches for therapeutic exploitation of these alterations, knowledge gaps and future directions in the field.
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Affiliation(s)
- Amal Qattan
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Taher Al-Tweigeri
- Department of Medical Oncology, Oncology Centre, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Kausar Suleman
- Department of Medical Oncology, Oncology Centre, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Wafa Alkhayal
- Department of Surgery, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Asma Tulbah
- Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
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Aria H, Azizi M, Nazem S, Mansoori B, Darbeheshti F, Niazmand A, Daraei A, Mansoori Y. Competing endogenous RNAs regulatory crosstalk networks: The messages from the RNA world to signaling pathways directing cancer stem cell development. Heliyon 2024; 10:e35208. [PMID: 39170516 PMCID: PMC11337742 DOI: 10.1016/j.heliyon.2024.e35208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 07/08/2024] [Accepted: 07/24/2024] [Indexed: 08/23/2024] Open
Abstract
Cancer stem cells (CSCs) are one of the cell types that account for cancer heterogeneity. The cancer cells arrest in G0 and generate non-CSC progeny through self-renewal and pluripotency, resulting in tumor recurrence, metastasis, and resistance to chemotherapy. They can stimulate tumor relapse and re-grow a metastatic tumor. So, CSCs is a promising target for eradicating tumors, and developing an anti-CSCs therapy has been considered. In recent years competing endogenous RNA (ceRNA) has emerged as a significant class of post-transcriptional regulators that affect gene expression via competition for microRNA (miRNA) binding. Furthermore, aberrant ceRNA expression is associated with tumor progression. Recent findings show that ceRNA network can cause tumor progression through the effect on CSCs. To overcome therapeutic resistance due to CSCs, we need to improve our current understanding of the mechanisms by which ceRNAs are implicated in CSC-related relapse. Thus, this review was designed to discuss the role of ceRNAs in CSCs' function. Targeting ceRNAs may open the path for new cancer therapeutic targets and can be used in clinical research.
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Affiliation(s)
- Hamid Aria
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahdieh Azizi
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shima Nazem
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Behnam Mansoori
- Pediatrics Department, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Farzaneh Darbeheshti
- Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Anoosha Niazmand
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Abdolreza Daraei
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
- Department of Medical Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Yaser Mansoori
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
- Department of Medical Genetics, Fasa University of Medical Sciences, Fasa, Iran
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Guo Q, Zhou Y, Xie T, Yuan Y, Li H, Shi W, Zheng L, Li X, Zhang W. Tumor microenvironment of cancer stem cells: Perspectives on cancer stem cell targeting. Genes Dis 2024; 11:101043. [PMID: 38292177 PMCID: PMC10825311 DOI: 10.1016/j.gendis.2023.05.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 05/25/2023] [Indexed: 02/01/2024] Open
Abstract
There are few tumor cell subpopulations with stem cell characteristics in tumor tissue, defined as cancer stem cells (CSCs) or cancer stem-like cells (CSLCs), which can reconstruct neoplasms with malignant biological behaviors such as invasiveness via self-renewal and unlimited generation. The microenvironment that CSCs depend on consists of various cellular components and corresponding medium components. Among these factors existing at a variety of levels and forms, cytokine networks and numerous signal pathways play an important role in signaling transduction. These factors promote or maintain cancer cell stemness, and participate in cancer recurrence, metastasis, and resistance. This review aims to summarize the recent molecular data concerning the multilayered relationship between CSCs and CSC-favorable microenvironments. We also discuss the therapeutic implications of targeting this synergistic interplay, hoping to give an insight into targeting cancer cell stemness for tumor therapy and prognosis.
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Affiliation(s)
- Qianqian Guo
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450003, China
| | - Yi Zhou
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Tianyuan Xie
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Yin Yuan
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Huilong Li
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Wanjin Shi
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Lufeng Zheng
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Xiaoman Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Wenzhou Zhang
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450003, China
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Piergentili R, Marinelli E, Cucinella G, Lopez A, Napoletano G, Gullo G, Zaami S. miR-125 in Breast Cancer Etiopathogenesis: An Emerging Role as a Biomarker in Differential Diagnosis, Regenerative Medicine, and the Challenges of Personalized Medicine. Noncoding RNA 2024; 10:16. [PMID: 38525735 PMCID: PMC10961778 DOI: 10.3390/ncrna10020016] [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: 12/15/2023] [Revised: 02/10/2024] [Accepted: 02/19/2024] [Indexed: 03/26/2024] Open
Abstract
Breast Cancer (BC) is one of the most common cancer types worldwide, and it is characterized by a complex etiopathogenesis, resulting in an equally complex classification of subtypes. MicroRNA (miRNA or miR) are small non-coding RNA molecules that have an essential role in gene expression and are significantly linked to tumor development and angiogenesis in different types of cancer. Recently, complex interactions among coding and non-coding RNA have been elucidated, further shedding light on the complexity of the roles these molecules fulfill in cancer formation. In this context, knowledge about the role of miR in BC has significantly improved, highlighting the deregulation of these molecules as additional factors influencing BC occurrence, development and classification. A considerable number of papers has been published over the past few years regarding the role of miR-125 in human pathology in general and in several types of cancer formation in particular. Interestingly, miR-125 family members have been recently linked to BC formation as well, and complex interactions (competing endogenous RNA networks, or ceRNET) between this molecule and target mRNA have been described. In this review, we summarize the state-of-the-art about research on this topic.
