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Jasim SA, Altalbawy FMA, Uthirapathy S, Bishoyi AK, Ballal S, Singh A, Devi A, Yumashev A, Mustafa YF, Abosaoda MK. Regulation of immune-mediated chemoresistance in cancer by lncRNAs: an in-depth review of signaling pathways. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04081-3. [PMID: 40202675 DOI: 10.1007/s00210-025-04081-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 03/20/2025] [Indexed: 04/10/2025]
Abstract
Resistance to cancer therapies is increasingly recognized as being influenced by long non-coding RNAs (lncRNAs), which are pivotal in regulating cellular functions and gene expression. Elucidating the intricate relationship between lncRNAs and the mechanisms underlying drug resistance is critical for advancing effective therapeutic strategies. This study offers an in-depth review of the regulatory roles lncRNAs play in various signaling and immunological pathways implicated in cancer chemoresistance. lncRNA-mediated influence on drug resistance-related signaling pathways will be presented, including immune evasion mechanisms and other essential signaling cascades. Furthermore, the interplay between lncRNAs and the immune landscape will be dissected, illustrating their substantial impact on the development of chemoresistance. Overall, the potential of lncRNA-mediated signaling networks as a therapeutic strategy to combat cancer resistance has been highlighted. This review reiterates the fundamental role of lncRNAs in chemoresistance and proposes promising avenues for future research and the development of targeted therapeutic interventions.
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Affiliation(s)
- Saade Abdalkareem Jasim
- Medical Laboratory Techniques Department, College of Health and Medical Technology, University of Al-Maarif, Anbar, Iraq.
| | - Farag M A Altalbawy
- Department of Chemistry, University College of Duba, University of Tabuk, Tabuk, Saudi Arabia
| | - Subasini Uthirapathy
- Pharmacy Department, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Ashok Kumar Bishoyi
- Marwadi University Research Center, Department of Microbiology, Faculty of Science, Marwadi University, Rajkot, 360003, Gujarat, India
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Abhayveer Singh
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - Anita Devi
- Department of Chemistry, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India
| | - Alexey Yumashev
- Department of Prosthetic Dentistry, Sechenov First Moscow State Medical University, Mosco, Russia
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Munther Kadhim Abosaoda
- College of Pharmacy, The Islamic University, Najaf, Iraq
- College of Pharmacy, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Pharmacy, The Islamic University of Babylon, Babylon, Iraq
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Sahebnasagh R, Deli H, Shadboorestan A, Vakili-Ghartavol Z, Salehi N, Komeili-Movahhed T, Azizi Z, Ghahremani MH. Identification of key lncRNAs associated with oxaliplatin resistance in colorectal cancer cells and isolated exosomes: From In-Silico prediction to In-Vitro validation. PLoS One 2024; 19:e0311680. [PMID: 39401197 PMCID: PMC11472961 DOI: 10.1371/journal.pone.0311680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 09/23/2024] [Indexed: 10/17/2024] Open
Abstract
One of the critical challenges in managing colorectal cancer (CRC) is the development of oxaliplatin (OXP) resistance. Long non-coding RNAs (lncRNAs) have a crucial role in CRC progression and chemotherapy resistance, with exosomal lncRNAs emerging as potential biomarkers. This study aimed to predict key lncRNAs involved in OXP-resistance using in-silico methods and validate them using RT-qPCR methods in CRC cells and their isolated exosomes. Two public datasets, GSE42387 and GSE119481, were downloaded from the GEO database to identify differentially expressed genes (DEGs) and miRNAs (DEmiRNAs) associated with OXP-resistance in the HCT116 cell line. The analysis of GSE42387 revealed 210 DEGs, and GSE119481 identified 73 DEmiRNAs. A protein-protein interaction (PPI) network analysis of the DEGs identified 133 interconnected genes, from which the top ten genes with the highest degree scores were selected. By intersecting predicted miRNAs targeting these genes with the DEmiRNAs, 38 common miRNAs were found. Subsequently, 224 lncRNAs targeting these common miRNAs were predicted. LncRNA-miRNA-mRNA network were constructed and the top five lncRNAs with the highest degree scores were identified. Analysis using the Kaplan-Meier plotter database revealed that the key lncRNAs NEAT1, OIP5-AS1, and MALAT1 are significantly associated with the overall survival of CRC patients. To validate these lncRNAs, OXP-resistant HCT116 sub-cell line (HCT116/OXR) was developed by exposing parental HCT116 cells to gradually increasing concentrations of OXP. Exosomes derived from both HCT116 and HCT116/OXR cells were isolated and characterized utilizing dynamic light scattering (DLS), transmission electron microscopy (TEM), and Western blotting. RT-qPCR confirmed elevated levels of NEAT1, OIP5-AS1, and MALAT1 in HCT116/OXR cells and their exosomes compared to parental HCT116 cells and their exosomes. This study concludes that NEAT1, OIP5-AS1, and MALAT1 are associated with the OXP-resistance in CRC. The high levels of these lncRNAs in exosomes of resistant cells suggest their involvement in intercellular communication and resistance propagation. This positioning makes them promising biomarkers for OXP-resistance in CRC.
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Affiliation(s)
- Roxana Sahebnasagh
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hoda Deli
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Shadboorestan
- Department of Toxicology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Zeynab Vakili-Ghartavol
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Najmeh Salehi
- School of Biology, College of Science, University of Tehran, Tehran, Iran
| | | | - Zahra Azizi
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Ghahremani
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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Lin Y, Zhao W, Pu R, Lv Z, Xie H, Li Y, Zhang Z. Long non‑coding RNAs as diagnostic and prognostic biomarkers for colorectal cancer (Review). Oncol Lett 2024; 28:486. [PMID: 39185489 PMCID: PMC11342420 DOI: 10.3892/ol.2024.14619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 07/29/2024] [Indexed: 08/27/2024] Open
Abstract
Colorectal cancer (CRC) ranks as the 3rd most common cancer globally and is the 2nd leading cause of cancer-related death. Owing to the lack of specific early symptoms and the limitations of existing early diagnostic methods, most patients with CRC are diagnosed at advanced stages. To overcome these challenges, researchers have increasingly focused on molecular biomarkers, with particular interest in long non-coding RNAs (lncRNAs). These non-protein-coding RNAs, which exceed 200 nucleotides in length, play critical roles in the development and progression of CRC. The stability and detectability of lncRNAs in the circulatory system make them promising candidate biomarkers. The analysis of circulating lncRNAs in peripheral blood represents a potential option for minimally invasive diagnostic tests based on liquid biopsy samples. The present review aimed to evaluate the efficacy of lncRNAs with altered expression levels in peripheral blood as diagnostic markers for CRC. Additionally, the clinical significance of lncRNAs as prognostic markers for this disease were summarized.
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Affiliation(s)
- Yuning Lin
- Medical Laboratory, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, Fujian 361009, P.R. China
| | - Wenzhen Zhao
- Medical Laboratory, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, Fujian 361009, P.R. China
| | - Ruonan Pu
- Medical Laboratory, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, Fujian 361009, P.R. China
| | - Zhenyi Lv
- Medical Laboratory, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, Fujian 361009, P.R. China
| | - Hongyan Xie
- Medical Laboratory, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, Fujian 361009, P.R. China
| | - Ying Li
- Department of Ultrasonography, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, Fujian 361003, P.R. China
| | - Zhongying Zhang
- Medical Laboratory, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, Fujian 361009, P.R. China
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Vana F, Szabo Z, Masarik M, Kratochvilova M. The interplay of transition metals in ferroptosis and pyroptosis. Cell Div 2024; 19:24. [PMID: 39097717 PMCID: PMC11297737 DOI: 10.1186/s13008-024-00127-9] [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: 03/26/2024] [Accepted: 07/08/2024] [Indexed: 08/05/2024] Open
Abstract
Cell death is one of the most important mechanisms of maintaining homeostasis in our body. Ferroptosis and pyroptosis are forms of necrosis-like cell death. These cell death modalities play key roles in the pathophysiology of cancer, cardiovascular, neurological diseases, and other pathologies. Transition metals are abundant group of elements in all living organisms. This paper presents a summary of ferroptosis and pyroptosis pathways and their connection to significant transition metals, namely zinc (Zn), copper (Cu), molybdenum (Mo), lead (Pb), cobalt (Co), iron (Fe), cadmium (Cd), nickel (Ni), mercury (Hg), uranium (U), platinum (Pt), and one crucial element, selenium (Se). Authors aim to summarize the up-to-date knowledge of this topic.In this review, there are categorized and highlighted the most common patterns in the alterations of ferroptosis and pyroptosis by transition metals. Special attention is given to zinc since collected data support its dual nature of action in both ferroptosis and pyroptosis. All findings are presented together with a brief description of major biochemical pathways involving mentioned metals and are visualized in attached comprehensive figures.This work concludes that the majority of disruptions in the studied metals' homeostasis impacts cell fate, influencing both death and survival of cells in the complex system of altered pathways. Therefore, this summary opens up the space for further research.
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Affiliation(s)
- Frantisek Vana
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
| | - Zoltan Szabo
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 656 53, Czech Republic
| | - Michal Masarik
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
- First Faculty of Medicine, BIOCEV, Charles University, Prumyslova 595, Vestec, CZ-252 50, Czech Republic
| | - Monika Kratochvilova
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic.
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Liu S, Yue M, Lu Y, Wang Y, Luo S, Liu X, Jiang J. Advancing the frontiers of colorectal cancer treatment: harnessing ferroptosis regulation. Apoptosis 2024; 29:86-102. [PMID: 37752371 DOI: 10.1007/s10495-023-01891-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/04/2023] [Indexed: 09/28/2023]
Abstract
In recent years, colorectal cancer incidence and mortality have increased significantly due to poor lifestyle choices. Despite the development of various treatments, their effectiveness against advanced/metastatic colorectal cancer remains unsatisfactory due to drug resistance. However, ferroptosis, a novel iron-dependent cell death process induced by lipid peroxidation and elevated reactive oxygen species (ROS) levels along with reduced activity of the glutathione peroxidase 4 (GPX4) antioxidant enzyme system, shows promise as a therapeutic target for colorectal cancer. This review aims to delve into the regulatory mechanisms of ferroptosis in colorectal cancer, providing valuable insights into potential therapeutic approaches. By targeting ferroptosis, new avenues can be explored for innovative therapies to combat colorectal cancer more effectively. In addition, understanding the molecular pathways involved in ferroptosis may help identify biomarkers for prognosis and treatment response, paving the way for personalized medicine approaches. Furthermore, exploring the interplay between ferroptosis and other cellular processes can uncover combination therapies that enhance treatment efficacy. Investigating the tumor microenvironment's role in regulating ferroptosis may offer strategies to sensitize cancer cells to cell death induction, leading to improved outcomes. Overall, ferroptosis presents a promising avenue for advancing the treatment of colorectal cancer and improving patient outcomes.
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Affiliation(s)
- Siyue Liu
- Institute of Infection, Immunology and Tumor Microenvironment, School of Medicine, Wuhan University of Science and Technology, Wuhan, 430065, China
| | - Ming Yue
- Department of Pharmacy, Tongji Medical College, the Central Hospital of Wuhan, Huazhong University of Science and Technology, Wuhan, 430014, China
| | - Yukang Lu
- Institute of Infection, Immunology and Tumor Microenvironment, School of Medicine, Wuhan University of Science and Technology, Wuhan, 430065, China
| | - Ying Wang
- Institute of Infection, Immunology and Tumor Microenvironment, School of Medicine, Wuhan University of Science and Technology, Wuhan, 430065, China
| | - Shiwen Luo
- Institute of Infection, Immunology and Tumor Microenvironment, School of Medicine, Wuhan University of Science and Technology, Wuhan, 430065, China
| | - Xiaoliu Liu
- Institute of Infection, Immunology and Tumor Microenvironment, School of Medicine, Wuhan University of Science and Technology, Wuhan, 430065, China.
| | - Jue Jiang
- Institute of Infection, Immunology and Tumor Microenvironment, School of Medicine, Wuhan University of Science and Technology, Wuhan, 430065, China.
- Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, Wuhan, 430065, China.
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Li Y, Lou S, Zhang J, Zhao S, Lou G. m 6A methylation-mediated regulation of LncRNA MEG3 suppresses ovarian cancer progression through miR-885-5p and the VASH1 pathway. J Transl Med 2024; 22:113. [PMID: 38281945 PMCID: PMC10823642 DOI: 10.1186/s12967-024-04929-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 01/24/2024] [Indexed: 01/30/2024] Open
Abstract
BACKGROUND Ovarian cancer poses a serious threat to women's health. Due to the difficulty of early detection, most patients are diagnosed with advanced-stage disease or peritoneal metastasis. We found that LncRNA MEG3 is a novel tumor suppressor, but its role in tumor occurrence and development is still unclear. METHODS We investigated the expression level of MEG3 in pan-cancer through bioinformatics analysis, especially in gynecological tumors. Function assays were used to detect the effect of MEG3 on the malignant phenotype of ovarian cancer. RIP, RNA pull-down, MeRIP-qPCR, actinomycin D test were carried out to explore the m6A methylation-mediated regulation on MEG3. Luciferase reporter gene assay, PCR and Western blot were implemented to reveal the potential mechanism of MEG3. We further confirmed the influence of MEG3 on tumor growth in vivo by orthotopic xenograft models and IHC assay. RESULTS In this study, we discovered that MEG3 was downregulated in various cancers, with the most apparent downregulation in ovarian cancer. MEG3 inhibited the proliferation, migration, and invasion of ovarian cancer cells. Overexpression of MEG3 suppressed the degradation of VASH1 by negatively regulating miR-885-5p, inhibiting the ovarian cancer malignant phenotype. Furthermore, we demonstrated that MEG3 was regulated at the posttranscriptional level. YTHDF2 facilitated MEG3 decay by recognizing METTL3‑mediated m6A modification. Compared with those injected with vector control cells, mice injected with MEG3 knockdown cells showed larger tumor volumes and faster growth rates. CONCLUSION We demonstrated that MEG3 is influenced by METTL3/YTHDF2 methylation and restrains ovarian cancer proliferation and metastasis by binding miR-885-5p to increase VASH1 expression. MEG3 is expected to become a therapeutic target for ovarian cancer.
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Affiliation(s)
- Yan Li
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Harbin Medical University, Harbin, 150007, Heilongjiang, China
- Department of Gynecology, Harbin Medical University Cancer Hospital, 150 HaPing Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Shenghan Lou
- Department of Gynecology, Harbin Medical University Cancer Hospital, 150 HaPing Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Jian Zhang
- Department of Gynecology, Harbin Medical University Cancer Hospital, 150 HaPing Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Shilu Zhao
- Department of Gynecology, Harbin Medical University Cancer Hospital, 150 HaPing Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Ge Lou
- Department of Gynecology, Harbin Medical University Cancer Hospital, 150 HaPing Road, Nangang District, Harbin, 150081, Heilongjiang, China.
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7
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Degirmenci Z, Unver S, Kilic T, Avsar T. Silencing of the MEG3 gene promoted anti-cancer activity and drug sensitivity in glioma. J Cell Mol Med 2023; 27:2603-2613. [PMID: 37525401 PMCID: PMC10468657 DOI: 10.1111/jcmm.17883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 07/14/2023] [Accepted: 07/19/2023] [Indexed: 08/02/2023] Open
Abstract
Aberrant expression of MEG3 has been shown in various cancers. The purpose of this study is to evaluate the effect of MEG3 on glioma cells and the use of potential chemotherapeutics in glioma by modulating MEG3 expression. Cell viability, migration and chemosensitivity were assayed. Cell death was evaluated in MEG3 overexpressing and MEG3 suppressed cells. MEG3 expression was compared in patient-derived glioma cells concerning IDH1 mutation and WHO grades. Silencing of MEG3 inhibited cell proliferation and reduced cell migration while overexpression of MEG3 promoted proliferation in glioma cells. MEG3 inhibition improved the chemosensitivity of glioma cells to 5-fluorouracil (5FU) but not to navitoclax. On the other hand, there is no significant effect of MEG3 expression on temozolamide (TMZ) treatment which is a standard chemotherapeutic agent in glioma. Suppression of the MEG3 gene in patient-derived oligodendroglioma cells also showed the same effect whereas glioblastoma cell proliferation and chemosensitivity were not affected by MEG3 inhibition. Further, as a possible cell death mechanism of action apoptosis was investigated. Although MEG3 is a widely known tumour suppressor gene and its loss is associated with several cancer types, here we reported that MEG3 inhibition can be used for improving the efficiency of known chemotherapeutic drug sensitivity. We propose that the level of MEG3 should be evaluated in the treatment of different glioma subtypes that are resistant to effective drugs to increase the potential effective drug applications.
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Affiliation(s)
- Zehra Degirmenci
- Neuroscience LaboratoryHealth Sciences Institute, Bahcesehir UniversityIstanbulTurkey
| | - Sena Unver
- Neuroscience LaboratoryHealth Sciences Institute, Bahcesehir UniversityIstanbulTurkey
| | - Turker Kilic
- Neuroscience LaboratoryHealth Sciences Institute, Bahcesehir UniversityIstanbulTurkey
- Department of NeurosurgeryBahcesehir University School of MedicineIstanbulTurkey
| | - Timucin Avsar
- Neuroscience LaboratoryHealth Sciences Institute, Bahcesehir UniversityIstanbulTurkey
- Department of Medical BiologyBahcesehir University School of MedicineIstanbulTurkey
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Golbashirzadeh M, Heidari HR, Aghamolayi AA, Fattahi Y, Talebi M, Khosroushahi AY. In vitro siRNA-mediated GPX4 and AKT1 silencing in oxaliplatin resistance cancer cells induces ferroptosis and apoptosis. Med Oncol 2023; 40:279. [PMID: 37632628 DOI: 10.1007/s12032-023-02130-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 02/21/2022] [Indexed: 08/28/2023]
Abstract
Oxaliplatin is a member of platinum-based chemotherapy drugs frequently used in colorectal cancer (CRC). However, resistance to oxaliplatin causes tumor progression and metastasis. Akt1 and Gpx4 are essential regulator genes of apoptosis and ferroptosis pathways. Inhibition of these genes might eradicate oxaliplatin resistance in resistant CRC cells. We compared two cell death strategies to reverse drug resistance in Caco-2 and HT-29 oxaliplatin-resistant cell lines. We used the AKT1-specific siRNA to induce apoptosis. Also, GPX4-specific siRNA and FIN56 were utilized to generate ferroptosis. The effect of these treatments was assessed by reactive oxygen species (ROS) formation, cell viability, and protein expression level assays. Besides, the expression of GPX4, CoQ10, and NRF2 was assessed in both cell lines after treatments. Correctly measuring the expression of these responsible genes and proteins confirms the occurrence of different types of cell death. In addition, the ability of Akt1/ GPX4 siRNA in resensitizing HT-29 and Caco-2 oxaliplatin resistance cells was evaluated. Our finding showed that the upregulation of GPX4/siRNA caused a reduction in GPX4 and CoQ10 expressions in both cell lines. However, the expression level of NRF2 showed the same level in our cell lines, so we observed a downregulation of NRF2 in resistant CRC cell lines. Cell viability assay indicated that induction of ferroptosis by GPX4/siRNA or FIN56 and apoptosis by Akt1/siRNA in resistant cell lines could reverse the oxaliplatin resistance. We concluded that downregulation of Akt1 or Gpx4 could increase the efficacy of oxaliplatin to overcome the resistance compared to FIN56.
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Affiliation(s)
- Morteza Golbashirzadeh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, P.O. 14766-51664, Tabriz, Iran
| | - Hamid Reza Heidari
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, P.O. 14766-51664, Tabriz, Iran.
| | - Ali Asghar Aghamolayi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, P.O. 14766-51664, Tabriz, Iran
| | - Yasin Fattahi
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, P.O. 14766-51664, Tabriz, Iran
| | - Mehdi Talebi
- Hematology and Oncology Research Center, Department of Applied Cell Sciences, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahmad Yari Khosroushahi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Medical Nanotechnology, Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Daneshgah Street, P.O.Box 51548-53431, Tabriz, Iran.
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Li J, Lv J, Chen Y, Li L. Tumor suppressor circPDE4D inhibits the progression of colorectal cancer and regulates oxaliplatin chemoresistance. Gene 2023; 864:147323. [PMID: 36858188 DOI: 10.1016/j.gene.2023.147323] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 02/08/2023] [Accepted: 02/23/2023] [Indexed: 03/03/2023]
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide, and it frequently develops resistance to chemotherapy. It was discovered that circular RNAs, which function as microRNA sponges, are involved in the pathogenesis of many cancers. This study aimed to investigate the biological functions of a circRNA derived from phosphodiesterase 4D (circPDE4D, hsa_circ_0072568) and its potential mechanism in oxaliplatin-resistant CRC. CircPDE4D expression were validated in human CRC cell lines and tissues. CircPDE4D siRNAs (si-circPDE4D) and LV003-circPDE4D plasmid were applied to investigate the function of circPDE4D. A quantitative real-time polymerase chain reaction was used to detect the levels of circPDE4D, its predicted sponge miRNAs, and their target genes. Cell proliferation was assessed by MTS（3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium） assay. Cell migration and invasion capacity were evaluated by transwell assay. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling was used to stain apoptotic cells. The results showed that circPDE4D expression was downregulated in CRC cells and tissues. Transfection with si-circPDE4D promoted cell proliferation, migration, and invasion, and inhibited apoptosis in DLD1 cells. Transfection with LV003-circPDE4D showed the opposite effect. Besides, circPDE4D presented higher expression in HCT116/L cells than that in HCT116 cells. Si-circPDE4D or lv003-circPDE4D transfection increased or decreased cell proliferationin in both two cells. Moreover, si-circPDE4D transfection inhibited cell apoptosis, while LV003-circPDE4D induced apoptosis in HCT116/L cells. LV003-CircPDE4D reduced hsa-miR-569 expression while increasing SPI1 expression in HCT116/L. CircPDE4D could inhibit tumorigenesis and progression of both CRC and oxaliplatin-resistant CRC, providing insight for the development of therapeutic strategies.
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Affiliation(s)
- Jiaying Li
- Department of Pharmacy, Branch of The First Affiliated Hospital of Xinjiang Medical University, Changji 831100, Xinjiang, China.
| | - Jingsen Lv
- Forevergen Biosciences Center, Guangzhou 510000, Guangdong, China
| | - Yuan Chen
- Information Section, Changji People's Hospital, Changji 831100, Xinjiang, China
| | - Li Li
- General Department of Party and government, Branch of The First Affiliated Hospital of Xinjiang Medical University, Changji 831100, Xinjiang, China.
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10
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Zeng M, Zhang T, Lin Y, Lin Y, Wu Z. The Common LncRNAs of Neuroinflammation-Related Diseases. Mol Pharmacol 2023; 103:113-131. [PMID: 36456192 DOI: 10.1124/molpharm.122.000530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 10/24/2022] [Accepted: 11/07/2022] [Indexed: 12/04/2022] Open
Abstract
Spatio-temporal specific long noncoding RNAs (lncRNAs) play important regulatory roles not only in the growth and development of the brain but also in the occurrence and development of neurologic diseases. Generally, the occurrence of neurologic diseases is accompanied by neuroinflammation. Elucidation of the regulatory mechanisms of lncRNAs on neuroinflammation is helpful for the clinical treatment of neurologic diseases. This paper focuses on recent findings on the regulatory effect of lncRNAs on neuroinflammatory diseases and selects 10 lncRNAs that have been intensively studied to analyze their mechanism action. The clinical treatment status of lncRNAs as drug targets is also reviewed. SIGNIFICANCE STATEMENT: Gene therapies such as clustered regularly interspaced short palindrome repeats technology, antisense RNA technology, and RNAi technology are gradually applied in clinical treatment, and the development of technology is based on a large number of basic research investigations. This paper focuses on the mechanisms of lncRNAs regulation of neuroinflammation, elucidates the beneficial or harmful effects of lncRNAs in neurosystemic diseases, and provides theoretical bases for lncRNAs as drug targets.
