|
1
|
Wu D, Huang C, Guan K. Mechanistic and therapeutic perspectives of miRNA-PTEN signaling axis in cancer therapy resistance. Biochem Pharmacol 2024; 226:116406. [PMID: 38969299 DOI: 10.1016/j.bcp.2024.116406] [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: 04/12/2024] [Revised: 06/25/2024] [Accepted: 07/01/2024] [Indexed: 07/07/2024]
Abstract
Cancer, being one of the most lethal illnesses, presents an escalating clinical dilemma on a global scale. Despite significant efforts and advancements in cancer treatment over recent decades, the persistent challenge of resistance to traditional chemotherapeutic agents and/or emerging targeted drugs remains a prominent issue in the field of cancer therapies. Among the frequently inactivated tumor suppressor genes in cancer, phosphatase and Tensin Homolog (PTEN) stands out, and its decreased expression may contribute to the emergence of therapeutic resistance. MicroRNAs (miRNAs), characterized by their short length of 22 nucleotides, exert regulatory control over target mRNA expression by binding to complementary sequences. Recent findings indicate that microRNAs play varied regulatory roles, encompassing promotion, suppression, and dual functions on PTEN, and their aberration is implicated in heightened resistance to anticancer therapies. Significantly, recent research has revealed that competitive endogenous RNAs (ceRNAs) play a pivotal role in influencing PTEN expression, and the regulatory network involving circRNA/lncRNA-miRNA-PTEN is intricately linked to resistance in various cancer types to anticancer therapies. Finally, our findings showcase that diverse approaches, such as herbal medicine, small molecule inhibitors, low-intensity ultrasound, and engineered exosomes, can effectively overcome drug resistance in cancer by modulating the miRNA-PTEN axis.
Collapse
Affiliation(s)
- Di Wu
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong 226001, China
| | - Chunjie Huang
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong 226001, China.
| | - Kaifeng Guan
- School of Advanced Agricultural Sciences, Peking University, Beijing 100871, China.
| |
Collapse
|
|
2
|
Katsushima K, Pokhrel R, Mahmud I, Yuan M, Murad R, Baral P, Zhou R, Chapagain P, Garrett T, Stapleton S, Jallo G, Bettegowda C, Raabe E, Wechsler-Reya RJ, Eberhart CG, Perera RJ. The oncogenic circular RNA circ_63706 is a potential therapeutic target in sonic hedgehog-subtype childhood medulloblastomas. Acta Neuropathol Commun 2023; 11:38. [PMID: 36899402 PMCID: PMC10007801 DOI: 10.1186/s40478-023-01521-0] [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: 01/23/2023] [Accepted: 01/24/2023] [Indexed: 03/12/2023] Open
Abstract
Medulloblastoma (MB) develops through various genetic, epigenetic, and non-coding (nc) RNA-related mechanisms, but the roles played by ncRNAs, particularly circular RNAs (circRNAs), remain poorly defined. CircRNAs are increasingly recognized as stable non-coding RNA therapeutic targets in many cancers, but little is known about their function in MBs. To determine medulloblastoma subgroup-specific circRNAs, publicly available RNA sequencing (RNA-seq) data from 175 MB patients were interrogated to identify circRNAs that differentiate between MB subgroups. circ_63706 was identified as sonic hedgehog (SHH) group-specific, with its expression confirmed by RNA-FISH analysis in clinical tissue samples. The oncogenic function of circ_63706 was characterized in vitro and in vivo. Further, circ_63706-depleted cells were subjected to RNA-seq and lipid profiling to identify its molecular function. Finally, we mapped the circ_63706 secondary structure using an advanced random forest classification model and modeled a 3D structure to identify its interacting miRNA partner molecules. Circ_63706 regulates independently of the host coding gene pericentrin (PCNT), and its expression is specific to the SHH subgroup. circ_63706-deleted cells implanted into mice produced smaller tumors, and mice lived longer than parental cell implants. At the molecular level, circ_63706-deleted cells elevated total ceramide and oxidized lipids and reduced total triglyceride. Our study implicates a novel oncogenic circular RNA in the SHH medulloblastoma subgroup and establishes its molecular function and potential as a future therapeutic target.
Collapse
Affiliation(s)
- Keisuke Katsushima
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, 1650 Orleans St., Baltimore, MD, 21231, USA.,Johns Hopkins All Children's Hospital, St. Petersburg, USA
| | - Rudramani Pokhrel
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, 1650 Orleans St., Baltimore, MD, 21231, USA.,Johns Hopkins All Children's Hospital, St. Petersburg, USA
| | - Iqbal Mahmud
- Department Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, USA.,Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, USA
| | - Menglang Yuan
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, 1650 Orleans St., Baltimore, MD, 21231, USA.,Johns Hopkins All Children's Hospital, St. Petersburg, USA
| | - Rabi Murad
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, USA
| | - Prabin Baral
- Department of Physics, Florida International University, Miami, USA
| | - Rui Zhou
- Johns Hopkins All Children's Hospital, St. Petersburg, USA
| | - Prem Chapagain
- Department of Physics, Florida International University, Miami, USA.,Biomolecular Sciences Institute, Florida International University, Miami, USA
| | - Timothy Garrett
- Department Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, USA
| | | | - George Jallo
- Johns Hopkins All Children's Hospital, St. Petersburg, USA.,Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Chetan Bettegowda
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, 1650 Orleans St., Baltimore, MD, 21231, USA.,Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Eric Raabe
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, 1650 Orleans St., Baltimore, MD, 21231, USA.,Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, USA
| | | | - Charles G Eberhart
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, 1650 Orleans St., Baltimore, MD, 21231, USA.,Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Ranjan J Perera
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, 1650 Orleans St., Baltimore, MD, 21231, USA. .,Johns Hopkins All Children's Hospital, St. Petersburg, USA. .,Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, USA.