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Affiliation(s)
- Roberto Piergentili
- Institute of Molecular Biology and Pathology, Italian National Research Council (CNR-IBPM), 00185 Rome, Italy;
| | - Enrico Marinelli
- Department of Medico-Surgical Sciences and Biotechnologies, “Sapienza” University of Rome, 04100 Latina, Italy;
| | - Gaspare Cucinella
- Department of Obstetrics and Gynecology, Villa Sofia Cervello Hospital, University of Palermo, 90146 Palermo, Italy; (G.C.); (A.L.); (G.G.)
| | - Alessandra Lopez
- Department of Obstetrics and Gynecology, Villa Sofia Cervello Hospital, University of Palermo, 90146 Palermo, Italy; (G.C.); (A.L.); (G.G.)
| | - Gabriele Napoletano
- Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Section of Forensic Medicine, “Sapienza” University of Rome, 00161 Rome, Italy;
| | - Giuseppe Gullo
- Department of Obstetrics and Gynecology, Villa Sofia Cervello Hospital, University of Palermo, 90146 Palermo, Italy; (G.C.); (A.L.); (G.G.)
| | - Simona Zaami
- Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Section of Forensic Medicine, “Sapienza” University of Rome, 00161 Rome, Italy;
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Zeng C, Li H, Liang W, Chen J, Zhang Y, Zhang H, Xiao H, Li Y, Guan H. Loss of STARD13 contributes to aggressive phenotype transformation and poor prognosis in papillary thyroid carcinoma. Endocrine 2024; 83:127-141. [PMID: 37541962 DOI: 10.1007/s12020-023-03468-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 07/22/2023] [Indexed: 08/06/2023]
Abstract
PURPOSE StAR Related Lipid Transfer Domain Containing 13 (STARD13) serves as a tumor suppressor and has been characterized in several types of malignancies. However, the role and the molecular mechanism of STARD13 in regulating the progression of papillary thyroid carcinoma (PTC) remain underexplored. METHODS The gene expression and clinical information of thyroid cancer were downloaded using "TCGAbiolinks" R package. Quantitative PCR and immunohistochemical staining were conducted to detect the expression of STARD13 in clinical tumor and adjacent non-tumor samples. Wound-healing assay, Transwell assay and 3D spheroid invasion assay were performed to evaluate the migratory and invasive capacities of PTC cells. Cell proliferation ability was determined by CCK-8 assay, colony formation assay and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay. The alterations of indicated proteins were detected by Western blotting. RESULTS In the present study, we found that STARD13 was significantly underexpressed in PTC, which was correlated with poor prognosis. Downregulation of STARD13 might be due to methylation of promoter region. Loss-and gain-of-function experiments demonstrated that STARD13 impeded migratory and invasive capacities of PTC cells in vitro and in vivo. In addition, we found that STARD13 regulated the morphology of PTC cells and inhibited epithelial-mesenchymal transition (EMT). CONCLUSION Our results suggest that STARD13 acts as a metastasis suppressor and might be a potential therapeutic target in PTC.
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Affiliation(s)
- Chuimian Zeng
- Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Hai Li
- Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Weiwei Liang
- Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Junxin Chen
- Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yilin Zhang
- Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Hanrong Zhang
- Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Haipeng Xiao
- Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yanbing Li
- Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| | - Hongyu Guan
- Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
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Wang Y, Lin G. Retraction Note: TP53INP1 3'-UTR functions as a ceRNA in repressing the metastasis of glioma cells by regulating miRNA activity. Biotechnol Lett 2023; 45:1581. [PMID: 37702835 DOI: 10.1007/s10529-023-03431-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/14/2023]
Affiliation(s)
- Yi Wang
- Department of Neurosurgery, The Cangzhou Central Hospital, Cangzhou, 061001, China.
| | - Guihua Lin
- Department of Blood Transfusion, The Affiliated Ningde Municipal Hospital, Fujian Medical University, Ningde, 352000, China
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Tesařová M, Boušková T, Cejnar P, Šantrůček J, Peterková L, Fík Z, Sázelová P, Kašička V, Hynek R. Characterization of vestibular schwannoma tissues using liquid chromatography-tandem mass spectrometry analysis of specific peptide fragments separated by in-sample tryptic protein digestion followed by mathematical analysis. J Sep Sci 2023; 46:e2300543. [PMID: 37735989 DOI: 10.1002/jssc.202300543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/12/2023] [Accepted: 09/15/2023] [Indexed: 09/23/2023]
Abstract
Vestibular schwannoma is the most common benign neoplasm of the cerebellopontine angle. Its first symptoms include hearing loss, tinnitus, and vestibular symptoms, followed by cerebellar and brainstem symptoms, along with palsy of the adjacent cranial nerves. However, the clinical picture has unpredictable dynamics and currently, there are no reliable predictors of tumor behavior. Hence, it is desirable to have a fast routine method for analysis of vestibular schwannoma tissues at the molecular level. The major objective of this study was to verify whether a technique using in-sample specific protein digestion with trypsin would have the potential to provide a proteomic characterization of these pathological tissues. The achieved results showed that the use of this approach with subsequent liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of released peptides allowed a fast identification of a considerable number of proteins in two differential parts of vestibular schwannoma tissue as well as in tissues of control healthy samples. Furthermore, mathematical analysis of MS data was able to discriminate between pathological vestibular schwannoma tissues and healthy tissues. Thus, in-sample protein digestion combined with LC-MS/MS separation and identification of released specific peptides followed by mathematical analysis appears to have the potential for routine characterization of vestibular schwannomas at the molecular level. Data are available via ProteomeXchange with identifier PXD045261.