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Affiliation(s)
- Meixing Zeng
- The First Affiliated Hospital of Shantou University Medical College (M.Z., Y.L., Z.W.) and The Second Affiliated Hospital of Shantou University Medical College (Y.L.), Shantou, Guangdong, China, and The Seventh Affiliated Hospital of Southern Medical University, Foshan, Guangdong, China(T.Z.)
| | - Ting Zhang
- The First Affiliated Hospital of Shantou University Medical College (M.Z., Y.L., Z.W.) and The Second Affiliated Hospital of Shantou University Medical College (Y.L.), Shantou, Guangdong, China, and The Seventh Affiliated Hospital of Southern Medical University, Foshan, Guangdong, China(T.Z.)
| | - Yan Lin
- The First Affiliated Hospital of Shantou University Medical College (M.Z., Y.L., Z.W.) and The Second Affiliated Hospital of Shantou University Medical College (Y.L.), Shantou, Guangdong, China, and The Seventh Affiliated Hospital of Southern Medical University, Foshan, Guangdong, China(T.Z.)
| | - Yongluan Lin
- The First Affiliated Hospital of Shantou University Medical College (M.Z., Y.L., Z.W.) and The Second Affiliated Hospital of Shantou University Medical College (Y.L.), Shantou, Guangdong, China, and The Seventh Affiliated Hospital of Southern Medical University, Foshan, Guangdong, China(T.Z.)
| | - Zhuomin Wu
- The First Affiliated Hospital of Shantou University Medical College (M.Z., Y.L., Z.W.) and The Second Affiliated Hospital of Shantou University Medical College (Y.L.), Shantou, Guangdong, China, and The Seventh Affiliated Hospital of Southern Medical University, Foshan, Guangdong, China(T.Z.)
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11
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Zhang Z, Shi S, Li J, Costa M. Long Non-Coding RNA MEG3 in Metal Carcinogenesis. TOXICS 2023; 11:toxics11020157. [PMID: 36851033 PMCID: PMC9962265 DOI: 10.3390/toxics11020157] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/23/2023] [Accepted: 01/31/2023] [Indexed: 06/06/2023]
Abstract
Most transcripts from human genomes are non-coding RNAs (ncRNAs) that are not translated into proteins. ncRNAs are divided into long (lncRNAs) and small non-coding RNAs (sncRNAs). LncRNAs regulate their target genes both transcriptionally and post-transcriptionally through interactions with proteins, RNAs, and DNAs. Maternally expressed gene 3 (MEG3), a lncRNA, functions as a tumor suppressor. MEG3 regulates cell proliferation, cell cycle, apoptosis, hypoxia, autophagy, and many other processes involved in tumor development. MEG3 is downregulated in various cancer cell lines and primary human cancers. Heavy metals, such as hexavalent chromium (Cr(VI)), arsenic, nickel, and cadmium, are confirmed human carcinogens. The exposure of cells to these metals causes a variety of cancers. Among them, lung cancer is the one that can be induced by exposure to all of these metals. In vitro studies have demonstrated that the chronic exposure of normal human bronchial epithelial cells (BEAS-2B) to these metals can cause malignant cell transformation. Metal-transformed cells have the capability to cause an increase in cell proliferation, resistance to apoptosis, elevated migration and invasion, and properties of cancer stem-like cells. Studies have revealed that MEG is downregulated in Cr(VI)-transformed cells, nickel-transformed cells, and cadmium (Cd)-transformed cells. The forced expression of MEG3 reduces the migration and invasion of Cr(VI)-transformed cells through the downregulation of the neuronal precursor of developmentally downregulated protein 9 (NEDD9). MEG3 suppresses the malignant cell transformation of nickel-transformed cells. The overexpression of MEG3 decreases Bcl-xL, causing reduced apoptosis resistance in Cd-transformed cells. This paper reviews the current knowledge of lncRNA MEG3 in metal carcinogenesis.
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12
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Luo ZD, Wang YF, Zhao YX, Yu LC, Li T, Fan YJ, Zeng SJ, Zhang YL, Zhang Y, Zhang X. Emerging roles of non-coding RNAs in colorectal cancer oxaliplatin resistance and liquid biopsy potential. World J Gastroenterol 2023; 29:1-18. [PMID: 36683709 PMCID: PMC9850945 DOI: 10.3748/wjg.v29.i1.1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 10/11/2022] [Accepted: 11/04/2022] [Indexed: 01/04/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies of the digestive tract, with the annual incidence and mortality increasing consistently. Oxaliplatin-based chemotherapy is a preferred therapeutic regimen for patients with advanced CRC. However, most patients will inevitably develop resistance to oxaliplatin. Many studies have reported that non-coding RNAs (ncRNAs), such as microRNAs, long non-coding RNAs, and circular RNAs, are extensively involved in cancer progression. Moreover, emerging evidence has revealed that ncRNAs mediate chemoresistance to oxaliplatin by transcriptional and post-transcriptional regulation, and by epigenetic modification. In this review, we summarize the mechanisms by which ncRNAs regulate the initiation and development of CRC chemoresistance to oxaliplatin. Furthermore, we investigate the clinical application of ncRNAs as promising biomarkers for liquid CRC biopsy. This review provides new insights into overcoming oxaliplatin resistance in CRC by targeting ncRNAs.
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Affiliation(s)
- Zheng-Dong Luo
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Yi-Feng Wang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Yu-Xiao Zhao
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Long-Chen Yu
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Tian Li
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Ying-Jing Fan
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Shun-Jie Zeng
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Yan-Li Zhang
- Department of Clinical Laboratory, Shandong Provincial Third Hospital, Jinan 250012, Shandong Province, China
| | - Yi Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Xin Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
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13
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Wang G, Wang JJ, Zhi-Min Z, Xu XN, Shi F, Fu XL. Targeting critical pathways in ferroptosis and enhancing antitumor therapy of Platinum drugs for colorectal cancer. Sci Prog 2023; 106:368504221147173. [PMID: 36718538 PMCID: PMC10450309 DOI: 10.1177/00368504221147173] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Colorectal cancer (CRC) can be resistant to platinum drugs, possibly through ferroptosis suppression, albeit the need for further work to completely understand this mechanism. This work aimed to sum up current findings pertaining to oxaliplatin resistance (OR) or resistance to ascertain the potential of ferroptosis to regulate oxaliplatin effects. In this review, tumor development relating to iron homeostasis, which includes levels of iron that ascertain cells' sensitivity to ferroptosis, oxidative stress, or lipid peroxidation in colorectal tumor cells that are connected with ferroptosis initiation, especially the role of c-Myc/NRF2 signaling in regulating iron homeostasis, coupled with NRF2/GPX4-mediated ferroptosis are discussed. Importantly, ferroptosis plays a key role in OR and ferroptotic induction may substantially reverse OR in CRC cells, which in turn could inhibit the imbalance of intracellular redox induced by oxaliplatin and ferroptosis, as well as cause chemotherapeutic resistance in CRC. Furthermore, fundamental research of small molecules, ferroptosis inducers, GPX4 inhibitors, or natural products for OR coupled with their clinical applications in CRC have also been summarized. Also, potential molecular targets and mechanisms of small molecules or drugs are discussed as well. Suggestively, OR of CRC cells could significantly be reversed by ferroptosis induction, wherein this result is discussed in the current review. Prospectively, the existing literature discussed in this review will provide a solid foundation for scientists to research the potential use of combined anticancer drugs which can overcome OR via targeting various mechanisms of ferroptosis. Especially, promising therapeutic strategies, challenges ,and opportunities for CRC therapy will be discussed.
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Affiliation(s)
- Gang Wang
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai, China
| | - Jun-Jie Wang
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai, China
| | - Zhu Zhi-Min
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai, China
| | - Xiao-Na Xu
- Department of Medicine, Jiangsu University, Zhenjiang City, Jiangsu Province, China
| | - Feng Shi
- Department of Medicine, Jiangsu University, Zhenjiang City, Jiangsu Province, China
| | - Xing-Li Fu
- Department of Medicine, Jiangsu University, Zhenjiang City, Jiangsu Province, China
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14
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Tsimberidou AM, Fountzilas E, Bleris L, Kurzrock R. Transcriptomics and solid tumors: The next frontier in precision cancer medicine. Semin Cancer Biol 2022; 84:50-59. [PMID: 32950605 PMCID: PMC11927324 DOI: 10.1016/j.semcancer.2020.09.007] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 08/16/2020] [Accepted: 09/09/2020] [Indexed: 01/08/2023]
Abstract
Transcriptomics, which encompasses assessments of alternative splicing and alternative polyadenylation, identification of fusion transcripts, explorations of noncoding RNAs, transcript annotation, and discovery of novel transcripts, is a valuable tool for understanding cancer mechanisms and identifying biomarkers. Recent advances in high-throughput technologies have enabled large-scale gene expression profiling. Importantly, RNA expression profiling of tumor tissue has been successfully used to determine clinically actionable molecular alterations. The WINTHER precision medicine clinical trial was the first prospective trial in diverse solid malignancies that assessed both genomics and transcriptomics to match treatments to specific molecular alterations. The use of transcriptome analysis in WINTHER and other trials increased the number of targetable -omic changes compared to genomic profiling alone. Other applications of transcriptomics involve the evaluation of tumor and circulating noncoding RNAs as predictive and prognostic biomarkers, the improvement of risk stratification by the use of prognostic and predictive multigene assays, the identification of fusion transcripts that drive tumors, and an improved understanding of the impact of DNA changes as some genomic alterations are silenced at the RNA level. Finally, RNA sequencing and gene expression analysis have been incorporated into clinical trials to identify markers predicting response to immunotherapy. Many issues regarding the complexity of the analysis, its reproducibility and variability, and the interpretation of the results still need to be addressed. The integration of transcriptomics with genomics, proteomics, epigenetics, and tumor immune profiling will improve biomarker discovery and our understanding of disease mechanisms and, thereby, accelerate the implementation of precision oncology.
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Affiliation(s)
- Apostolia M Tsimberidou
- The University of Texas MD Anderson Cancer Center, Department of Investigational Cancer Therapeutics, Houston, TX, USA.
| | - Elena Fountzilas
- Department of Medical Oncology, Euromedica General Clinic, Thessaloniki, Greece
| | - Leonidas Bleris
- Bioengineering Department, The University of Texas at Dallas, Richardson, TX, USA
| | - Razelle Kurzrock
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, UC San Diego Moores Cancer Center, San Diego, CA, USA
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15
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Wang Y, Zhang Z, Sun W, Zhang J, Xu Q, Zhou X, Mao L. Ferroptosis in colorectal cancer: Potential mechanisms and effective therapeutic targets. Biomed Pharmacother 2022; 153:113524. [PMID: 36076606 DOI: 10.1016/j.biopha.2022.113524] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 08/03/2022] [Accepted: 08/08/2022] [Indexed: 01/17/2023] Open
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16
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Xie W, Chu M, Song G, Zuo Z, Han Z, Chen C, Li Y, Wang ZW. Emerging roles of long noncoding RNAs in chemoresistance of pancreatic cancer. Semin Cancer Biol 2022; 83:303-318. [PMID: 33207266 DOI: 10.1016/j.semcancer.2020.11.004] [Citation(s) in RCA: 79] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/04/2020] [Accepted: 11/05/2020] [Indexed: 02/08/2023]
Abstract
Pancreatic cancer is one of the most common causes of cancer death in the world due to the lack of early symptoms, metastasis occurrence and chemoresistance. Therefore, early diagnosis by detection of biomarkers, blockade of metastasis, and overcoming chemoresistance are the effective strategies to improve the survival of pancreatic cancer patients. Accumulating evidence has revealed that long noncoding RNA (lncRNA) and circular RNAs (circRNAs) play essential roles in modulating chemosensitivity in pancreatic cancer. In this review article, we will summarize the role of lncRNAs in drug resistance of pancreatic cancer cells, including HOTTIP, HOTAIR, PVT1, linc-ROR, GAS5, UCA1, DYNC2H1-4, MEG3, TUG1, HOST2, HCP5, SLC7A11-AS1 and CASC2. We also highlight the function of circRNAs, such as circHIPK3 and circ_0000284, in regulation of drug sensitivity of pancreatic cancer cells. Moreover, we describe a number of compounds, including curcumin, genistein, resveratrol, quercetin, and salinomycin, which may modulate the expression of lncRNAs and enhance chemosensitivity in pancreatic cancers. Therefore, targeting specific lncRNAs and cicrRNAs could contribute to reverse chemoresistance of pancreatic cancer cells. We hope this review might stimulate the studies of lncRNAs and cicrRNAs, and develop the new therapeutic strategy via modulating these noncoding RNAs to promote chemosensitivity of pancreatic cancer cells.