| |
Collapse
|
|
3
|
Zhao S, Tang Y, Wang R, Najafi M. Mechanisms of cancer cell death induction by paclitaxel: an updated review. Apoptosis 2022; 27:647-667. [PMID: 35849264 DOI: 10.1007/s10495-022-01750-z] [Citation(s) in RCA: 85] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/01/2022] [Indexed: 02/07/2023]
Abstract
Chemoresistance of cancer cells is a major problem in treating cancer. Knowledge of how cancer cells may die or resist cancer drugs is critical to providing certain strategies to overcome tumour resistance to treatment. Paclitaxel is known as a chemotherapy drug that can suppress the proliferation of cancer cells by inducing cell cycle arrest and induction of mitotic catastrophe. However, today, it is well known that paclitaxel can induce multiple kinds of cell death in cancers. Besides the induction of mitotic catastrophe that occurs during mitosis, paclitaxel has been shown to induce the expression of several pro-apoptosis mediators. It also can modulate the activity of anti-apoptosis mediators. However, certain cell-killing mechanisms such as senescence and autophagy can increase resistance to paclitaxel. This review focuses on the mechanisms of cell death, including apoptosis, mitotic catastrophe, senescence, autophagic cell death, pyroptosis, etc., following paclitaxel treatment. In addition, mechanisms of resistance to cell death due to exposure to paclitaxel and the use of combinations to overcome drug resistance will be discussed.
Collapse
Affiliation(s)
- Shuang Zhao
- School of Basic Medicine, Shaoyang University, Shaoyang, 422000, Hunan, China.
| | - Yufei Tang
- College of Medical Technology, Shaoyang University, Shaoyang, 422000, Hunan, China
| | - Ruohan Wang
- School of Nursing, Shaoyang University, Shaoyang, 422000, Hunan, China.
| | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran.
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| |
Collapse
|
|
4
|
Vaghari-Tabari M, Targhazeh N, Moein S, Qujeq D, Alemi F, Majidina M, Younesi S, Asemi Z, Yousefi B. From inflammatory bowel disease to colorectal cancer: what's the role of miRNAs? Cancer Cell Int 2022; 22:146. [PMID: 35410210 PMCID: PMC8996392 DOI: 10.1186/s12935-022-02557-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 03/21/2022] [Indexed: 12/27/2022] Open
Abstract
Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease with relapse and remission periods. Ulcerative colitis and Crohn's disease are two major forms of the disease. IBD imposes a lot of sufferings on the patient and has many consequences; however, the most important is the increased risk of colorectal cancer, especially in patients with Ulcerative colitis. This risk is increased with increasing the duration of disease, thus preventing the progression of IBD to cancer is very important. Therefore, it is necessary to know the details of events contributed to the progression of IBD to cancer. In recent years, the importance of miRNAs as small molecules with 20-22 nucleotides has been recognized in pathophysiology of many diseases, in which IBD and colorectal cancer have not been excluded. As a result, the effectiveness of these small molecules as therapeutic target is hopefully confirmed. This paper has reviewed the related studies and findings about the role of miRNAs in the course of events that promote the progression of IBD to colorectal carcinoma, as well as a review about the effectiveness of some of these miRNAs as therapeutic targets.
Collapse
Affiliation(s)
- Mostafa Vaghari-Tabari
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Niloufar Targhazeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soheila Moein
- Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
| | - Forough Alemi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidina
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Simin Younesi
- Schoole of Health and Biomedical Sciences, RMIT University, Melborne, VIC, Australia
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran.
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
5
|
Gui L, Zhang S, Xu Y, Zhang H, Zhu Y, Kong L. UBE2S promotes cell chemoresistance through PTEN-AKT signaling in hepatocellular carcinoma. Cell Death Dis 2021; 7:357. [PMID: 34785642 PMCID: PMC8595659 DOI: 10.1038/s41420-021-00750-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 10/20/2021] [Accepted: 11/01/2021] [Indexed: 12/24/2022]
Abstract
Ubiquitination displays a crucial role in various biological functions, such as protein degradation, signal transduction, and cellular homeostasis. Accumulating evidence has indicated that ubiquitination is essential in cancer progression. Ubiquitin-conjugating enzyme E2S (UBE2S) is a member of ubiquitin-conjugating enzyme family of the ubiquitin system and its role in hepatocellular cancer (HCC) is largely unknown. We investigated the role of UBE2S in HCC and found UBE2S upregulation is relevant with large tumor size, recurrence, and advanced TNM stage, serving as an independent risk factor of overall survival (OS) and disease-free survival (DFS) for HCC patients. We conducted in vitro experiments and found that in HCC cells, UBE2S overexpression increases the resistance to 5-FU and oxaliplatin, while UBE2S knockdown achieves an opposite effect. UBE2S is transcriptionally activated by the binding of FOXM1 to UBE2S promoter, which induces its upregulation and reduces PTEN protein level by promoting PTEN ubiquitination at Lys60 and Lys327 and facilitating AKT phosphorylation. The promotional effect of FOXM1-UBE2S axis on HCC cell chemoresistance is attenuated by allosteric AKT inhibitor, MK2206. In conclusion, our results reveal that UBE2S is a prognostic biomarker for HCC patients, and the FOXM1-UBE2S-PTEN-p-AKT signaling axis might be a promising target for the treatment of HCC.