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Affiliation(s)
- Michaela Tesařová
- Department of Otorhinolaryngology and Head and Neck Surgery, First Faculty of Medicine Charles University and Motol University Hospital, Prague 5, Czech Republic
- Institute of Anatomy, First Faculty of Medicine, Charles University, Prague 2, Czech Republic
| | - Tereza Boušková
- Department of Biochemistry and Microbiology, University of Chemistry and Technology, Prague 6, Czech Republic
| | - Pavel Cejnar
- Department of Mathematics, Informatics and Cybernetics, University of Chemistry and Technology, Prague 6, Czech Republic
| | - Jiří Šantrůček
- Department of Biochemistry and Microbiology, University of Chemistry and Technology, Prague 6, Czech Republic
| | - Lenka Peterková
- Department of Otorhinolaryngology and Head and Neck Surgery, First Faculty of Medicine Charles University and Motol University Hospital, Prague 5, Czech Republic
- Institute of Anatomy, First Faculty of Medicine, Charles University, Prague 2, Czech Republic
| | - Zdeněk Fík
- Department of Otorhinolaryngology and Head and Neck Surgery, First Faculty of Medicine Charles University and Motol University Hospital, Prague 5, Czech Republic
| | - Petra Sázelová
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague 6, Czech Republic
| | - Václav Kašička
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague 6, Czech Republic
| | - Radovan Hynek
- Department of Biochemistry and Microbiology, University of Chemistry and Technology, Prague 6, Czech Republic
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Wang L, Wang X, Sun H, Wang W, Cao L. A pan-cancer analysis of the role of HOXD1, HOXD3, and HOXD4 and validation in renal cell carcinoma. Aging (Albany NY) 2023; 15:10746-10766. [PMID: 37827698 PMCID: PMC10599751 DOI: 10.18632/aging.205116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 09/26/2023] [Indexed: 10/14/2023]
Abstract
HOXD1, HOXD3, and HOXD4 are members of the HOXD genes family and are related to tumorigenesis of the tumor. However, whether HOXDs (1, 3, 4) have a crucial role across pan-cancer is still unknown. HOXD1, HOXD3, and HOXD4 expressions were analyzed using public databases in 33 types of tumors. The UCSC Xena website was carried out to investigate the relationship between the expression of genes and the progress of cancers. The biological functions of HOXD3 were tested by colony forming, transwell, wound healing, and xenograft assay in vitro and in vivo. GSEA was used to identify the associated cancer hallmarks with HOXDs expression. Immune cell infiltration analysis was applied to verify the immune cell infiltrations related to genes. The results showed HOXD1, HOXD3, and HOXD4 co-low expressed in BRCA, COAD, KICH, KIRC, KIRP, READ, and TGCT. In the KIRC, all of HOXDs expression was connected with tumor stage and histological grade. Upregulation of HOXDs was associated with improved OS, DSS, and PFI. Down-expression of HOXD3 induced cell proliferation, migration, and invasion in vivo and in vitro. In addition, HOXDs were connected with immune-activated hallmarks and cancer immune cell infiltrations. These findings demonstrated that HOXDs may be indicative biomarkers for the prognosis and immunotherapy in pan-cancer.
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Affiliation(s)
- Lumin Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710004, P.R. China
| | - Xiaofei Wang
- Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi 710061, P.R. China
| | - Haifeng Sun
- The Third Department of Medical Oncology, Shaanxi Provincial Cancer Hospital Affiliated to Medical College of Xi’an Jiaotong University, Xi’an, Shaanxi 710065, P.R. China
| | - Wenjing Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, P.R. China
| | - Li Cao
- Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi 710061, P.R. China
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Liu Y, Chen Y, Zhao Q, Xie T, Xiang C, Guo Q, Zhang W, Zhou Y, Yuan Y, Zhang Y, Xi T, Li X, Zheng L. A positive TGF-β/miR-9 regulatory loop promotes the expansion and activity of tumour-initiating cells in breast cancer. Br J Pharmacol 2023; 180:2280-2297. [PMID: 37060166 DOI: 10.1111/bph.16092] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 02/17/2023] [Accepted: 03/19/2023] [Indexed: 04/16/2023] Open
Abstract
BACKGROUND AND PURPOSE MicroRNA-9 (miR-9) has previously been described as a dual-functional RNA during breast cancer progression and its roles need to be clarified thoroughly. EXPERIMENTAL APPROACH A miR-9 knockout mode of mouse breast cancer, the MMTV-PyMT model (PyMT-miR-9-/- ), combined with different human breast cancer cell lines were used to evaluate the effects of miR-9 on breast cancer initiation, progression and metastasis. Lin-NECs (Neoplastic mammary epithelial cells) and pNECs (Pre-neoplastic mammary epithelial cells) were isolated and subjected to tumour-initiation assay. Whole-mount staining of mammary gland and histology was performed to determine mammary gland growth. Tumour-initiating analysis combining a series of in vitro experiments were carried out to evaluate miR-9 roles in tumour-initiating ability. RNA-sequencing of human breast cancer cells, and mammary glands at hyperplastic stages and established tumours in PyMT and PyMT-miR-9-/- mice, ChIP and luciferase report assays were conducted to reveal the underlying mechanisms. KEY RESULTS MiR-9 is ectopically expressed in breast cancer and its level is negatively correlated with the prognosis, especially in basal-like breast cancer patients. Additionally, miR-9 is essential for breast cancer progression by promoting the expansion and activity of tumour-initiating cells (TICs) in preneoplastic glands, established tumours and xenograft modes. Mechanistically, the activity of TICs hinges on a positive TGF-β/miR-9 regulatory loop mediated by the STARD13/YAP axis. CONCLUSIONS AND IMPLICATIONS These findings demonstrate that miR-9 is an oncogenic miRNA rather than a tumour-suppressor in breast cancer, calling for rectification of the model for this conserved and highly abundant miRNA.