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Affiliation(s)
- Wangkai Xie
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China
| | - Man Chu
- Center of Scientific Research, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Gendi Song
- Center of Scientific Research, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Ziyi Zuo
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China
| | - Zheng Han
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China
| | - Chenbin Chen
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China
| | - Yuyun Li
- Bengbu Medical College Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, School of Laboratory Medicine, Bengbu Medical College, Anhui, 233030, China.
| | - Zhi-Wei Wang
- Center of Scientific Research, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China.
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17
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Lin Y, Liao X, Zhang Y, Wu G, Ye J, Luo S, He X, Luo M, Xie M, Zhang J, Li Q, Huang Y, Liao S, Li Y, Liang R. Homologous Recombination Pathway Alternation Predicts Prognosis of Colorectal Cancer With Chemotherapy. Front Pharmacol 2022; 13:920939. [PMID: 35734400 PMCID: PMC9207269 DOI: 10.3389/fphar.2022.920939] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 05/23/2022] [Indexed: 11/28/2022] Open
Abstract
Background: Chemotherapy is the basic treatment for colorectal cancer (CRC). However, colorectal cancer cells often develop resistance to chemotherapy drugs, leading to recurrence and poor prognosis. More and more studies have shown that the Homologous recombination (HR) pathway plays an important role in chemotherapy treatment for tumors. However, the relationship between HR pathway, chemotherapy sensitivity, and the prognosis of CRC patients is still unclear. Methods: We collected 35 samples of CRC patients after chemotherapy treatment from Guangxi Medical University Cancer Hospital, then collected mutation data and clinical prognosis data from the group. We also downloaded Mondaca-CRC, TCGA-CRC cohorts for chemotherapy treatment. Result: We found that HR mutant-type (HR-MUT) patients are less likely to experience tumor metastasis after receiving chemotherapy. Additionally, our univariate and multivariate cox regression models showed that HR-MUT can be used as an independent predictor of the prognosis of chemotherapy for CRC patients. The KM curve showed that patients with HR-MUT CRC had significantly prolonged overall survival (OS) time (log-rank p = 0.017; hazard ratio (HR) = 0.69). Compared to HR mutant-type (HR-WT), HR-MUT has a significantly lower IC50 value with several chemotherapeutic drugs. Pathway enrichment analysis further revealed that the HR-MUT displayed a significantly lower rate of DNA damage repair ability, tumor growth, metastasis activity, and tumor fatty acid metabolism activity than HR-WT, though its immune response activity was notably higher. Conclusion: These findings indicate that HR-MUT may be a relevant marker for CRC patients receiving chemotherapy, as it is closely related to improving OS time and reducing chemotherapy resistance.
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Affiliation(s)
- Yan Lin
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xiaoli Liao
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yumei Zhang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Guobin Wu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jiazhou Ye
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Shanshan Luo
- Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xinxin He
- Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Min Luo
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Mingzhi Xie
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jinyan Zhang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Qian Li
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yu Huang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Sina Liao
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yongqiang Li
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
- *Correspondence: Rong Liang, ; Yongqiang Li,
| | - Rong Liang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
- *Correspondence: Rong Liang, ; Yongqiang Li,
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18
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Targeting non-coding RNAs to overcome cancer therapy resistance. Signal Transduct Target Ther 2022; 7:121. [PMID: 35418578 PMCID: PMC9008121 DOI: 10.1038/s41392-022-00975-3] [Citation(s) in RCA: 233] [Impact Index Per Article: 77.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 03/07/2022] [Accepted: 03/07/2022] [Indexed: 02/07/2023] Open
Abstract
It is now well known that non-coding RNAs (ncRNAs), rather than protein-coding transcripts, are the preponderant RNA transcripts. NcRNAs, particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are widely appreciated as pervasive regulators of multiple cancer hallmarks such as proliferation, apoptosis, invasion, metastasis, and genomic instability. Despite recent discoveries in cancer therapy, resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy continue to be a major setback. Recent studies have shown that ncRNAs also play a major role in resistance to different cancer therapies by rewiring essential signaling pathways. In this review, we present the intricate mechanisms through which dysregulated ncRNAs control resistance to the four major types of cancer therapies. We will focus on the current clinical implications of ncRNAs as biomarkers to predict treatment response (intrinsic resistance) and to detect resistance to therapy after the start of treatment (acquired resistance). Furthermore, we will present the potential of targeting ncRNA to overcome cancer treatment resistance, and we will discuss the challenges of ncRNA-targeted therapy—especially the development of delivery systems.
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19
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Sun Y, Hao G, Zhuang M, Lv H, Liu C, Su K. MEG3 LncRNA from Exosomes Released from Cancer-Associated Fibroblasts Enhances Cisplatin Chemoresistance in SCLC via a MiR-15a-5p/CCNE1 Axis. Yonsei Med J 2022; 63:229-240. [PMID: 35184425 PMCID: PMC8860932 DOI: 10.3349/ymj.2022.63.3.229] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 11/05/2021] [Accepted: 11/16/2021] [Indexed: 11/27/2022] Open
Abstract
PURPOSE Long non-coding RNAs (lncRNAs) may act as oncogenes in small-cell lung cancer (SCLC). Exosomes containing lncRNAs released from cancer-associated fibroblasts (CAF) accelerate tumorigenesis and confer chemoresistance. This study aimed to explore the action mechanism of the CAF-derived lncRNA maternally expressed gene 3 (MEG3) on cisplatin (DDP) chemoresistance and cell processes in SCLC. MATERIALS AND METHODS Quantitative real-time PCR was conducted to determine the expression levels of MEG3, miR-15a-5p, and CCNE1. Cell viability and metastasis were measured by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-h-tetrazolium bromide and invasion assays, respectively. A xenograft tumor model was developed to confirm the effect of MEG3 overexpression on SCLC progression in vivo. Relationships between miR-15a-5p and MEG3/CCNE1 were predicted using StarBase software and validated by dual luciferase reporter assay. Western blotting was used to determine protein levels. A co-culture model was established to explore the effects of exosomes on MEG3 expression in SCLC cell lines. RESULTS MEG3 was overexpressed in SCLC tissues and cells. MEG3 silencing significantly repressed cell viability and metastasis in SCLC. High expression of MEG3 was observed in CAF-derived conditioned medium (CM) and exosomes, and promoted chemoresistance and cancer progression. Additionally, MEG3 was found to serve as a sponge of miR-15a-5p to mediate CCNE1 expression. Overexpression of miR-15a-5p and knockout of CCNE1 reversed the effects of MEG3 overexpression on cell viability and metastasis. CONCLUSION MEG3 lncRNA released from CAF-derived exosomes promotes DDP chemoresistance via regulation of a miR-15a-5p/CCNE1 axis. These findings may provide insight into SCLC therapy.
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Affiliation(s)
- Yulu Sun
- Department of Oncology, The Fourth People's Hospital of Jinan, Jinan, China
| | - Guijun Hao
- Department of Oncology, The Fourth People's Hospital of Jinan, Jinan, China
| | - Mengqi Zhuang
- Department of Oncology, The Fourth People's Hospital of Jinan, Jinan, China
| | - Huijuan Lv
- Department of Oncology, The Third Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Chunhong Liu
- Department of Oncology, The Fourth People's Hospital of Jinan, Jinan, China
| | - Keli Su
- Department of Oncology, The Fourth People's Hospital of Jinan, Jinan, China.
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20
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Hemmati-Dinarvand M, Ahmadvand H, Seghatoleslam A. Nitazoxanide and Cancer Drug Resistance: Targeting Wnt/β-catenin Signaling Pathway. Arch Med Res 2021; 53:263-270. [DOI: 10.1016/j.arcmed.2021.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 11/24/2021] [Accepted: 12/07/2021] [Indexed: 11/02/2022]
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21
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Payandeh Z, Pirpour Tazehkand A, Mansoori B, Khaze V, Asadi M, Baradaran B, Samadi N. The Impact of Nrf2 Silencing on Nrf2-PD-L1 Axis to Overcome Oxaliplatin Resistance and Migration in Colon Cancer Cells. Avicenna J Med Biotechnol 2021; 13:116-122. [PMID: 34484640 PMCID: PMC8377400 DOI: 10.18502/ajmb.v13i3.6371] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 02/06/2021] [Indexed: 11/24/2022] Open
Abstract
Background: Nuclear factor-erythroid 2-related factor 2 (Nrf2) plays a key role in promoting chemoresistance in various cancers. PD-L1 is one of the downstream targets of the Nrf2 signaling pathway. This molecule has some beneficial impacts on tumors growth by inhibition of the immune system. This study aimed to investigate the potential role of the Nrf2-PD-L1 axis in the promotion of oxaliplatin resistance in colon cancer cells. Methods: We examined Nrf2, PD- L1, and CD80 expression in the tumor and margin tissue samples from CRC patients. After that role of the Nrf2-PD-L1 axis in promotion of Oxaliplatin resistance was investigated. Results: Our data revealed that Nrf2 and PD-L1 mRNA expressions were markedly higher in tumor tissues compared to margin tissues. The PD-L1 mRNA expression level was also increased in the resistant cells. However, Nrf2 expression was decreased in SW480/Res cells and increased in LS174T/Res cells. The inhibition of Nrf2 through siRNA treatment in SW480/Res and LS174T/Res cells has decreased the IC50 values of oxaliplatin. Inhibition of the Nrf2 has significantly increased the oxaliplatin-induced apoptosis, and reduced the migration in SW480/Res cells. Conclusion: It is suggested that effective inhibition of Nrf2-PD-L1 signaling pathways can be considered as a novel approach to improve oxaliplatin efficacy in colon cancer patients.
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Affiliation(s)
- Zahra Payandeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abbas Pirpour Tazehkand
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, 5000, Odense, Denmark.,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahid Khaze
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Milad Asadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasser Samadi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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22
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Research updates on the clinical implication of long noncoding RNA in digestive system cancers and chemoresistance. 3 Biotech 2021; 11:423. [PMID: 34603923 DOI: 10.1007/s13205-021-02971-w] [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: 03/20/2021] [Accepted: 08/19/2021] [Indexed: 10/20/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) are implicated in various biological processes, such as cell proliferation, differentiation, apoptosis, migration, and invasion. They are also key players in various biological pathways. LncRNA was considered as 'translational noise' before 1980s. It has been reported that lncRNAs are aberrantly expressed in different cancers, either as oncogene or tumor suppressor gene. Therefore, more and more lncRNAs are recognized as potential diagnostic biomarkers and/or therapeutic targets. As competitive endogenous RNA, lncRNAs can interact with microRNA to alter the expression of target genes, which may have extensive clinical implications in cancers, including diagnosis, treatment, prognosis, and chemoresistance. This review comprehensively summarizes the functions and clinical relevance of lncRNAs in digestive system cancers, especially as a potential tool to overcome chemoresistance.