Collapse
Affiliation(s)
- Liang Gui
- grid.452509.f0000 0004 1764 4566Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 210009 Nanjing, Jiangsu China
| | - Sicai Zhang
- grid.452509.f0000 0004 1764 4566Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 210009 Nanjing, Jiangsu China
| | - Yongzi Xu
- grid.452509.f0000 0004 1764 4566Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 210009 Nanjing, Jiangsu China
| | - Hongwei Zhang
- grid.452509.f0000 0004 1764 4566Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 210009 Nanjing, Jiangsu China
| | - Ying Zhu
- Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 210009, Nanjing, Jiangsu, China.
| | - Lianbao Kong
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, 210029, Nanjing, Jiangsu Province, China.
| |
Collapse
|
|
6
|
Moazzendizaji S, Sevbitov A, Ezzatifar F, Jalili HR, Aalii M, Hemmatzadeh M, Aslani S, Gholizadeh Navashenaq J, Safari R, Hosseinzadeh R, Rahmany MR, Mohammadi H. microRNAs: Small molecules with a large impact on colorectal cancer. Biotechnol Appl Biochem 2021; 69:1893-1908. [PMID: 34550619 DOI: 10.1002/bab.2255] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 09/03/2021] [Indexed: 12/23/2022]
Abstract
Colorectal cancer (CRC) accounts for one of the main cancer-related mortality and morbidity worldwide. The molecular mechanisms of CRC development have been broadly investigated and, over the last decade, it has become evident that aberrant transcription of microRNAs (miRNAs), a class of small, noncoding RNA molecules, has a significant role in the inception and promotion of CRC. In the involved tissues of CRC, the transcription profile of miRNAs is modulated, and their expression templates are related with prognosis, diagnosis, and treatment outcomes. Here, in the current review, we attempted to discuss the latest information regarding the aberrantly expressed miRNAs in CRC and the advantages of utilizing miRNAs as biomarkers for early diagnosis and prognosis of CRC as well as potential therapeutic application. The effect of miRNAs involved in various signaling pathways, primarily p53, EGFR, Wnt, and TGF-β pathways, was clarified.
Collapse
Affiliation(s)
- Sahand Moazzendizaji
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Andrey Sevbitov
- Head of Department of Propaedeutics of Dental Diseases, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Fatemeh Ezzatifar
- Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hamid Reza Jalili
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Morteza Aalii
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Maryam Hemmatzadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saeed Aslani
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Roghaiyeh Safari
- Molecular and Cellular Epigenetics (GIGA), University of Liege, Sart-Tilman Liège, Belgium.,13. Molecular and Cellular Biology (TERRA), Gembloux Agro-Bio Tech, University of Liege, Gembloux, Belgium
| | - Ramin Hosseinzadeh
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Rahmany
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Hamed Mohammadi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.,Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| |
Collapse
|
|
7
|
Diao ZB, Sun TX, Zong Y, Lin BC, Xia YS. Identification of plasma microRNA-22 as a marker for the diagnosis, prognosis, and chemosensitivity prediction of osteosarcoma. J Int Med Res 2021; 48:300060520967818. [PMID: 33284712 PMCID: PMC7724422 DOI: 10.1177/0300060520967818] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Objective MicroRNA (miR)-22 plays crucial roles in malignant tumors and is involved in
regulation of chemosensitivity. Additionally, altered expression of
circulating miR-22 has been reported in various cancers. This study was
designed to investigate plasma miR-22 expression in patients with
osteosarcoma (OS) and determine its diagnostic, prognostic, and
chemosensitivity prediction value. Methods Plasma miR-22 levels in 120 patients with OS and 120 healthy controls were
detected by real-time quantitative reverse transcription PCR. Associations
of plasma miR-22 expression with the patients’ clinicopathological features
and prognosis were then assessed. Results Plasma miR-22 levels in patients with OS were significantly lower than those
in healthy controls. Low plasma miR-22 levels were correlated with large
tumor size, advanced clinical stages, positive distant metastasis, and poor
tumor response to preoperative chemotherapy. Plasma miR-22 could
discriminate OS patients from controls and distinguish patients with a good
response to therapy from those with a poor response to therapy. Multivariate
analysis revealed that low plasma miR-22 expression was a significant
independent predictor of unfavorable prognosis. Conclusions Altered plasma levels of miR-22 might serve as a novel, noninvasive biomarker
for OS diagnosis, prognosis, and chemosensitivity prediction.
Collapse
Affiliation(s)
- Zhen-Bin Diao
- Department of Orthopaedics, Daqing Oilfield General Hospital, Daqing, Heilongjiang Province, China
| | - Tian-Xiao Sun
- Department of Anesthesiology, Daqing Oilfield General Hospital, Daqing, Heilongjiang Province, China
| | - Yi Zong
- Department of Orthopaedics, Daqing Oilfield General Hospital, Daqing, Heilongjiang Province, China
| | - Bo-Chuan Lin
- Department of Orthopaedics, Daqing Oilfield General Hospital, Daqing, Heilongjiang Province, China
| | - Yuan-Sheng Xia
- Department of Orthopaedics, Daqing Oilfield General Hospital, Daqing, Heilongjiang Province, China
| |
Collapse
|
|
8
|
Emami Nejad A, Najafgholian S, Rostami A, Sistani A, Shojaeifar S, Esparvarinha M, Nedaeinia R, Haghjooy Javanmard S, Taherian M, Ahmadlou M, Salehi R, Sadeghi B, Manian M. The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment. Cancer Cell Int 2021; 21:62. [PMID: 33472628 PMCID: PMC7816485 DOI: 10.1186/s12935-020-01719-5] [Citation(s) in RCA: 367] [Impact Index Per Article: 91.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 12/11/2020] [Accepted: 12/16/2020] [Indexed: 12/13/2022] Open
Abstract
Hypoxia is a common feature of solid tumors, and develops because of the rapid growth of the tumor that outstrips the oxygen supply, and impaired blood flow due to the formation of abnormal blood vessels supplying the tumor. It has been reported that tumor hypoxia can: activate angiogenesis, thereby enhancing invasiveness and risk of metastasis; increase survival of tumor, as well as suppress anti-tumor immunity and hamper the therapeutic response. Hypoxia mediates these effects by several potential mechanisms: altering gene expression, the activation of oncogenes, inactivation of suppressor genes, reducing genomic stability and clonal selection. We have reviewed the effects of hypoxia on tumor biology and the possible strategiesto manage the hypoxic tumor microenvironment (TME), highlighting the potential use of cancer stem cells in tumor treatment.