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Affiliation(s)
- Yichen Liu
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Ying Chen
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Qiong Zhao
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Tianyuan Xie
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Chenxi Xiang
- Department of Pathology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Qianqian Guo
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Wenzhou Zhang
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yi Zhou
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Yin Yuan
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Yuxin Zhang
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Tao Xi
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Xiaoman Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Lufeng Zheng
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
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Wang L, Qiao C, Cao L, Cai S, Ma X, Song X, Jiang Q, Huang C, Wang J. Significance of HOXD transcription factors family in progression, migration and angiogenesis of cancer. Crit Rev Oncol Hematol 2022; 179:103809. [PMID: 36108961 DOI: 10.1016/j.critrevonc.2022.103809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 09/05/2022] [Accepted: 09/06/2022] [Indexed: 10/31/2022] Open
Abstract
The transcription factors (TFs) of the HOX family play significant roles during early embryonic development and cellular processes. They also play a key role in tumorigenesis as tumor oncogenes or suppressors. Furthermore, TFs of the HOXD geFIne cluster affect proliferation, migration, and invasion of tumors. Consequently, dysregulated activity of HOXD TFs has been linked to clinicopathological characteristics of cancer. HOXD TFs are regulated by non-coding RNAs and methylation of DNA on promoter and enhancer regions. In addition, HOXD genes modulate the biological function of cancer cells via the MEK and AKT signaling pathways, thus, making HOXD TFs, a suitable molecular marker for cancer prognosis and therapy. In this review, we summarized the roles of HOXD TFs in different cancers and highlighted its potential as a diagnostic and therapeutic target.
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Affiliation(s)
- Lumin Wang
- Gastroenterology department, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China; Institute of precision medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China
| | - Chenyang Qiao
- Gastroenterology department, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China
| | - Li Cao
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China
| | - Shuang Cai
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China
| | - Xiaoping Ma
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China
| | - Xinqiu Song
- Department of Cell Biology and Genetics, Medical College of Yan'an University, Yan'an, Shaanxi, PR China
| | - Qiuyu Jiang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China
| | - Chen Huang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China.
| | - Jinhai Wang
- Gastroenterology department, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China; Institute of precision medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China.
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14
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Ye D, Liu Y, Chen Y, Li G, Sun B, Peng J, Xu Q. Identification of lncRNA biomarkers in hepatocellular carcinoma by comprehensive analysis of the lncRNA-mediated ceRNA network. Front Genet 2022; 13:832952. [PMID: 36105104 PMCID: PMC9465287 DOI: 10.3389/fgene.2022.832952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 07/18/2022] [Indexed: 12/24/2022] Open
Abstract
Growing evidence implicates that miRNAs can interact with long non-coding RNAs (lncRNAs) to regulate target mRNAs through competitive interactions. However, this mechanism that regulate tumorigenesis and cancer progression remains largely unexplored. Long non-coding RNAs (lncRNAs) act as competing endogenous RNAs (ceRNAs), which play a significant role in regulating gene expression. The purpose of our study was to determine potential lncRNA biomarkers to predict the prognosis of HCC by comprehensive analysis of a ceRNA network. The edgeR package was used to obtain the differentially expressed RNA datasets by analyzing 370 HCC tissues and 50 adjacent non-HCC tissues from The Cancer Genome Atlas (TCGA). Through investigating the differentially expressed between HCC tissues and adjacent non-HCC tissues, a total of 947 lncRNAs, 52 miRNAs, and 1,650 mRNAs were obtained. The novel constructed ceRNA network incorporated 99 HCC-specific lncRNAs, four miRNAs, and 55 mRNAs. Survival analysis identified 22 differentially expressed mRNAs, four miRNAs, and nine lncRNAs which were associated with overall survival (OS) time in HCC (p < 0.05), and further exploration was performed to assess the correlation of these differentially expressed genes with tumor stage. The Interpretation of the potential functions of these differentially expressed genes in HCC was realized by Gene ontology (GO) and KEGG pathway enrichment analyses. Seven lncRNAs were confirmed based on univariate Cox regression analysis, lasso COX regression analysis and multivariate Cox regression analysis to construct a predictive model in HCC patients which were related to the prognosis of OS. In summary, ceRNAs contributed to explore the mechanism of tumorigenesis and development, and a model with seven lncRNAs might be potential biomarker to predict the prognosis of HCC. These findings supported the need to studies on the mechanisms involved in the regulation of HCC by ceRNAs.
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Affiliation(s)
- Dingde Ye
- Medicine School of Southeast University Nanjing Drum Tower Hospital, Nanjing, China
- The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yaping Liu
- School of Life Science and Technology, Southeast University, Nanjing, China
| | - Yanuo Chen
- Medicine School of Southeast University Nanjing Drum Tower Hospital, Nanjing, China
| | - Guoqiang Li
- Department of General Surgery, Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing, China
| | - Beicheng Sun
- The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Department of General Surgery, Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing, China
- *Correspondence: Beicheng Sun, ; Jin Peng, ; Qingxiang Xu,
| | - Jin Peng
- Department of General Surgery, Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing, China
- *Correspondence: Beicheng Sun, ; Jin Peng, ; Qingxiang Xu,
| | - Qingxiang Xu
- Medicine School of Southeast University Nanjing Drum Tower Hospital, Nanjing, China
- Department of General Surgery, Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing, China
- *Correspondence: Beicheng Sun, ; Jin Peng, ; Qingxiang Xu,
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15
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Li X, Jia Q, Zhou Y, Jiang X, Song L, Wu Y, Wang A, Chen W, Wang S, Lu Y. Tanshinone IIA attenuates the stemness of breast cancer cells via targeting the miR-125b/STARD13 axis. Exp Hematol Oncol 2022; 11:2. [PMID: 35057866 PMCID: PMC8781032 DOI: 10.1186/s40164-022-00255-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 01/06/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Tanshinone II A is an effective component extracted from Salvia miltiorrhiza and the roles of Tanshinone IIA in regulating the stemness of tumor cells remain unclear. This work aims to explore the roles and underlying mechanisms of Tanshinone IIA in breast cancer stemness. METHODS In vitro mammary spheroid formation, flow cytometry assay on CD24-/CD44+ sub-population, ALDH activity detection, cell viability assay and western blot analysis, and in vivo tumor-initiating analysis were performed to examine the effects of Tanshinone IIA on the stemness of breast cancer cells. MiRNAs-based transcriptome sequencing and data analysis, online dataset analysis, luciferase reporter assay combined with rescuing experiments were constructed to explore the underlying mechanisms. RESULTS Tanshinone IIA attenuated the stemness of breast cancer cells, evident by downregulating the expression of stemness markers, hindering the capacity of spheroid formation, decreasing the CD24-/CD44+ sub-population in a concentration-dependent manner and reducing the tumor-initiating ability of breast cancer cells. Additionally, Tanshinone IIA enhanced adriamycin sensitivity and attenuated adriamycin resistance of breast cancer cells. Combined with miRNAs-based transcriptome sequencing assay, it was found that Tanshinone IIA downregulated miR-125b level and upregulated its target gene STARD13 (StAR-related lipid transfer protein 13) level, thus inactivating the miR-125b/STARD13 axis, which had been previously confirmed to promote breast cancer progression. Notably, miR-125b overexpression enhanced the stemness of breast cancer cells, and miR-125b overexpression or STARD13 knockdown impaired the inhibitory effects of Tanshinone IIA on the stemness of breast cancer cells. CONCLUSIONS Tanshinone IIA could attenuate the stemness of breast cancer cells via targeting the miR-125b/STARD13 axis.