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23
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Circulating non-coding RNAs as new biomarkers and novel therapeutic targets in colorectal cancer. Clin Transl Oncol 2021; 23:2220-2236. [PMID: 34275108 DOI: 10.1007/s12094-021-02639-0] [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: 10/14/2020] [Accepted: 05/06/2021] [Indexed: 12/24/2022]
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors, and a large number of patients are diagnosed and die every year. Due to the lack of appropriate diagnosis, prediction and treatment, early diagnosis rate of CRC is low and the prognosis is poor. Studies have found that abnormally expressed non-coding RNAs (ncRNAs) (including microRNAs (miRNAs), circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs),etc.) play an important regulatory role in the occurrence and development of CRC. Some studies have shown that they are stable in the blood and can be detected repeatedly. They are expected to be non-invasive biomarkers for early diagnosis, prognosis evaluation, and prediction of drug sensitivity of CRC, as well as potential applications in the treatment of CRC.
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Micallef I, Baron B. The Mechanistic Roles of ncRNAs in Promoting and Supporting Chemoresistance of Colorectal Cancer. Noncoding RNA 2021; 7:24. [PMID: 33807355 PMCID: PMC8103280 DOI: 10.3390/ncrna7020024] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 03/03/2021] [Accepted: 03/29/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal Cancer (CRC) is one of the most common gastrointestinal malignancies which has quite a high mortality rate. Despite the advances made in CRC treatment, effective therapy is still quite challenging, particularly due to resistance arising throughout the treatment regimen. Several studies have been carried out to identify CRC chemoresistance mechanisms, with research showing different signalling pathways, certain ATP binding cassette (ABC) transporters and epithelial mesenchymal transition (EMT), among others to be responsible for the failure of CRC chemotherapies. In the last decade, it has become increasingly evident that certain non-coding RNA (ncRNA) families are involved in chemoresistance. Research investigations have demonstrated that dysregulation of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) contribute towards promoting resistance in CRC via different mechanisms. Considering the currently available data on this phenomenon, a better understanding of how these ncRNAs participate in chemoresistance can lead to suitable solutions to overcome this problem in CRC. This review will first focus on discussing the different mechanisms of CRC resistance identified so far. The focus will then shift onto the roles of miRNAs, lncRNAs and circRNAs in promoting 5-fluorouracil (5-FU), oxaliplatin (OXA), cisplatin and doxorubicin (DOX) resistance in CRC, specifically using ncRNAs which have been recently identified and validated under in vivo or in vitro conditions.
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Affiliation(s)
| | - Byron Baron
- Centre for Molecular Medicine and Biobanking, University of Malta, MSD2080 Msida, Malta;
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Poursheikhani A, Abbaszadegan MR, Kerachian MA. Mechanisms of long non-coding RNA function in colorectal cancer tumorigenesis. Asia Pac J Clin Oncol 2020; 17:7-23. [PMID: 32970938 DOI: 10.1111/ajco.13452] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 08/03/2020] [Indexed: 12/14/2022]
Abstract
Colorectal cancer (CRC) is one of the most common cancers globally. Although a variety of CRC screening methods have been developed, many patients are diagnosed at advanced stages of CRC with tumor invasion and distance metastasis. Several studies have suggested the long noncoding RNAs (lncRNAs) as one of the main contributors in CRC tumorigenesis, although the exact underlying mechanism of lncRNAs in CRC is still unknown. Numerous studies have indicated aberrant expression of lncRNAs in CRC through different modes of action such as cell proliferation, apoptosis, cell cycle, DNA repair response, drug-resistance, migration, and metastasis. Furthermore, lncRNA polymorphisms can influence the risk of CRC development. Accordingly, lncRNAs can be served as promising diagnostic or prognostic biomarkers and also desired therapeutic targets affecting the outcome of patients with CRC. In this review, we summarized the updated and novel evidence that identifies different roles of lncRNAs in the tumorigenesis of CRC.
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Affiliation(s)
- Arash Poursheikhani
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Abbaszadegan
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Amin Kerachian
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Cancer Genetics Research Unit, Reza Radiotherapy, and Oncology Center, Mashhad, Iran
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Vacante M, Ciuni R, Basile F, Biondi A. The Liquid Biopsy in the Management of Colorectal Cancer: An Overview. Biomedicines 2020; 8:E308. [PMID: 32858879 PMCID: PMC7555636 DOI: 10.3390/biomedicines8090308] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 08/19/2020] [Accepted: 08/24/2020] [Indexed: 02/07/2023] Open
Abstract
Currently, there is a crucial need for novel diagnostic and prognostic biomarkers with high specificity and sensitivity in patients with colorectal cancer. A "liquid biopsy" is characterized by the isolation of cancer-derived components, such as circulating tumor cells, circulating tumor DNA, microRNAs, long non-coding RNAs, and proteins, from peripheral blood or other body fluids and their genomic or proteomic assessment. The liquid biopsy is a minimally invasive and repeatable technique that could play a significant role in screening and diagnosis, and predict relapse and metastasis, as well as monitoring minimal residual disease and chemotherapy resistance in colorectal cancer patients. However, there are still some practical issues that need to be addressed before liquid biopsy can be widely used in clinical practice. Potential challenges may include low amounts of circulating tumor cells and circulating tumor DNA in samples, lack of pre-analytical and analytical consensus, clinical validation, and regulatory endorsement. The aim of this review was to summarize the current knowledge of the role of liquid biopsy in the management of colorectal cancer.
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Affiliation(s)
- Marco Vacante
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Via S. Sofia 78, 95123 Catania, Italy; (R.C.); (F.B.); (A.B.)
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The potential impact of trigonelline loaded micelles on Nrf2 suppression to overcome oxaliplatin resistance in colon cancer cells. Mol Biol Rep 2020; 47:5817-5829. [PMID: 32661875 DOI: 10.1007/s11033-020-05650-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 07/08/2020] [Indexed: 12/12/2022]
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) has a pivotal role in promoting chemoresistance by regulation of antioxidants and detoxification enzymes. Trigonelline is one of the major alkaloids in raw coffee which has been recently introduced as potent inhibitor of Nrf2. This study investigated the role of trigonelline and trigonelline loaded micelles in Nrf2 inhibition to break down oxaliplatin resistance in colon cancer cells. The PCL-PEG-PCL and PLA-PCL-PEG-PCL-PLA copolymers and trigonelline loaded micelles were prepared and characterized for fourier transforms infrared (FTIR), hydrogen nuclear magnetic resonance (1H-NMR), carbon nuclear magnetic resonance (13C-NMR) spectroscopy, particle size, zeta potential, scanning electron microscopy (SEM) and entrapment efficiency. Cell viability and apoptosis were evaluated by using MTT and flow cytometry assays, respectively. Nrf2, MRP1, NQO1, HO-1, Bax, and Bcl2 gene expressions were examined by qRT-PCR. Our results revealed that micelles had spherical shapes with narrow sizes and zeta potential indexes of - 9.06 ± 6.94 mV for trigonelline loaded 3Block and - 7.47 ± 6.08 mV for trigonelline loaded 5Block micelles. After Nrf2 inhibition by trigonelline, antioxidant response element (ARE) related gene expressions were decreased (p < 0.05) with a significantly higher impact by trigonelline loaded micelles (p < 0.05). Trigonelline loaded micelles also strongly decreased IC50 value of oxaliplatin in resistant colon cancer cells (p < 0.05). Furthermore, trigonelline loaded 5Block micelle increased oxaliplatin-induced apoptosis in a Nrf2/ARE dependent manner. Altogether, the current study suggests that delivery of trigonelline loaded micelles as potent Nrf2 inhibitors can be considered as a promising strategy to overcome oxaliplatin resistance in colon cancer patients.
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Qi FF, Yang Y, Zhang H, Chen H. Long non-coding RNAs: Key regulators in oxaliplatin resistance of colorectal cancer. Biomed Pharmacother 2020; 128:110329. [PMID: 32502843 DOI: 10.1016/j.biopha.2020.110329] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 05/22/2020] [Accepted: 05/23/2020] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies in the world with high relapse and mortality rates. Although oxaliplatin (OXA), a platinum-based anticancer drug, is widely used in CRC treatment, the resulting chemoresistance dramatically attenuates the drug efficacy and increases the failure rate of this therapy. Thus, the study on OXA-induced chemoresistance is extremely urgent. In recent years, emerging evidence has shown that lncRNAs play irreplaceable roles in drug resistance. However, we only have a limited knowledge of the lncRNAs that are closely related to oxaliplatin resistance in CRC. In present study, we identify and characterize these lncRNAs, including their functions, underlying mechanisms and possible applications.
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Affiliation(s)
- Fang-Fang Qi
- Department of Histology and Embryology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, PR China; Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Yunyao Yang
- Department of Histology and Embryology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, PR China; Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Haowen Zhang
- Department of Histology and Embryology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, PR China; Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Hongping Chen
- Department of Histology and Embryology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, PR China; Jiangxi Key Laboratory of Experimental Animals, Nanchang University, Nanchang, Jiangxi 330006, PR China.
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Russano M, Napolitano A, Ribelli G, Iuliani M, Simonetti S, Citarella F, Pantano F, Dell'Aquila E, Anesi C, Silvestris N, Argentiero A, Solimando AG, Vincenzi B, Tonini G, Santini D. Liquid biopsy and tumor heterogeneity in metastatic solid tumors: the potentiality of blood samples. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:95. [PMID: 32460897 PMCID: PMC7254767 DOI: 10.1186/s13046-020-01601-2] [Citation(s) in RCA: 152] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 05/20/2020] [Indexed: 12/14/2022]
Abstract
In a large number of cancer types, treatment selection depends on the presence of specific tumor biomarkers. Due to the dynamic nature of cancer, very often these predictive biomarkers are not uniformly present in all cancer cells. Tumor heterogeneity represents indeed one of the main causes of therapeutic failure, and its decoding remains a major ongoing challenge in the field. Liquid biopsy is the sampling and analysis of non-solid biological tissue often through rapid and non-invasive methods, which allows the assessment in real-time of the evolving landscape of cancer. Samples can be obtained from blood and most other bodily fluids. A blood-based liquid biopsy can capture circulating tumor cells and leukocytes, as well as circulating tumor-derived nucleic acids. In this review, we discuss the current and possibly future applications of blood-based liquid biopsy in oncology, its advantages and its limitations in clinical practice. We specifically focused on its role as a tool to capture tumor heterogeneity in metastatic cancer patients.
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Affiliation(s)
- Marco Russano
- Department of Medical Oncology, Campus Bio-Medico University of Rome, Álvaro del Portillo, 21, 00128, Rome, Italy
| | - Andrea Napolitano
- Department of Medical Oncology, Campus Bio-Medico University of Rome, Álvaro del Portillo, 21, 00128, Rome, Italy
| | - Giulia Ribelli
- Department of Medical Oncology, Campus Bio-Medico University of Rome, Álvaro del Portillo, 21, 00128, Rome, Italy.