Collapse
Affiliation(s)
- Asieh Emami Nejad
- Department of Biology, Payame Noor University (PNU), P.O.Box 19395-3697, Tehran, Iran
| | - Simin Najafgholian
- Department of Emergency Medicine, School of Medicine , Arak University of Medical Sciences, Arak, Iran
| | - Alireza Rostami
- Department of Surgery, School of Medicine Amiralmomenin Hospital, Arak University of Medical Sciences, Arak, Iran
| | - Alireza Sistani
- Department of Emergency Medicine, School of Medicine Valiasr Hospital, Arak University of Medical Sciences, Arak, Iran
| | - Samaneh Shojaeifar
- Department of Midwifery, Faculty of Nursing and Midwifery , Arak University of Medical Sciences , Arak, Iran
| | - Mojgan Esparvarinha
- Department of Immunology, School of Medicine , Tabriz University of Medical Sciences , Tabriz, Iran
| | - Reza Nedaeinia
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease , Isfahan University of Medical Sciences , Isfahan, Iran
| | - Shaghayegh Haghjooy Javanmard
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences , Isfahan, Iran
| | - Marjan Taherian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mojtaba Ahmadlou
- Sciences Medical of University Arak, Hospital Amiralmomenin, Center Development Research Clinical, Arak, Iran
| | - Rasoul Salehi
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease , Isfahan University of Medical Sciences , Isfahan, Iran.,Department of Genetics and Molecular Biology, School of Medicine , Isfahan University of Medical Sciences , Isfahan, Iran
| | - Bahman Sadeghi
- Department of Health and Community Medicine, School of Medicine, Arak University of Medical Sciences, Arak, 3848176341, Iran.
| | - Mostafa Manian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. .,Department of Medical Laboratory Science, Faculty of Medical Science Kermanshah Branch, Islamic Azad University, Imam Khomeini Campus, Farhikhtegan Bld., Shahid J'afari St., Kermanshah, 3848176341, Iran.
| |
Collapse
|
|
9
|
Xiao Y, Sun Y, Ma X, Wang C, Zhang L, Wang J, Wang G, Li Z, Tian W, Zhao Z, Jing Q, Zhou J, Jing Z. MicroRNA-22 Inhibits the Apoptosis of Vascular Smooth Muscle Cell by Targeting p38MAPKα in Vascular Remodeling of Aortic Dissection. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 22:1051-1062. [PMID: 33294292 PMCID: PMC7691156 DOI: 10.1016/j.omtn.2020.08.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 08/19/2020] [Indexed: 02/03/2023]
Abstract
MicroRNA 22 (miR-22) was found in diverse cardiovascular diseases to have a role in regulating multiple cellular processes. However, the regulatory role of miR-22 in aortic dissection (AD) was still unclear. The miR-22 expression in human aorta was explored. A series of mimic, inhibitor, or small interfering RNA (siRNA) plasmids were delivered into vascular smooth muscle cells (VSMCs) to explore the effects of miR-22 and p38 mitogen-activated protein kinase α (p38MAPKα) in controlling VSMC apoptosis in vitro. In addition, a mouse AD model was established, and histopathologic analyses were performed to evaluate the regulatory effects of miR-22. Reduced miR-22 and increased apoptosis of VSMCs was seen in human AD aorta. Downregulation of miR-22 increased the apoptosis of VSMCs in vitro. Bioinformatics analyses revealed that p38MAPKα was a target of miR-22. Inhibiting p38MAPKα expression could reverse the apoptosis of VSMCs induced by miR-22 downregulation. Knockdown of miR-22 in the AD mouse model significantly promoted the development of AD. Our data underscore the importance of vascular remodeling and VSMC function in AD. miR-22 may represent a new therapeutic approach for AD by regulating the apoptosis of VSMCs through the MAPK signaling pathway.