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Affiliation(s)
- Xiaoman Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Qi Jia
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yinyin Zhou
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xuan Jiang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Li Song
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yuanyuan Wu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Aiyun Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.,State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China.,Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China
| | - Wenxing Chen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.,State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China.,Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China
| | - Shijun Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
| | - Yin Lu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. .,State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China. .,Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China.
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16
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Liu Y, Zhao Q, Xi T, Zheng L, Li X. MicroRNA-9 as a paradoxical but critical regulator of cancer metastasis: Implications in personalized medicine. Genes Dis 2021; 8:759-768. [PMID: 34522706 PMCID: PMC8427239 DOI: 10.1016/j.gendis.2020.10.005] [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: 06/15/2020] [Revised: 09/27/2020] [Accepted: 10/18/2020] [Indexed: 12/24/2022] Open
Abstract
Metastasis, is a development of secondary tumor growths at a distance from the primary site, and closely related to poor prognosis and mortality. However, there is still no effective treatment for metastatic cancer. Therefore, there is an urgent need to find an effective therapy for cancer metastasis. Plenty of evidence indicates that miR-9 can function as a promoter or suppressor in cancer metastasis and coordinate multistep of metastatic process. In this review, we summarize the different roles of miR-9 with the corresponding molecular mechanisms in metastasis of twelve common cancers and the multiple mechanisms underlying miR-9-mediated regulation of metastasis, benefiting the further research of miR-9 and metastasis, and hoping to bridge it with clinical applications.
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Affiliation(s)
- Yichen Liu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, 210023, PR China
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, Jiangsu Province, 211198, PR China
| | - Qiong Zhao
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, Jiangsu Province, 211198, PR China
| | - Tao Xi
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, Jiangsu Province, 211198, PR China
| | - Lufeng Zheng
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, Jiangsu Province, 211198, PR China
| | - Xiaoman Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, 210023, PR China
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Qian Y, Zhang Y, Ji H, Shen Y, Zheng L, Cheng S, Lu X. LINC01089 suppresses lung adenocarcinoma cell proliferation and migration via miR-301b-3p/STARD13 axis. BMC Pulm Med 2021; 21:242. [PMID: 34281560 PMCID: PMC8287768 DOI: 10.1186/s12890-021-01568-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 06/18/2021] [Indexed: 11/10/2022] Open
Abstract
Background Lung adenocarcinoma (LUAD) is one of the most common cancers with high morbidity and mortality worldwide. Long non-coding RNAs (lncRNAs) serve as tumor promoters or suppressors in the development of various human malignancies, including LUAD. Although long intergenic non-protein coding RNA 1089 (LINC01089) suppresses the progression of breast cancer, its mechanism in LUAD requires further exploration. Thus, we aimed to investigate the underlying function and mechanism of LINC01089 in LUAD. Methods The expression of LINC01089 in LUAD and normal cell lines was detected. Functional assays were applied to measure cell proliferation, apoptosis and migration. Besides, mechanism experiments were employed for assessing the interplay among LINC01089, miR-301b-3p and StAR related lipid transfer domain containing 13 (STARD13). Data achieved in this study was statistically analyzed with Student’s t test or one-way analysis of variance. Results LINC01089 expression was significantly down-regulated in LUAD tissues and cells and its overexpression could reduce cell proliferation and migration. Moreover, LINC01089 could regulate STARD13 expression through competitively binding to miR-301b-3p in LUAD. Additionally, rescue assays uncovered that STARD13 depletion or miR-301b-3p overexpression could countervail the restraining effect of LINC01089 knockdown on the phenotypes of LUAD cells. Conclusion LINC01089 served as a tumor-inhibitor in LUAD by targeting miR-301b-3p/STARD13 axis, providing an innovative insight into LUAD therapies. Trial registration Not applicable. Supplementary Information The online version contains supplementary material available at 10.1186/s12890-021-01568-6.
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Affiliation(s)
- Ye Qian
- Department of Oncology, Haian People's Hospital of Jiangsu Province, No.17 Zhongba Middle Road, Haian, 226600, Jiangsu, China
| | - Yan Zhang
- Department of Oncology, Haian People's Hospital of Jiangsu Province, No.17 Zhongba Middle Road, Haian, 226600, Jiangsu, China
| | - Haoming Ji
- Department of Oncology, Haian People's Hospital of Jiangsu Province, No.17 Zhongba Middle Road, Haian, 226600, Jiangsu, China
| | - Yucheng Shen
- Department of Oncology, Haian People's Hospital of Jiangsu Province, No.17 Zhongba Middle Road, Haian, 226600, Jiangsu, China
| | - Liangfeng Zheng
- Department of Oncology, Haian People's Hospital of Jiangsu Province, No.17 Zhongba Middle Road, Haian, 226600, Jiangsu, China
| | - Shouliang Cheng
- Department of Oncology, Haian People's Hospital of Jiangsu Province, No.17 Zhongba Middle Road, Haian, 226600, Jiangsu, China
| | - Xiaomin Lu
- Department of Oncology, Haian People's Hospital of Jiangsu Province, No.17 Zhongba Middle Road, Haian, 226600, Jiangsu, China.