| | - Michele Iuliani
- Department of Medical Oncology, Campus Bio-Medico University of Rome, Álvaro del Portillo, 21, 00128, Rome, Italy
| | - Sonia Simonetti
- Department of Medical Oncology, Campus Bio-Medico University of Rome, Álvaro del Portillo, 21, 00128, Rome, Italy
| | - Fabrizio Citarella
- Department of Medical Oncology, Campus Bio-Medico University of Rome, Álvaro del Portillo, 21, 00128, Rome, Italy
| | - Francesco Pantano
- Department of Medical Oncology, Campus Bio-Medico University of Rome, Álvaro del Portillo, 21, 00128, Rome, Italy
| | - Emanuela Dell'Aquila
- Department of Medical Oncology, Campus Bio-Medico University of Rome, Álvaro del Portillo, 21, 00128, Rome, Italy
| | - Cecilia Anesi
- Department of Medical Oncology, Campus Bio-Medico University of Rome, Álvaro del Portillo, 21, 00128, Rome, Italy
| | - Nicola Silvestris
- Medical Oncology Unit, IRCCS-Istituto Tumori "Giovanni Paolo II" of Bari, 70124, Bari, Italy.,Department of Biomedical Sciences and Human Oncology, University of Bari 'Aldo Moro', 70124, Bari, Italy
| | - Antonella Argentiero
- Medical Oncology Unit, IRCCS-Istituto Tumori "Giovanni Paolo II" of Bari, 70124, Bari, Italy
| | - Antonio Giovanni Solimando
- Medical Oncology Unit, IRCCS-Istituto Tumori "Giovanni Paolo II" of Bari, 70124, Bari, Italy.,Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine 'G. Baccelli', University of Bari Medical School, 70124, Bari, Italy
| | - Bruno Vincenzi
- Department of Medical Oncology, Campus Bio-Medico University of Rome, Álvaro del Portillo, 21, 00128, Rome, Italy
| | - Giuseppe Tonini
- Department of Medical Oncology, Campus Bio-Medico University of Rome, Álvaro del Portillo, 21, 00128, Rome, Italy
| | - Daniele Santini
- Department of Medical Oncology, Campus Bio-Medico University of Rome, Álvaro del Portillo, 21, 00128, Rome, Italy
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Rodrigues de Bastos D, Nagai MA. In silico analyses identify lncRNAs: WDFY3-AS2, BDNF-AS and AFAP1-AS1 as potential prognostic factors for patients with triple-negative breast tumors. PLoS One 2020; 15:e0232284. [PMID: 32401758 PMCID: PMC7219740 DOI: 10.1371/journal.pone.0232284] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 04/10/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs) are characterized as having 200 nucleotides or more and not coding any protein, and several been identified as differentially expressed in several human malignancies, including breast cancer. METHODS Here, we evaluated lncRNAs differentially expressed in triple-negative breast cancer (TNBC) from a cDNA microarray data set obtained in a previous study from our group. Using in silico analyses in combination with a review of the current literature, we identify three lncRNAs as potential prognostic factors for TNBC patients. RESULTS We found that the expression of WDFY3-AS2, BDNF-AS, and AFAP1-AS1 was associated with poor survival in patients with TNBCs. WDFY3-AS2 and BDNF-AS are lncRNAs known to play an important role in tumor suppression of different types of cancer, while AFAP1-AS1 exerts oncogenic activity. CONCLUSION Our findings provided evidence that WDFY3-AS2, BDNF-AS, and AFAP1-AS1 may be potential prognostic factors in TNBC development.
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Affiliation(s)
- Daniel Rodrigues de Bastos
- Discipline of Oncology, Department of Radiology and Oncology, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
- Laboratory of Molecular Genetics, Center for Translational Research in Oncology, Cancer Institute of São Paulo, São Paulo, Brazil
| | - Maria A. Nagai
- Discipline of Oncology, Department of Radiology and Oncology, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
- Laboratory of Molecular Genetics, Center for Translational Research in Oncology, Cancer Institute of São Paulo, São Paulo, Brazil
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Jiang W, Xia J, Xie S, Zou R, Pan S, Wang ZW, Assaraf YG, Zhu X. Long non-coding RNAs as a determinant of cancer drug resistance: Towards the overcoming of chemoresistance via modulation of lncRNAs. Drug Resist Updat 2020; 50:100683. [DOI: 10.1016/j.drup.2020.100683] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 02/18/2020] [Accepted: 02/21/2020] [Indexed: 12/11/2022]
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Ali MA, Shaker OG, Alazrak M, AbdelHafez MN, Khalefa AA, Hemeda NF, Abdelmoktader A, Ahmed FA. Association analyses of a genetic variant in long non-coding RNA MEG3 with breast cancer susceptibility and serum MEG3 expression level in the Egyptian population. Cancer Biomark 2020; 28:49-63. [PMID: 32176630 DOI: 10.3233/cbm-191072] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND LncRNA MEG3 rs7158663 has been shown to confer cancer susceptibility, maybe through altering its gene expression level. OBJECTIVE We aimed to weigh the effect of rs7158663 on MEG3 serum level and breast cancer susceptibility. METHODS We genotyped rs7158663 G > A and measured serum MEG3 in 150 breast cancer, 95 fibroadenoma , and 154 controls by the TaqMan method. RESULTS The presence of rs7158663 G > A is a risk factor for breast cancer among fibroadenoma patients and controls, AA vs. GG genotypes (OR = 6.320, 95% CI = 2.587-15.439, P< 0.0001 when compared to controls and OR = 10.825, 95% CI = 1.929-60.742, P= 0.007 when compared to fibroadenoma). Decreased serum MEG3 was observed in breast cancer group when compared with fibroadenoma and/or controls [median (IQR) = 0.43 (0.27-0.55)] (P< 0.0001). However, increased serum MEG3 was noted in fibroadenoma group when compared with controls (P< 0.0001). A significance decreased serum MEG3 was found to be associated with mutant A allele than with wild G allele (P< 0.0001). The results showed that rs7158663 and lower MEG3 were significantly associated with patients with higher TNM staging and larger tumor size > 5 cm. CONCLUSION The presence of both rs7158663 and low MEG3 are diagnostic and unfavorable prognostic factors for BC patients.
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Affiliation(s)
- Marwa A Ali
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Olfat G Shaker
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | - Marwa N AbdelHafez
- Department of Medical Oncology, National Cancer Institute, Cairo University, Egypt
| | - Abeer A Khalefa
- Department of Physiology, Faculty of Medicine, Zagazig University, Egypt
| | - Nada F Hemeda
- Department of Genetics, Faculty of Agriculture, Fayoum University, Fayoum, Egypt
| | - Abdelrahman Abdelmoktader
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Fatma A Ahmed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
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Mohamed DI, Khairy E, Khedr SA, Habib EK, Elayat WM, El-Kharashi OA. N-acetylcysteine (NAC) alleviates the peripheral neuropathy associated with liver cirrhosis via modulation of neural MEG3/PAR2/ NF-ҡB axis. Neurochem Int 2019; 132:104602. [PMID: 31751619 DOI: 10.1016/j.neuint.2019.104602] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 11/07/2019] [Accepted: 11/11/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Oxidative stress (OS) is accused in pathogenesis of many diseases, including liver cirrhosis by many mechanisms. One of them is the disturbance of long non coding maternally expressed 3 (MEG3)/protease activated receptor 2 (PAR2) downstream pathway. We aimed to investigate the role of this axis in cirrhotic neuropathy and whether an antioxidant compound such as N-acetylcysteine (NAC) could improve the peripheral nerve function through repression of MEG3/PAR2. METHODS Thirty Wistar rats were used and divided into 5 groups; naive, thiacetamide (TAA) (200 mg/kg 3 times/week. i.p. for 8 weeks) and TAA+NAC (50 or 100 or 200 mg/kg/day) groups. Von Frey (VF) test for mechanical nociceptive responses, hepatic& neural MEG3, NF-ҡB and neural PAR2 expression by PCR, histological studies for liver and sciatic nerve together with the dorsopedal skin thickness were done. RESULTS TAA induced significant decrease in liver function, negative VF test, an increase in the expression of hepatic& neural MEG3, NF-ҡB and neural PAR2. The histological studies showed cirrhotic changes with atrophy of the sciatic nerve and the dorsal skin. NAC improved the liver function together with reversal of the neural: functional, biochemical and histological changes in a dose dependent manner. CONCLUSIONS NAC could improve the peripheral neuropathy in cirrhotic rat through suppression of MEG3/PAR2 expression.
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Affiliation(s)
- Doaa I Mohamed
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Eman Khairy
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Sara A Khedr
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Eman K Habib
- Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Wael M Elayat
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Omnyah A El-Kharashi
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
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Wang L, Cho KB, Li Y, Tao G, Xie Z, Guo B. Long Noncoding RNA (lncRNA)-Mediated Competing Endogenous RNA Networks Provide Novel Potential Biomarkers and Therapeutic Targets for Colorectal Cancer. Int J Mol Sci 2019; 20:E5758. [PMID: 31744051 PMCID: PMC6888455 DOI: 10.3390/ijms20225758] [Citation(s) in RCA: 440] [Impact Index Per Article: 73.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 11/12/2019] [Accepted: 11/14/2019] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer and has a high metastasis and reoccurrence rate. Long noncoding RNAs (lncRNAs) play an important role in CRC growth and metastasis. Recent studies revealed that lncRNAs participate in CRC progression by coordinating with microRNAs (miRNAs) and protein-coding mRNAs. LncRNAs function as competitive endogenous RNAs (ceRNAs) by competitively occupying the shared binding sequences of miRNAs, thus sequestering the miRNAs and changing the expression of their downstream target genes. Such ceRNA networks formed by lncRNA/miRNA/mRNA interactions have been found in a broad spectrum of biological processes in CRC, including liver metastasis, epithelial to mesenchymal transition (EMT), inflammation formation, and chemo-/radioresistance. In this review, we summarize typical paradigms of lncRNA-associated ceRNA networks, which are involved in the underlying molecular mechanisms of CRC initiation and progression. We comprehensively discuss the competitive crosstalk among RNA transcripts and the novel targets for CRC prognosis and therapy.
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Affiliation(s)
- Liye Wang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX,77204, USA; (K.B.C.); (Y.L.); (G.T.); (Z.X.)
| | | | | | | | | | - Bin Guo
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX,77204, USA; (K.B.C.); (Y.L.); (G.T.); (Z.X.)
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Nath A, Lau EYT, Lee AM, Geeleher P, Cho WCS, Huang RS. Discovering long noncoding RNA predictors of anticancer drug sensitivity beyond protein-coding genes. Proc Natl Acad Sci U S A 2019; 116:22020-22029. [PMID: 31548386 PMCID: PMC6825320 DOI: 10.1073/pnas.1909998116] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Large-scale cancer cell line screens have identified thousands of protein-coding genes (PCGs) as biomarkers of anticancer drug response. However, systematic evaluation of long noncoding RNAs (lncRNAs) as pharmacogenomic biomarkers has so far proven challenging. Here, we study the contribution of lncRNAs as drug response predictors beyond spurious associations driven by correlations with proximal PCGs, tissue lineage, or established biomarkers. We show that, as a whole, the lncRNA transcriptome is equally potent as the PCG transcriptome at predicting response to hundreds of anticancer drugs. Analysis of individual lncRNAs transcripts associated with drug response reveals nearly half of the significant associations are in fact attributable to proximal cis-PCGs. However, adjusting for effects of cis-PCGs revealed significant lncRNAs that augment drug response predictions for most drugs, including those with well-established clinical biomarkers. In addition, we identify lncRNA-specific somatic alterations associated with drug response by adopting a statistical approach to determine lncRNAs carrying somatic mutations that undergo positive selection in cancer cells. Lastly, we experimentally demonstrate that 2 lncRNAs, EGFR-AS1 and MIR205HG, are functionally relevant predictors of anti-epidermal growth factor receptor (EGFR) drug response.
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Affiliation(s)
- Aritro Nath
- Department of Experimental and Clinical Pharmacology, University of Minnesota Minneapolis, MN 55455
| | - Eunice Y T Lau
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China
| | - Adam M Lee
- Department of Experimental and Clinical Pharmacology, University of Minnesota Minneapolis, MN 55455
| | - Paul Geeleher
- Department of Computational Biology, St. Jude Children's Research Hospital Memphis, TN 38105
| | - William C S Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China
| | - R Stephanie Huang
- Department of Experimental and Clinical Pharmacology, University of Minnesota Minneapolis, MN 55455;
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36
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Bermúdez M, Aguilar-Medina M, Lizárraga-Verdugo E, Avendaño-Félix M, Silva-Benítez E, López-Camarillo C, Ramos-Payán R. LncRNAs as Regulators of Autophagy and Drug Resistance in Colorectal Cancer. Front Oncol 2019; 9:1008. [PMID: 31632922 PMCID: PMC6783611 DOI: 10.3389/fonc.2019.01008] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 09/19/2019] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) is a common malignancy with 1. 8 million cases in 2018. Autophagy helps to maintain an adequate cancer microenvironment in order to provide nutritional supplement under adverse conditions such as starvation and hypoxia. Additionally, most of the cases of CRC are unresponsive to chemotherapy, representing a significant challenge for cancer therapy. Recently, autophagy induced by therapy has been shown as a unique mechanism of resistance to anticancer drugs. In this regard, long non-coding RNAs (lncRNAs) analysis are important for cancer detection, progression, diagnosis, therapy response, and prognostic values. With increasing development of quantitative detection techniques, lncRNAs derived from patients' non-invasive samples (i.e., blood, stools, and urine) has become into a novel approach in precision oncology. Tumorspecific GAS5, HOTAIR, H19, and MALAT are novels CRC related lncRNAs detected in patients. Nonetheless, the effect and mechanism of lncRNAs in cancer autophagy and chemoresistance have not been extensively characterized. Chemoresistance and autophagy are relevant for cancer treatment and lncRNAs play a pivotal role in resistance acquisition for several drugs. LncRNAs such as HAGLROS, KCNQ1OT1, and H19 are examples of lncRNAs related to chemoresistance leaded by autophagy. Finally, clinical implications of lncRNAs in CRC are relevant, since they have been associated with tumor differentiation, tumor size, histological grade, histological types, Dukes staging, degree of differentiation, lymph node metastasis, distant metastasis, recurrent free survival, and overall survival (OS).