Collapse
Affiliation(s)
- Yu Xiao
- Department of Vascular Surgery, Changhai Hospital, Navy Medical University, Shanghai 200433, China
| | - Yudong Sun
- Department of Vascular Surgery, Changhai Hospital, Navy Medical University, Shanghai 200433, China.,Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Xiang Ma
- Department of Vascular Surgery, Changhai Hospital, Navy Medical University, Shanghai 200433, China
| | - Chen Wang
- Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China
| | - Lei Zhang
- Department of Vascular Surgery, Changhai Hospital, Navy Medical University, Shanghai 200433, China
| | - Jiannan Wang
- Department of Vascular Surgery, Changhai Hospital, Navy Medical University, Shanghai 200433, China
| | - Guokun Wang
- Institution of Cardiac Surgery, Department of Cardiovascular Surgery, Changhai Hospital, Navy Medical University, Shanghai, China
| | - Zhenjiang Li
- Department of Vascular Surgery, The First Affiliated Hospital of Medical School of Zhejiang University, Hangzhou, China
| | - Wen Tian
- Department of Vascular Surgery, Changhai Hospital, Navy Medical University, Shanghai 200433, China
| | - Zhiqing Zhao
- Department of Vascular Surgery, Changhai Hospital, Navy Medical University, Shanghai 200433, China
| | - Qing Jing
- Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China
| | - Jian Zhou
- Department of Vascular Surgery, Changhai Hospital, Navy Medical University, Shanghai 200433, China
| | - Zaiping Jing
- Department of Vascular Surgery, Changhai Hospital, Navy Medical University, Shanghai 200433, China
| |
Collapse
|
|
10
|
Vaghari-Tabari M, Majidinia M, Moein S, Qujeq D, Asemi Z, Alemi F, Mohamadzadeh R, Targhazeh N, Safa A, Yousefi B. MicroRNAs and colorectal cancer chemoresistance: New solution for old problem. Life Sci 2020; 259:118255. [PMID: 32818543 DOI: 10.1016/j.lfs.2020.118255] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 08/01/2020] [Accepted: 08/09/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies with a significant mortality rate. Despite the great advances in cancer treatment in the last few decades, effective treatment of CRC is still under challenge. One of the main problems associated with CRC treatment is the resistance of cancer cells to chemotherapy drugs. METHODS Many studies have been carried out to identify CRC chemoresistance mechanisms, and shed light on the role of ATP-binding cassette transporters (ABC transporters), enzymes as thymidylate synthase, some signaling pathways, and cancer stem cells (CSC) in chemoresistance and failed CRC chemotherapies. Other studies have also been recently carried out to find solutions to overcome chemoresistance. Some of these studies have identified the role of miRNAs in chemoresistance of the CRC cells and the effective use of these micro-molecules to CRC treatment. RESULTS Considering the results of these studies, more focus on miRNAs likely leads to a proper solution to overcome CRC chemoresistance. CONCLUSION The current study has reviewed the related literature while discussing the efficacy of miRNAs as potential clinical tools for overcoming CRC chemoresistance and reviewing the most important chemoresistance mechanisms in CRC cells.
Collapse
Affiliation(s)
- Mostafa Vaghari-Tabari
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Soheila Moein
- Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran; Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Forough Alemi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ramin Mohamadzadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nilofar Targhazeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amin Safa
- Institute of Research and Development, Duy Tan University, Da Nang, Vietnam; Faculty of Medicine, Zabol University of Medical Sciences, Zabol, Iran.
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
11
|
Das PK, Islam F, Lam AK. The Roles of Cancer Stem Cells and Therapy Resistance in Colorectal Carcinoma. Cells 2020; 9:1392. [PMID: 32503256 PMCID: PMC7348976 DOI: 10.3390/cells9061392] [Citation(s) in RCA: 143] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 05/29/2020] [Accepted: 06/02/2020] [Indexed: 12/22/2022] Open
Abstract
Cancer stem cells (CSCs) are the main culprits involved in therapy resistance and disease recurrence in colorectal carcinoma (CRC). Results using cell culture, animal models and tissues from patients with CRC suggest the indispensable roles of colorectal CSCs in therapeutic failure. Conventional therapies target proliferating and mature cancer cells, while CSCs are mostly quiescent and poorly differentiated, thereby they can easily survive chemotherapeutic insults. The aberrant activation of Wnt/β-catenin, Notch, Hedgehog, Hippo/YAP (Yes-associated protein) and phosphatidylinositol 3-kinase/protein kinase B facilitates CSCs with excessive self-renewal and therapy resistance property in CRC. CSCs survive the chemo-radiotherapies by escaping therapy mediated DNA damage via altering the cell cycle checkpoints, increasing DNA damage repair capacity and by an efficient scavenging of reactive oxygen species. Furthermore, dysregulations of miRNAs e.g., miR-21, miR-93, miR-203, miR-215, miR-497 etc., modulate the therapeutic sensitivity of colorectal CSCs by regulating growth and survival signalling. In addition, a reversible quiescent G0 state and the re-entering cell cycle capacity of colorectal CSCs can accelerate tumour regeneration after treatment. Moreover, switching to favourable metabolic signatures during a therapeutic regimen will add more complexity in therapeutic outcomes against CSCs. Therapeutic strategies targeting these underlying mechanisms of CSCs' therapy resistance could provide a promising outcome, however, deep understanding and concerted research are necessary to design novel therapies targeting CSCs. To conclude, the understanding of these mechanisms of CSC in CRC could lead to the improved management of patients with CRC.
Collapse
Affiliation(s)
- Plabon Kumar Das
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi 6205, Bangladesh;
| | - Farhadul Islam
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi 6205, Bangladesh;
- Institute for Glycomics, Griffith University, Gold Coast, QLD 4222, Australia
| | - Alfred K. Lam
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, QLD 4222, Australia
| |
Collapse
|
|
12
|
Zhang J, Xue ZQ, Wang B, Wen JX, Wang YX. Inhibition of miR-22 enhanced the efficacy of icotinib plus pemetrexed in a rat model of non-small cell lung cancer. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2020; 23:329-336. [PMID: 32440319 PMCID: PMC7229502 DOI: 10.22038/ijbms.2019.39291.9320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Objective(s): To investigate the role of miR-22 in the efficacy of combined icotinib (BPI-2009H) and pemetrexed (LY-231514) on tumor growth and apoptosis in rats with non-small cell lung cancer (NSCLC). Materials and Methods: Rats were injected with HCC827 cells, which were transfected with anti-miR-22, followed by the treatment of BPI-2009H and/or LY-231514. MTT assay was used to detect the inhibition rate of HCC827 cells. qRT-PCR was performed to examine miR-22 expression in HCC827 cells and lung tumor tissues. Moreover, immunohistochemistry and Western blotting were performed to detect the related-molecule expressions, while TUNEL staining was used to observe cell apoptosis of lung tumor tissues. Results: MiR-22 expression was decreased in HCC827 cells after the treatment of BPI-2009H or LY-231514 in a dose-dependent manner. Both BPI-2009H and LY-231514 increased the inhibition rate of HCC827 cells, which was enhanced by anti-miR-22 with decreased IC50 values. Furthermore, the decreased expression of miR-22 was found after the treatment of BPI-2009H or/and LY-231514 in lung tumor tissues. In addition, the expressions of PCNA, Ki67, and Bcl-2 were reduced, but Bax and Caspase-3 were increased in treated rats, typically in those rats treated with the combination of anti-miR-22, BPI-2009H, and LY-231514. Conclusion: Inhibition of miR-22 could enhance the efficacy of icotinib combined with pemetrexed in rats with NSCLC, providing a new perspective for NSCLC therapy.