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18
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Sun J, Cheng X, Pan S, Wang L, Dou W, Liu J, Shi X. Dichloroacetate attenuates the stemness of colorectal cancer cells via trigerring ferroptosis through sequestering iron in lysosomes. ENVIRONMENTAL TOXICOLOGY 2021; 36:520-529. [PMID: 33166055 DOI: 10.1002/tox.23057] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 10/22/2020] [Indexed: 06/11/2023]
Abstract
Colorectal cancer stem cell (CSC) has been regarded to be the root of colorectal cancer progression. However, there is still no effective therapeutic method targeting colorectal CSC in clinical application. Here, we investigated the effects of dichloroacetate (DCA) on colorectal cancer cell stemness. We showed that DCA could reduce colorectal cancer cell stemness in a dose-dependent manner, which is evident by the decreased expression of stemness markers, tumor cell sphere-formation and cell migration ability. In addition, it was found that DCA trigerred the ferroptosis of colorectal CSC, which is characterized as the upregulation of iron concentration, lipid peroxides, and glutathione level, and decreased cell viability. Mechanistic studies demonstrated that DCA could sequester iron in lysosome and thus trigger ferroptosis, which is necessary for DCA-mediated attenuation on colorectal cancer cell stemness. Taken together, this work suggests that DCA might be a colorectal CSC-killer.
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Affiliation(s)
- Jie Sun
- Department of Gastroenterology, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, Jiangsu, China
| | - Xiuqin Cheng
- Department of Gastroenterology, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, Jiangsu, China
| | - Shubo Pan
- Department of Gastroenterology, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, Jiangsu, China
| | - Liangjing Wang
- Department of Gastroenterology, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, Jiangsu, China
| | - Wenhuan Dou
- Department of Gastroenterology, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, Jiangsu, China
| | - Jie Liu
- Department of Gastroenterology, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, Jiangsu, China
| | - Xiaohua Shi
- Department of Gastroenterology, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, Jiangsu, China
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Wang Y, Zhou X, Han P, Lu Y, Zhong X, Yang Y, Li D, Liu D, Li Q, Pan N, Mo Y, Luo W, Li P, Zhou X, Liudmila M. Inverse correlation of miR-27a-3p and CDH5 expression serves as a diagnostic biomarker of proliferation and metastasis of clear cell renal carcinoma. Pathol Res Pract 2021; 220:153393. [PMID: 33740544 DOI: 10.1016/j.prp.2021.153393] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 02/18/2021] [Accepted: 02/20/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Cadherin-5 (CDH5) is aberrantly expressed in a variety of human cancers and plays an important role in angiogenesis. The present study provides further insight into the role of miR-27a-3p in the regulation of CDH5 expression in renal clear cell carcinoma (ccRCC). METHODS Thedysregulation of CDH5 expression in ccRCC and its association with clinicopathological characteristics were analyzed using the TCGA database. A meta-analysis was performed to verify the alteration of CDH5 expression in ccRCC using the GEO database. Quantitative RT-PCR and immunohistochemical staining were applied to assess the transcriptional and protein levels of CDH5. TargetScan and Tarbase were employed to predict the miRNAs with the potential to target mRNA of CDH5. RESULTS The mRNA level of CDH5 in ccRCCwas significantly higher than in normal tissue. CDH5 mRNA expression could therefore serve as a potential diagnostic biomarker for ccRCC (AUC = 0.844). However, the reduced CDH5 transcription levels were significantly correlated with patients in the T3-4 stage, lymph node, and distant metastasis, as well as with a worse clinical outcome. We further observed that CDH5, at the protein level, was almost absent in ccRCC samples. In addition, a few databases screen showed that mir-27a-3p is a highly conserved miRNA targeting CDH5. The expression of mir-27a-3p was significantly elevated in ccRCC tissues in contrast to normal tissues. Importantly, it was positively associated with the T3-4 stage and M stage, respectively, suggesting that the expression level of mir-27a-3p could serve as a diagnostic biomarker for ccRCC (AUC = 0.775). CONCLUSION Our data suggest that thereduced translational level of CDH5 in ccRCC was related to the overexpression of mir-27a-3p. The higher mir-27a-3p and lower CDH5 expression significantly correlated with advanced clinical stages for ccRCC patients.
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Affiliation(s)
- Yifang Wang
- Life Science Institute, Guangxi Medical University, China
| | - Xiaohui Zhou
- Life Science Institute, Guangxi Medical University, China
| | - Peipei Han
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, China
| | - Yunliang Lu
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, China
| | - Xuemin Zhong
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, China
| | - Yanping Yang
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, China
| | - Danping Li
- Life Science Institute, Guangxi Medical University, China
| | - Deling Liu
- Life Science Institute, Guangxi Medical University, China
| | - Qiuyun Li
- Life Science Institute, Guangxi Medical University, China
| | - Nenghui Pan
- Life Science Institute, Guangxi Medical University, China
| | - Yingxi Mo
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, China
| | - Wenqi Luo
- Department of Pathology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Ping Li
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, China
| | - Xiaoying Zhou
- Life Science Institute, Guangxi Medical University, China.
| | - Matskova Liudmila
- Institute of Living Systems, Immanuel Kant Baltic Federal University, Kaliningrad, Russia.