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Affiliation(s)
- Mercedes Bermúdez
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacán, Mexico
| | - Maribel Aguilar-Medina
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacán, Mexico
| | - Erik Lizárraga-Verdugo
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacán, Mexico
| | - Mariana Avendaño-Félix
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacán, Mexico
| | | | - Cesar López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Mexico City, Mexico
| | - Rosalío Ramos-Payán
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacán, Mexico
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Galamb O, Barták BK, Kalmár A, Nagy ZB, Szigeti KA, Tulassay Z, Igaz P, Molnár B. Diagnostic and prognostic potential of tissue and circulating long non-coding RNAs in colorectal tumors. World J Gastroenterol 2019; 25:5026-5048. [PMID: 31558855 PMCID: PMC6747286 DOI: 10.3748/wjg.v25.i34.5026] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 07/26/2019] [Accepted: 08/07/2019] [Indexed: 02/06/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) are members of the non-protein coding RNA family longer than 200 nucleotides. They participate in the regulation of gene and protein expression influencing apoptosis, cell proliferation and immune responses, thereby playing a critical role in the development and progression of various cancers, including colorectal cancer (CRC). As CRC is one of the most frequently diagnosed malignancies worldwide with high mortality, its screening and early detection are crucial, so the identification of disease-specific biomarkers is necessary. LncRNAs are promising candidates as they are involved in carcinogenesis, and certain lncRNAs (e.g., CCAT1, CRNDE, CRCAL1-4) show altered expression in adenomas, making them potential early diagnostic markers. In addition to being useful as tissue-specific markers, analysis of circulating lncRNAs (e.g., CCAT1, CCAT2, BLACAT1, CRNDE, NEAT1, UCA1) in peripheral blood offers the possibility to establish minimally invasive, liquid biopsy-based diagnostic tests. This review article aims to describe the origin, structure, and functions of lncRNAs and to discuss their contribution to CRC development. Moreover, our purpose is to summarise lncRNAs showing altered expression levels during tumor formation in both colon tissue and plasma/serum samples and to demonstrate their clinical implications as diagnostic or prognostic biomarkers for CRC.
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Affiliation(s)
- Orsolya Galamb
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest H-1088, Hungary
| | - Barbara K Barták
- 2nd Department of Internal Medicine, Semmelweis University, Budapest H-1088, Hungary
| | - Alexandra Kalmár
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest H-1088, Hungary
| | - Zsófia B Nagy
- 2nd Department of Internal Medicine, Semmelweis University, Budapest H-1088, Hungary
| | - Krisztina A Szigeti
- 2nd Department of Internal Medicine, Semmelweis University, Budapest H-1088, Hungary
| | - Zsolt Tulassay
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest H-1088, Hungary
| | - Peter Igaz
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest H-1088, Hungary
- 2nd Department of Internal Medicine, Semmelweis University, Budapest H-1088, Hungary
| | - Béla Molnár
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest H-1088, Hungary
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38
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Wang H, Huang C, Yao X. The functions of long non-coding RNAs in colorectal cancer. Transl Cancer Res 2019; 8:2192-2204. [PMID: 35116969 PMCID: PMC8797667 DOI: 10.21037/tcr.2019.08.23] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 07/25/2019] [Indexed: 02/05/2023]
Abstract
Colorectal cancer (CRC) is the third most prevalent malignant neoplasm worldwide. Recently, in terms of the mechanism of CRC, most studies have focused on protein-coding genes. However, studies have increasingly shown that long non-coding RNAs (lncRNAs) play crucial roles in the proliferation and metastasis of CRC. Investigating this molecular mechanism may provide potential diagnostic tools and therapeutic targets for CRC. This review closely examines the dysregulation of lncRNAs in CRC. On account of different mechanisms being involved in the occurrence and development of CRC, there are several categories of lncRNAs, including lncRNAs related to the Wnt/β-catenin pathway, epithelial mesenchymal transition, epigenetic regulation, angiopoiesis, and chemoresistance. This review summarizes lncRNAs related to the progression of CRC, which may provide insight into the mechanisms and potential markers for prognostic prediction and monitoring relapse of CRC.
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Affiliation(s)
- Huaiming Wang
- Second Clinical Medical College, Southern Medical University, Guangzhou 510515, China
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
- Department of Gastrointestinal Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | - Chengzhi Huang
- Department of Gastrointestinal Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
- Medical College, Shantou University, Shantou 515063, China
| | - Xueqing Yao
- Second Clinical Medical College, Southern Medical University, Guangzhou 510515, China
- Department of Gastrointestinal Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
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39
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Sun F, Liang W, Qian J. The identification of CRNDE, H19, UCA1 and HOTAIR as the key lncRNAs involved in oxaliplatin or irinotecan resistance in the chemotherapy of colorectal cancer based on integrative bioinformatics analysis. Mol Med Rep 2019; 20:3583-3596. [PMID: 31432188 PMCID: PMC6755158 DOI: 10.3892/mmr.2019.10588] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 06/24/2019] [Indexed: 12/24/2022] Open
Abstract
With the increasing rate of chemoresistance in colorectal cancer (CRC) patients with advanced tumor stages, it is a matter of urgent importance to delineate the factors involved in the drug resistance process. In this study, gene expression profiles were downloaded from the Gene Expression Omnibus database and an integrated analysis with the aim of detecting hub long non‑coding RNAs (lncRNAs) and their regulated, differentially expressed genes (DEGs) during treatment with oxaliplatin (OxPt) or irinotecan was conducted. A total of seven differentially expressed lncRNAs were correlated with OxPt resistance and 21 were correlated with resistance to SN‑38, the active metabolite of irinotecan. Gene Ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis confirmed that drug resistance was strongly associated with an imbalance between cell proliferation and apoptosis, cell energetic metabolism under hypoxic conditions, and angiogenesis. Moreover, a large number of lncRNA‑targeted DEGs were located in extracellular exosomes. Further analyses identified four hub lncRNAs involved in the process of drug resistance, including CRNDE, H19, UCA1 and HOTAIR, which are predictive factors for treatment sensitivity. Among them, HOTAIR stands out as a strong factor, the elevated expression of which is also associated with advanced tumor node and metastasis stage and poor CRC disease prognosis.
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Affiliation(s)
- Fangfang Sun
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention) China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Weiwei Liang
- Department of Endocrinology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, P.R. China
| | - Jing Qian
- Research Center of Infection and Immunity, ZJU‑UCLA Joint Center for Medical Education and Research, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P.R. China
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40
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The emerging role of noncoding RNAs in colorectal cancer chemoresistance. Cell Oncol (Dordr) 2019; 42:757-768. [DOI: 10.1007/s13402-019-00466-8] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2019] [Indexed: 02/06/2023] Open
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41
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Maternally expressed gene 3 (MEG3): A tumor suppressor long non coding RNA. Biomed Pharmacother 2019; 118:109129. [PMID: 31326791 DOI: 10.1016/j.biopha.2019.109129] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 06/10/2019] [Accepted: 06/12/2019] [Indexed: 12/12/2022] Open
Abstract
Maternally expressed gene 3 (MEG3) is a long non-coding RNA (lncRNA) located on chromosome 14q32.3. Direct sequencing experiments have shown monoallelic expression of this lncRNA. Several studies have shown down-regulation of this lncRNA in human cancers. In some cases, hypermethylation of the promoter region has been suggested as the underlying mechanism. Functional studies have shown that this lncRNA controls expression of several tumor suppressor genes and oncogenes among them are p53, RB, MYC and TGF-β. Through regulation of Wnt-β-catenin pathway, it also affects epithelial-mesenchymal transition. In vitro studies have demonstrated contribution of MEG3 in defining response to chemotherapeutic agents such as paclitaxel, cisplatin and oxaliplatin. Certain polymorphisms within MEG3 are implicated in cancer risk (rs7158663, rs4081134 and rs11160608) or therapeutic response of cancer patients (rs10132552). Taken together, this lncRNA is regarded as a putative cancer biomarker and treatment target. In the current review, several aspects of the participation of MEG3 in carcinogenesis are discussed.
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42
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Dynamic Gene Network Analysis of Caco-2 Cell Response to Shiga Toxin-Producing Escherichia coli-Associated Hemolytic-Uremic Syndrome. Microorganisms 2019; 7:microorganisms7070195. [PMID: 31288487 PMCID: PMC6680469 DOI: 10.3390/microorganisms7070195] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 06/27/2019] [Accepted: 07/03/2019] [Indexed: 01/26/2023] Open
Abstract
Shiga toxin-producing Escherichia coli (STEC) O113:H21 strains are associated with human diarrhea and some strains may cause hemolytic-uremic syndrome (HUS). In Brazil, these strains are commonly found in cattle but, so far, were not isolated from HUS patients. Here, a system biology approach was used to investigate the differential transcriptomic and phenotypic responses of enterocyte-like Caco-2 cells to two STEC O113:H21 strains with similar virulence factor profiles (i.e. expressing stx2, ehxA, epeA, espA, iha, saa, sab, and subA): EH41 (Caco-2/EH41), isolated from a HUS patient in Australia, and Ec472/01 (Caco-2/Ec472), isolated from bovine feces in Brazil, during a 3 h period of bacteria-enterocyte interaction. Gene co-expression network analysis for Caco-2/EH41 revealed a quite abrupt pattern of topological variation along 3 h of enterocyte-bacteria interaction when compared with networks obtained for Caco-2/Ec472. Transcriptional module characterization revealed that EH41 induces inflammatory and apoptotic responses in Caco-2 cells just after the first hour of enterocyte-bacteria interaction, whereas the response to Ec472/01 is associated with cytoskeleton organization at the first hour, followed by the expression of immune response modulators. Scanning electron microscopy showed more intense microvilli destruction in Caco-2 cells exposed to EH41 when compared to those exposed to Ec472/01. Altogether, these results show that EH41 expresses virulence genes, inducing a distinctive host cell response, and is likely associated with severe pathogenicity.
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Circulating Noncoding RNAs Have a Promising Future Acting as Novel Biomarkers for Colorectal Cancer. DISEASE MARKERS 2019; 2019:2587109. [PMID: 31275444 PMCID: PMC6589288 DOI: 10.1155/2019/2587109] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 04/23/2019] [Accepted: 05/21/2019] [Indexed: 02/08/2023]
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors worldwide, causing a large number of cancer-related deaths each year. Patients are usually diagnosed at advanced and incurable stages due to the lack of suitable screening methods for early detection. Noncoding RNAs (ncRNAs), including small and long noncoding RNAs (lncRNA), are known to have significant regulatory functions, and accumulating evidence suggests that circulating ncRNAs have potential applications as noninvasive biomarkers for diagnosing CRC, evaluating its prognosis, or predicting chemosensitivity in the general population. In this review, we summarize the origins of circulating ncRNAs and provide details of single and multiple circulating ncRNAs that might have roles as diagnostic and prognostic biomarkers in CRC. We end by discussing circulating ncRNAs that may distinguish patients with resistance to chemotherapy.