Collapse
Affiliation(s)
- Jing Zhang
- Department of Thoracic Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Zhi-Qiang Xue
- Department of Thoracic Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Bin Wang
- Department of Thoracic Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Jia-Xin Wen
- Department of Thoracic Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Yun-Xi Wang
- Department of Thoracic Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| |
Collapse
|
|
13
|
Douglas JK, Callahan RE, Hothem ZA, Cousineau CS, Kawak S, Thibodeau BJ, Bergeron S, Li W, Peeples CE, Wasvary HJ. Genomic variation as a marker of response to neoadjuvant therapy in locally advanced rectal cancer. Mol Cell Oncol 2020; 7:1716618. [PMID: 32391418 PMCID: PMC7199754 DOI: 10.1080/23723556.2020.1716618] [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: 10/14/2019] [Revised: 01/08/2020] [Accepted: 01/13/2020] [Indexed: 02/07/2023]
Abstract
There is variation in the responsiveness of locally advanced rectal cancer to neoadjuvant chemoradiation, from complete response to total resistance. This study compared genetic variation in rectal cancer patients who had a complete response to chemoradiation versus poor response, using tumor tissue samples sequenced with genomics analysis software. Rectal cancer patients treated with chemoradiation and proctectomy June 2006-March 2017 were grouped based on response to chemoradiation: those with no residual tumor after surgery (CR, complete responders, AJCC-CPR tumor grade 0, n = 8), and those with poor response (PR, AJCC-CPR tumor grade two or three on surgical resection, n = 8). We identified 195 variants in 83 genes in tissue specimens implicated in colorectal cancer biopathways. PR patients showed mutations in four genes not mutated in complete responders: KDM6A, ABL1, DAXX-ZBTB22, and KRAS. Ten genes were mutated only in the CR group, including ARID1A, PMS2, JAK1, CREBBP, MTOR, RB1, PRKAR1A, FBXW7, ATM C11orf65, and KMT2D, with specific discriminating variants noted in DMNT3A, KDM6A, MTOR, APC, and TP53. Although conclusions may be limited by small sample size in this pilot study, we identified multiple genetic variations in tumor DNA from rectal cancer patients who are poor responders to neoadjuvant chemoradiation, compared to complete responders.
Collapse
Affiliation(s)
| | - Rose E. Callahan
- Department of Surgical Research, Beaumont Research Institute, Royal Oak, MI, USA
| | | | | | - Samer Kawak
- Department of Surgery, Beaumont Health, Royal Oak, MI, USA
| | | | | | - Wei Li
- Department of Pathology, Beaumont Health, Royal Oak, MI, USA
| | | | | |
Collapse
|
|
14
|
Zhang Z, Li M, Zhang Z. lncRNA MALAT1 modulates oxaliplatin resistance of gastric cancer via sponging miR-22-3p. Onco Targets Ther 2020; 13:1343-1354. [PMID: 32104001 PMCID: PMC7026158 DOI: 10.2147/ott.s196619] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 01/30/2019] [Indexed: 02/06/2023] Open
Abstract
Objective Various regulatory mechanisms have been demonstrated to be associated with cancer progression. ncRNA and mRNA play important roles in gastric cancer (GC) cell growth and drug resistance, respectively. However, the regulatory network of ncRNA and mRNA in GC oxaliplatin (OXA) resistance has not been fully clarified. Methods The expression of miR-22-3p, MALAT1, and zinc finger protein 91 (ZFP91) was detected in tissues and cells using quantitative real-time PCR. The protein level of ZFP91 was measured by Western blot analysis. Luciferase reporter, pull-down, and RNA immunoprecipitation assays were used to determine the relationship between MALAT1, miR-22-3p, and ZFP91. MTT assay was applied to measure cell survival and proliferation. Cell apoptosis was detected using flow cytometry. Tumor xenograft assay was used to detect the function of miR-22-3p in vivo. Results In this study, we found that MALAT1 and ZFP91 expression was upregulated while the expression of miR-22-3p was downregulated in GC/OXA tissues and cells. Additionally, miR-22-3p was a target miRNA of MALAT1 and ZFP91 was a target mRNA of miR-22-3p. Functional studies showed that the knockdown of MALAT1 or overexpression of miR-22-3p inhibited GC/OXA cell survival, proliferation, and drug resistance as well as induced apoptosis, which could be reversed by the inhibition of miR-22-3p or overexpression of ZFP91. Conclusion We observed a new regulatory network for MALAT1 in drug resistance of GC. MALAT1 modulates ZFP91 to promote GC cells OXA resistance via sponging miR-22-3p.