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Jaafar L, Fakhoury I, Saab S, El-Hajjar L, Abou-Kheir W, El-Sibai M. StarD13 differentially regulates migration and invasion in prostate cancer cells. Hum Cell 2021; 34:607-623. [PMID: 33420961 DOI: 10.1007/s13577-020-00479-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 12/24/2020] [Indexed: 11/26/2022]
Abstract
Prostate cancer is the second most commonly diagnosed cancer in men and one of the main leading causes of cancer deaths among men worldwide. Rapid uncontrolled growth and the ability to metastasize to other sites are key hallmarks in cancer development and progression. The Rho family of GTPases and its activators the GTPase-activating proteins (GAPs) are required for regulating cancer cell proliferation and migration. StarD13 is a GAP for Rho GTPases, specifically for RhoA and Cdc42. We have previously shown that StarD13 acts as a tumor suppressor in astrocytoma as well as breast and colorectal cancer. In this study, we performed a functional comparative analysis of StarD13 targets/and or interacting molecules to understand the general role that StarD13 plays in cancers. Our data highlight the importance of StarD13 in modulating several hallmarks of cancer. Findings from database mining and immunohistochemistry revealed that StarD13 is underexpressed in prostate cancers, in addition knocking down Stard13 increased cancer cell proliferation, consistent with its role as a tumor suppressor. Stard13 depletion, however, led to an increase in cell adhesion, which inhibited 2D cell migration. Most interestingly, StarD13 depletion increases invasion and matrix degradation, at least in part, through its regulation of Cdc42. Altogether, the data presented suggest that StarD13 acts as a tumor suppressor inhibiting prostate cancer cell invasion.
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Affiliation(s)
- Leila Jaafar
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Chouran, P.O. Box 13-5053, Beirut, 1102 2801, Lebanon
| | - Isabelle Fakhoury
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Chouran, P.O. Box 13-5053, Beirut, 1102 2801, Lebanon
| | - Sahar Saab
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Chouran, P.O. Box 13-5053, Beirut, 1102 2801, Lebanon
| | - Layal El-Hajjar
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Mirvat El-Sibai
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Chouran, P.O. Box 13-5053, Beirut, 1102 2801, Lebanon.
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Zou C, Wan Y, He L, Zheng JH, Mei Y, Shi J, Zhang M, Dong Z, Zhang D. RBM38 in cancer: role and mechanism. Cell Mol Life Sci 2021; 78:117-128. [PMID: 32642788 PMCID: PMC11072576 DOI: 10.1007/s00018-020-03593-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 06/18/2020] [Accepted: 07/01/2020] [Indexed: 12/22/2022]
Abstract
Cancer is the second leading cause of death globally. Abnormity in gene expression regulation characterizes the trajectory of tumor development and progression. RNA-binding proteins (RBPs) are widely dysregulated, and thus implicated, in numerous human cancers. RBPs mainly regulate gene expression post-transcriptionally, but emerging studies suggest that many RBPs can impact transcription by acting on chromatin as transcription factors (TFs) or cofactors. Here, we review the evidence that RBM38, an intensively studied RBP, frequently plays a tumor-suppressive role in multiple human cancer types. Genetic studies in mice deficient in RBM38 on different p53 status also establish RBM38 as a tumor suppressor (TS). By uncovering a spectrum of transcripts bound by RBM38, we discuss the diversity in its mechanisms of action in distinct biological contexts. Examination of the genomic features and expression pattern of RBM38 in human tissues reveals that it is generally lost but rarely mutated, in cancers. By assessing future trends in the study of RBM38 in cancer, we signify the possibility of targeting RBM38 and its related pathways as therapeutic strategies against cancer.
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Affiliation(s)
- Cheng Zou
- College of Biology, Hunan University, Changsha, 410082, China
| | - Ying Wan
- College of Biomedicine and Health and College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China
| | - Lingjing He
- College of Biology, Hunan University, Changsha, 410082, China
| | - Jin Hai Zheng
- College of Biology, Hunan University, Changsha, 410082, China
| | - Yang Mei
- College of Biology, Hunan University, Changsha, 410082, China
| | - Junfeng Shi
- College of Biology, Hunan University, Changsha, 410082, China
| | - Min Zhang
- College of Biomedicine and Health and College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China
| | - Zhiqiang Dong
- College of Biomedicine and Health and College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China.
| | - Dingxiao Zhang
- College of Biology, Hunan University, Changsha, 410082, China.
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Integrated analysis of long non-coding RNAs and mRNA profiles reveals potential sex-dependent biomarkers of bevacizumab/erlotinib response in advanced lung cancer. PLoS One 2020; 15:e0240633. [PMID: 33075110 PMCID: PMC7571718 DOI: 10.1371/journal.pone.0240633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Accepted: 09/25/2020] [Indexed: 11/19/2022] Open
Abstract
Background While lung cancer patient outcomes are well-recognized to vary as a function of patient sex, there has been insufficient research regarding the relationship between patient sex and EGFR(Epidermal growth factor receptor) response efficacy. The present study therefore sought to identify novel sex-related biomarkers of bevacizumab/erlotinib (BE) responses in non-small cell lung cancer (NSCLC) patients. Methods The exon array data in the Gene Expression Omnibus (GEO) dataset were analyzed in order to identify patterns of mRNA and lncRNA expression associated with BE resistance in NSCLC. These differentially expressed (DE) lncRNAs and mRNAs were identified via DE Analysis Filtering. These DE mRNAs were then assessed for their potential functional roles via pathway enrichment analyses, with overlapping functions possibly associated with the BE resistance. The mRNAs in these overlapping groups were then assessed for their correlations with patient survival, and lncRNA-mRNA co-expression networks were generated for each patient subset. A protein-protein interaction (PPI) network was also generated based upon these DE mRNAs. Results In females we identified 172 DE lncRNAs and 1766 DE mRNAs associated with BE responses, while in males we identified 78 DE lncRNAs and 485 DE mRNAs associated with such responses. Based on the overlap between these two datasets, we identified a total of 37 GO functions and 18 pathways associated with BE responses. Co-expression and PPI networks suggested that the key lncRNAs and mRNAs associated with these BE response mechanisms weredifferent in the male and female patients. Conclusions This work is the first to conduct a global profiling of the relationship between lncRNA and mRNA expression patterns, patient sex, and BE responses in individuals suffering from NSCLC. Together these results suggest that the integrative lncRNA-mRNA expression analyses may offer invaluable new therapeutic insights that can guide the tailored treatment of lung cancer in order to ensure optimal BE responses.