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44
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Molnár B, Galamb O, Kalmár A, Barták BK, Nagy ZB, Tóth K, Tulassay Z, Igaz P, Dank M. Circulating cell-free nucleic acids as biomarkers in colorectal cancer screening and diagnosis - an update. Expert Rev Mol Diagn 2019; 19:477-498. [PMID: 31046485 DOI: 10.1080/14737159.2019.1613891] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 04/29/2019] [Indexed: 12/15/2022]
Abstract
Introduction: Screening methods for one of the most frequently diagnosed malignancy, colorectal cancer (CRC), have limitations. Circulating cell-free nucleic acids (cfNA) hold clinical relevance as screening, prognostic and therapy monitoring markers. Area covered: In this review, we summarize potential CRC-specific cfNA biomarkers, the recently developed sample preparation techniques, their applications, and pitfalls. Expert opinion: Automated extraction of cfDNA is highly reproducible, however, cfDNA yield is less compared to manual isolation. Quantitative and highly sensitive detection techniques (e.g. digital PCR, NGS) can be applied to analyze genetic and epigenetic changes. Detection of DNA mutations or methylation in cfDNA and related altered levels of mRNA, miRNA, and lncRNA may improve early cancer recognition, based on specific, CRC-related patterns. Detection of cfDNA mutations (e.g. TP53, KRAS, APC) has limited diagnostic sensitivity (40-60%), however, methylated DNA including SEPT9, SFRP1, SDC2 can be applied with higher sensitivity (up to 90%) for CRC. Circulating miRNAs (e.g. miR-21, miR-92, miR-141) provide comparably high sensitivity for CRC as the circulating tumor cell mRNA markers (e.g. EGFR, CK19, CK20, CEA). Automation of cfNA isolation coupled with quantitative analysis of CRC-related, highly sensitive biomarkers may enhance CRC screening and early detection in the future.
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Affiliation(s)
- Béla Molnár
- a 2nd Department of Internal Medicine , Semmelweis University , Budapest , Hungary
- b MTA-SE Molecular Medicine Research Unit , Hungarian Academy of Sciences and Semmelweis University , Budapest , Hungary
| | - Orsolya Galamb
- a 2nd Department of Internal Medicine , Semmelweis University , Budapest , Hungary
- b MTA-SE Molecular Medicine Research Unit , Hungarian Academy of Sciences and Semmelweis University , Budapest , Hungary
| | - Alexandra Kalmár
- a 2nd Department of Internal Medicine , Semmelweis University , Budapest , Hungary
- b MTA-SE Molecular Medicine Research Unit , Hungarian Academy of Sciences and Semmelweis University , Budapest , Hungary
| | - Barbara Kinga Barták
- a 2nd Department of Internal Medicine , Semmelweis University , Budapest , Hungary
| | - Zsófia Brigitta Nagy
- a 2nd Department of Internal Medicine , Semmelweis University , Budapest , Hungary
| | - Kinga Tóth
- a 2nd Department of Internal Medicine , Semmelweis University , Budapest , Hungary
| | - Zsolt Tulassay
- a 2nd Department of Internal Medicine , Semmelweis University , Budapest , Hungary
- b MTA-SE Molecular Medicine Research Unit , Hungarian Academy of Sciences and Semmelweis University , Budapest , Hungary
| | - Péter Igaz
- a 2nd Department of Internal Medicine , Semmelweis University , Budapest , Hungary
- b MTA-SE Molecular Medicine Research Unit , Hungarian Academy of Sciences and Semmelweis University , Budapest , Hungary
| | - Magdolna Dank
- c Department of Oncology , Semmelweis University , Budapest , Hungary
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Deng R, Fan FY, Yi H, Liu F, He GC, Sun HP, Su Y. MEG3 affects the progression and chemoresistance of T-cell lymphoblastic lymphoma by suppressing epithelial-mesenchymal transition via the PI3K/mTOR pathway. J Cell Biochem 2019; 120:8144-8153. [PMID: 30556337 DOI: 10.1002/jcb.28093] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 10/29/2018] [Indexed: 01/24/2023]
Abstract
Long noncoding RNAs (lncRNA) are emerging as integral functional and regulatory components in the development of different diseases including cancer. Maternally expressed gene 3 (MEG3), is a lncRNA, that has a depressed expression in multiple tumor types, including T-cell lymphoblastic lymphoma (T-LBL). However, the molecular mechanisms that regulate the tumorigenic functions of MEG3 in T-LBL remain largely unknown. In this study, we aimed to discover and identify the function of MEG3 in T-LBL tumorigenesis, epithelial-mesenchymal transition (EMT) and drug resistance, and explore their mechanisms of action. Knockdown MEG3 promoted the proliferation, migration, invasion, and drug resistance of T-LBL cells while overexpression of MEG3 gets the opposite results. The mechanism study showed that decreased MEG3 expression in T-LBL cells could activate PI3K/mTOR signaling pathways, increase the expression of p-glycoprotein and affect the expression of EMT markers for transforming to mesenchymal cells in vitro and in vivo. Together, these results indicate that MEG3 could inhibit the migration, invasion, and drug resistance in T-LBL cells by suppression of the PI3K/mTOR pathway. MEG3 might be a potential target, through which poor prognosis with high recurrence and drug resistance of T-LBL in a clinical setting could be reversed.
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Affiliation(s)
- Rui Deng
- Department of Hematology, Hematopoietic Stem Cell Transplantation/Cell Immunotherapy Center, Cheng Du Military General Hospital of PLA, Cheng Du, China
| | - Fang-Yi Fan
- Department of Hematology, Hematopoietic Stem Cell Transplantation/Cell Immunotherapy Center, Cheng Du Military General Hospital of PLA, Cheng Du, China
| | - Hai Yi
- Department of Hematology, Hematopoietic Stem Cell Transplantation/Cell Immunotherapy Center, Cheng Du Military General Hospital of PLA, Cheng Du, China
| | - Fang Liu
- Department of Hematology, Hematopoietic Stem Cell Transplantation/Cell Immunotherapy Center, Cheng Du Military General Hospital of PLA, Cheng Du, China
| | - Guang-Cui He
- Department of Hematology, Hematopoietic Stem Cell Transplantation/Cell Immunotherapy Center, Cheng Du Military General Hospital of PLA, Cheng Du, China
| | - Hao-Ping Sun
- Department of Hematology, Hematopoietic Stem Cell Transplantation/Cell Immunotherapy Center, Cheng Du Military General Hospital of PLA, Cheng Du, China
| | - Yi Su
- Department of Hematology, Hematopoietic Stem Cell Transplantation/Cell Immunotherapy Center, Cheng Du Military General Hospital of PLA, Cheng Du, China
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46
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Feng W, Su Z, Yin Q, Zong W, Shen X, Ju S. ncRNAs associated with drug resistance and the therapy of digestive system neoplasms. J Cell Physiol 2019; 234:19143-19157. [PMID: 30941775 DOI: 10.1002/jcp.28551] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 02/25/2019] [Accepted: 03/05/2019] [Indexed: 12/19/2022]
Abstract
Digestive system cancer remains a common cancer and the main cause of cancer-related death worldwide. Drug resistance is a major challenge in the therapy of digestive system cancer, and represents a primary obstacle in the treatment of cancer by restricting the efficiency of both traditional chemotherapy and biological therapies. Existing studies indicate that noncoding RNAs play an important role in the evolution and progression of drug resistance in digestive system cancer, mainly by modulating drug transporter-related proteins, DNA damage repair, cell-cycle-related proteins, cell apoptosis-related proteins, drug target-related proteins, and the tumor microenvironment. In this review, we address the potential mechanisms of ncRNAs underlying drug resistance in digestive system tumors and discuss the possible application of ncRNAs against drug resistance in digestive system tumors.
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Affiliation(s)
- Wei Feng
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Zhangyao Su
- School of Medicine, Nantong University, Nantong, China
| | - Qingqing Yin
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Wei Zong
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Xianjuan Shen
- Clinical Medical Research Center, Affiliated Hospital of Nantong University, Nantong, China
| | - Shaoqing Ju
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
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47
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LncRNA-MEG3 protects against ganglion cell dysplasia in congenital intestinal atresia through directly regulating miR-211-5p/GDNF axis. Biomed Pharmacother 2019; 111:436-442. [DOI: 10.1016/j.biopha.2018.11.089] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 11/07/2018] [Accepted: 11/25/2018] [Indexed: 12/20/2022] Open
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48
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Abstract
Long noncoding RNAs (lncRNAs) have recently considered as central regulators in diverse biological processes and emerged as vital players controlling tumorigenesis. Several lncRNAs can be classified into oncogenes and tumor suppressor genes depending on their function in cancer. A maternally expressed gene 3 (MEG3) gene transcripts a 1.6 kb lncRNA whose act as an antitumor component in different cancer cells, such as breast, liver, glioma, colorectal, cervical, gastric, lung, ovarian and osteosarcoma cancer cells. The present review highlights biological function of MEG3 to repress tumor through regulating the major tumor suppressor genes p53 and Rb, inhibiting angiogenesis-related factor, or controlling miRNAs. On the other hand, previous studies have also suggested that MEG3 mediates epithelial-mesenchymal transition (EMT). However, deregulation of MEG3 is associated with the development and progression of cancer, suggesting that MEG3 may function as a potential biomarker and therapeutic target for human cancers.
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49
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Long noncoding RNAs in cancer cells. Cancer Lett 2019; 419:152-166. [PMID: 29414303 DOI: 10.1016/j.canlet.2018.01.053] [Citation(s) in RCA: 139] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 01/15/2018] [Accepted: 01/18/2018] [Indexed: 12/11/2022]
Abstract
Long noncoding RNA (lncRNA) has recently been investigated as key modulators that regulate many biological processes in human cancers via diverse mechanisms. LncRNAs can interact with macromolecules such as DNA, RNA, or protein to exert cellular effects and to act as either tumor promoters or tumor suppressors in various malignancies. Moreover, the aberrant expression of lncRNAs may be detected in multiple cancer phenotypes by employing the rapidly developing modern gene chip technology and bioinformatics analysis. Herein, we highlight the mechanisms of action of lncRNAs, their functional cellular roles and their involvement in cancer progression. Finally, we provide an overview of recent progress in the lncRNA field and future potential for lncRNAs as cancer diagnostic markers and therapeutics.
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50
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Zhao D, Dong JT. Upregulation of Long Non-Coding RNA DRAIC Correlates with Adverse Features of Breast Cancer. Noncoding RNA 2018; 4:ncrna4040039. [PMID: 30544991 PMCID: PMC6315495 DOI: 10.3390/ncrna4040039] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Revised: 11/30/2018] [Accepted: 12/07/2018] [Indexed: 12/23/2022] Open
Abstract
DRAIC (also known as LOC145837 and RP11-279F6.1), is a long non-coding RNA associated with several types of cancer including prostate cancer, lung cancer, and breast cancer. Its expression is elevated in tumor tissues compared to adjacent benign tissues in breast cancer patients and is regulated by estrogen treatment in breast cancer cells. In addition, expression analysis of DRAIC in more than 100 cell lines showed that DRAIC expression is high in luminal and basal subtypes compared to claudin low subtype, suggesting a prognostic value of DRAIC expression in breast cancer. In the present study, we analyzed DRAIC expression in 828 invasive breast carcinomas and 105 normal samples of RNA sequencing datasets from The Cancer Genome Atlas (TCGA) and found that DRAIC expression was correlated with estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status, and is increased in cancerous tissues. Additionally, higher DRAIC expression was associated with poorer survival of patients, especially in ER positive breast cancer. DRAIC was also investigated in the Oncomine database and we found that DRAIC expression predicted patients’ response to paclitaxel and FEC as well as lapatinib, which are commonly used therapy options for breast cancer. Finally, DRAIC expression in breast cancer was negatively correlated with immune cell infiltration. These results reinforce the importance of DRAIC in breast cancer.
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Affiliation(s)
- Dan Zhao
- Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
| | - Jin-Tang Dong
- Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
- Department of Hematology and Medical Oncology, School of Medicine, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
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