Collapse
Affiliation(s)
- Zhenming Zhang
- Department II of General Surgery, Zhangye People's Hospital Affiliated to Hexi University, Zhangye, Gansu, China
| | - Ming Li
- Department II of General Surgery, Zhangye People's Hospital Affiliated to Hexi University, Zhangye, Gansu, China
| | - Zhitao Zhang
- Department of Oncology, Zhangye People's Hospital Affiliated to Hexi University, Zhangye, Gansu, China
| |
Collapse
|
|
15
|
Meng CY, Zhao ZQ, Bai R, Zhao W, Wang YX, Xue HQ, Sun L, Sun C, Feng W, Guo SB. MicroRNA‑22 mediates the cisplatin resistance of osteosarcoma cells by inhibiting autophagy via the PI3K/Akt/mTOR pathway. Oncol Rep 2020; 43:1169-1186. [PMID: 32323781 PMCID: PMC7057943 DOI: 10.3892/or.2020.7492] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 01/27/2020] [Indexed: 12/13/2022] Open
Abstract
Osteosarcoma (OS) is the most common primary malignant tumor of the bone affecting children and adolescents. Chemotherapy is now considered as a standard component of OS treatment, not only for children, but also for adults. However, chemoresistance continues to pose a challenge to therapy. Inhibition of autophagy has been demonstrated to decrease chemoresistance in OS. Moreover, microRNA-22 (miR-22) inhibits autophagy, leading to an improvement in the sensitivity of cisplatin (CDDP) in OS. The aim of the present study was therefore to investigate whether miR-22 could mediate the CDDP resistance of OS cells by inhibiting autophagy via the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. Cell proliferation assay, LC3 flow cytometry assay and monodansylcadaverine staining in MG63 cells and CDDP resistance cells (MG63/CDDP) were performed to explore to role of miR-22 and CDDP in OS chemoresistance. Inoculation of tumor cells in an in vivo model, reverse transcription-quantitative PCR (RT-qPCR) assay, western blot analysis, and immunohistochemistry analysis were performed to investigate the role of miR-22 and CDDP in the PI3K/Akt/mTOR pathway as it is affected by autophagy. The results revealed that miR-22 inhibited the proliferation of MG63 and MG63/CDDP cells, and enhanced the anti-proliferative ability of CDDP in vivo and in vitro. miR-22 mediated the CDDP resistance of OS cells by inhibiting autophagy and decreasing CDDP-induced autophagy via downregulation of the expression of PI3K, Akt, and mTOR at the mRNA level, and the expression of PI3K, phosphorylated (p)-Akt, and p-mTOR at the protein level. It was also convincingly demonstrated that miR-22 mediates the CDDP resistance of OS by inhibiting autophagy via the PI3K/Akt/mTOR pathway. Furthermore, in the MG63 cells that were affected by CDDP, the role of miR-22 was shown to be similar to that of the investigated inhibitor of PI3K (wortmannin) in terms of regulating the PI3K/Akt/mTOR pathway, and wortmannin could also promote the effect of miR-22. Interestingly, CDDP was demonstrated to induce autophagy by inhibiting the PI3K/Akt/mTOR pathway, whereas the pathway was upregulated in the state of chemoresistance. In conclusion, downregulation of the PI3K/Akt/mTOR pathway was shown to assist in the process of preventing chemoresistance.
Collapse
Affiliation(s)
- Chen-Yang Meng
- Department of Orthopedic Surgery, Second Affiliated Hospital of Inner Mongolia Medical University, Huimin, Hohhot, Inner Mongolia 010030, P.R. China
| | - Zhen-Qun Zhao
- Department of Orthopedic Surgery, Second Affiliated Hospital of Inner Mongolia Medical University, Huimin, Hohhot, Inner Mongolia 010030, P.R. China
| | - Rui Bai
- Department of Orthopedic Surgery, Second Affiliated Hospital of Inner Mongolia Medical University, Huimin, Hohhot, Inner Mongolia 010030, P.R. China
| | - Wei Zhao
- Department of Orthopedic Surgery, Second Affiliated Hospital of Inner Mongolia Medical University, Huimin, Hohhot, Inner Mongolia 010030, P.R. China
| | - Yu-Xing Wang
- Department of Orthopedic Surgery, Second Affiliated Hospital of Inner Mongolia Medical University, Huimin, Hohhot, Inner Mongolia 010030, P.R. China
| | - Hui-Qin Xue
- Department of Rehabilitation, Second Affiliated Hospital of Inner Mongolia Medical University, Huimin, Hohhot, Inner Mongolia 010030, P.R. China
| | - Liang Sun
- Department of Orthopedic Surgery, Second Affiliated Hospital of Inner Mongolia Medical University, Huimin, Hohhot, Inner Mongolia 010030, P.R. China
| | - Chao Sun
- Department of Orthopedic Surgery, Second Affiliated Hospital of Inner Mongolia Medical University, Huimin, Hohhot, Inner Mongolia 010030, P.R. China
| | - Wei Feng
- Department of Orthopedic Surgery, Second Affiliated Hospital of Inner Mongolia Medical University, Huimin, Hohhot, Inner Mongolia 010030, P.R. China
| | - Shi-Bing Guo
- Department of Orthopedic Surgery, Second Affiliated Hospital of Inner Mongolia Medical University, Huimin, Hohhot, Inner Mongolia 010030, P.R. China
| |
Collapse
|
|
16
|
Naghizadeh S, Mansoori B, Mohammadi A, Sakhinia E, Baradaran B. Gene Silencing Strategies in Cancer Therapy: An Update for Drug Resistance. Curr Med Chem 2019; 26:6282-6303. [DOI: 10.2174/0929867325666180403141554] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Revised: 03/10/2018] [Accepted: 03/29/2018] [Indexed: 12/14/2022]
Abstract
RNAi, post-transcriptional gene silencing mechanism, could be considered as one of the
most important breakthroughs and rapidly growing fields in science. Researchers are trying to use this
discovery in the treatment of various diseases and cancer is one of them although there are multiple
treatment procedures for treatment-resistant cancers, eradication of resistance remain as an unsolvable
problem yet. The current review summarizes both transcriptional and post-transcriptional gene silencing
mechanisms, and highlights mechanisms leading to drug-resistance such as, drug efflux, drug inactivation,
drug target alteration, DNA damages repair, and the epithelial-mesenchymal transition, as
well as the role of tumor cell heterogeneity and tumor microenvironment, involving genes in these
processes. It ultimately points out the obstacles of RNAi application for in vivo treatment of diseases
and progressions that have been achieved in this field.