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Bai Z, Li H, Li C, Sheng C, Zhao X. Integrated analysis identifies a long non-coding RNAs-messenger RNAs signature for prediction of prognosis in hepatitis B virus-hepatocellular carcinoma patients. Medicine (Baltimore) 2020; 99:e21503. [PMID: 33019382 PMCID: PMC7535691 DOI: 10.1097/md.0000000000021503] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC), but HBV-HCC related prognosis signature remains rarely investigated. This study was to identify an integrated long non-coding RNAs-messenger RNAs (lncRNA-mRNA) signature for prediction of overall survival (OS) and explore their underlying functions.One RNA-sequencing dataset (training set, n = 95) and one microarray dataset E-TABM-36 (validation set, n = 44) were collected. Least absolute shrinkage and selection operator analysis was performed to identify an lncRNA-mRNA prognosis signature. The OS difference of patients in the high-risk and low-risk risk groups was evaluated by Kaplan-Meier curve. Area under the receiver operating characteristic curve (AUC), Harrell concordance index (C-index) calculation, and multivariate analyses with clinical characteristics were used to determine the prognostic ability. Furthermore, a coexpression network was constructed to interpret the functions.Nine signature genes (3 lncRNAs and 6 mRNAs) were selected to generate the risk score model. Patients belonging to the high-risk group showed a significantly shorter survival than those of the low-risk group. The prediction accuracy of the risk score for 5-year OS was 0.936 and 0.905 for the training set and validation set, respectively. Also, this risk score was independent of various clinical variables for the prognosis prediction. Incorporation of the risk score remarkably increased the predictive power of the routine clinical prognostic factors (vascular invasion status, tumor recurrence status) (AUC = 0.942 vs 0.628; C-index = 0.7997 vs 0.6908). Furthermore, LncRNA insulin-like growth factor 2 antisense RNA (IGF2-AS) and long intergenic non-protein coding RNA 342 (LINC00342) were predicted to exert tumor suppression effects by regulating homeobox D1 (HOXD1) and secreted frizzled related protein 5 (SFRP5), respectively; while lncRNA rhophilin Rho GTPase binding protein 1 antisense RNA 1 (RHPN1-AS1) may possess carcinogenic potential by promoting the transcription of chromobox 2 (CBX2), cell division cycle 20 (CDC20), matrix metallopeptidase 12 (MMP12), stratifin (SFN), tripartite motif containing 16 (TRIM16), and uroplakin 3A (UPK3A). These mRNAs may be associated with cell proliferation or apoptosis related pathways.This study may provide a novel, effective prognostic biomarker, and some therapeutic targets for HBV-HCC patients.
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Al Haddad M, El-Rif R, Hanna S, Jaafar L, Dennaoui R, Abdellatef S, Miskolci V, Cox D, Hodgson L, El-Sibai M. Differential regulation of rho GTPases during lung adenocarcinoma migration and invasion reveals a novel role of the tumor suppressor StarD13 in invadopodia regulation. Cell Commun Signal 2020; 18:144. [PMID: 32900380 PMCID: PMC7487901 DOI: 10.1186/s12964-020-00635-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 08/03/2020] [Indexed: 11/11/2022] Open
Abstract
Background Lung cancer is the second most commonly occurring cancer. The ability to metastasize and spread to distant locations renders the tumor more aggressive. Members of the Rho subfamily of small GTP-binding proteins (GTPases) play a central role in the regulation of the actin cytoskeleton and in cancer cell migration and metastasis. In this study we investigated the role of the RhoA/Cdc42 GAP, StarD13, a previously described tumor suppressor, in malignancy, migration and invasion of the lung cancer cells A549. Methods We knocked down StarD13 expression in A549 lung cancer cells and tested the effect on cell migration and invadopodia formation using time lapse imaging and invasion assays. We also performed rescue experiments to determine the signaling pathways downstream of StarD13 and transfected the cells with FRET biosensors for RhoGTPases to identify the proteins involved in invadopodia formation. Results We observed a decrease in the level of expression of StarD13 in lung tumor tissues compared to normal lung tissues through immunohistochemistry. StarD13 also showed a lower expression in the lung adenocarcinoma cell line A549 compared to normal lung cells, WI38. In addition, the depletion of StarD13 increased cell proliferation and viability in WI38 and A549 cells, suggesting that StarD13 might potentially be a tumor suppressor in lung cancer. The depletion of StarD13, however, inhibited cell motility, conversely demonstrating a positive regulatory role in cell migration. This was potentially due to the constitutive activation of RhoA detected by pull down and FRET assays. Surprisingly, StarD13 suppressed cell invasion by inhibiting Cdc42-mediated invadopodia formation. Indeed, TKS4 staining and invadopodia assay revealed that StarD13 depletion increased Cdc42 activation as well as invadopodia formation and matrix degradation. Normal lung cells depleted of StarD13 also produced invadopodia, otherwise a unique hallmark of invasive cancer cells. Cdc42 knock down mimicked the effects of StarD13, while overexpression of a constitutively active Cdc42 mimicked the effects of its depletion. Finally, immunostaining and FRET analysis revealed the absence of StarD13 in invadopodia as compared to Cdc42, which was activated in invadopodia at the sites of matrix degradation. Conclusion In conclusion, StarD13 plays distinct roles in lung cancer cell migration and invasion through its differential regulation of Rho GTPases.
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