Collapse
Affiliation(s)
- Sanaz Naghizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Mohammadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ebrahim Sakhinia
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
|
17
|
Soleimani A, Rahmani F, Ferns GA, Ryzhikov M, Avan A, Hassanian SM. Role of Regulatory Oncogenic or Tumor Suppressor miRNAs of PI3K/AKT Signaling Axis in the Pathogenesis of Colorectal Cancer. Curr Pharm Des 2019; 24:4605-4610. [PMID: 30636581 DOI: 10.2174/1381612825666190110151957] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 12/24/2018] [Accepted: 12/31/2018] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is the leading cause of cancer death worldwide and its incidence is increasing. In most patients with CRC, the PI3K/AKT signaling axis is over-activated. Regulatory oncogenic or tumor suppressor microRNAs (miRNAs) for PI3K/AKT signaling regulate cell proliferation, migration, invasion, angiogenesis, as well as resistance to chemo-/radio-therapy in colorectal cancer tumor tissues. Thus, regulatory miRNAs of PI3K/AKT/mTOR signaling represent novel biomarkers for new patient diagnosis and obtaining clinically invaluable information from post-treatment CRC patients for improving therapeutic strategies. This review summarizes the current knowledge of miRNAs' regulatory roles of PI3K/AKT signaling in CRC pathogenesis.
Collapse
Affiliation(s)
- Atena Soleimani
- Department of Medical Biochemistry, faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farzad Rahmani
- Department of Medical Biochemistry, faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, United Kingdom
| | - Mikhail Ryzhikov
- Division of Pulmonary and Critical Care Medicine, Washington University, School of Medicine, Saint Louis, MO, United States
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of M edical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Department of Medical Biochemistry, faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
18
|
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
|
|
19
|
Neve B, Jonckheere N, Vincent A, Van Seuningen I. Epigenetic Regulation by lncRNAs: An Overview Focused on UCA1 in Colorectal Cancer. Cancers (Basel) 2018; 10:E440. [PMID: 30441811 PMCID: PMC6266399 DOI: 10.3390/cancers10110440] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 11/06/2018] [Accepted: 11/08/2018] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancers have become the second leading cause of cancer-related deaths. In particular, acquired chemoresistance and metastatic lesions occurring in colorectal cancer are a major challenge for chemotherapy treatment. Accumulating evidence shows that long non-coding (lncRNAs) are involved in the initiation, progression, and metastasis of cancer. We here discuss the epigenetic mechanisms through which lncRNAs regulate gene expression in cancer cells. In the second part of this review, we focus on the role of lncRNA Urothelial Cancer Associated 1 (UCA1) to integrate research in different types of cancer in order to decipher its putative function and mechanism of regulation in colorectal cancer cells. UCA1 is highly expressed in cancer cells and mediates transcriptional regulation on an epigenetic level through the interaction with chromatin modifiers, by direct regulation via chromatin looping and/or by sponging the action of a diversity of miRNAs. Furthermore, we discuss the role of UCA1 in the regulation of cell cycle progression and its relation to chemoresistance in colorectal cancer cells.
Collapse
Affiliation(s)
- Bernadette Neve
- Inserm UMR-S 1172, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc), Team "Mucins, Epithelial Differentiation and Carcinogenesis"; University Lille; CHU Lille,59045, Lille CEDEX, France.
| | - Nicolas Jonckheere
- Inserm UMR-S 1172, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc), Team "Mucins, Epithelial Differentiation and Carcinogenesis"; University Lille; CHU Lille,59045, Lille CEDEX, France.
| | - Audrey Vincent
- Inserm UMR-S 1172, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc), Team "Mucins, Epithelial Differentiation and Carcinogenesis"; University Lille; CHU Lille,59045, Lille CEDEX, France.
| | - Isabelle Van Seuningen
- Inserm UMR-S 1172, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc), Team "Mucins, Epithelial Differentiation and Carcinogenesis"; University Lille; CHU Lille,59045, Lille CEDEX, France.
| |
Collapse
|
|
20
|
Pan H, Zhu L. Angelica sinensis polysaccharide protects rat cardiomyocytes H9c2 from hypoxia-induced injury by down-regulation of microRNA-22. Biomed Pharmacother 2018; 106:225-231. [DOI: 10.1016/j.biopha.2018.06.120] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 06/21/2018] [Accepted: 06/22/2018] [Indexed: 10/28/2022] Open
|
|
21
|
A dual role of miR-22 modulated by RelA/p65 in resensitizing fulvestrant-resistant breast cancer cells to fulvestrant by targeting FOXP1 and HDAC4 and constitutive acetylation of p53 at Lys382. Oncogenesis 2018; 7:54. [PMID: 30057418 PMCID: PMC6064715 DOI: 10.1038/s41389-018-0063-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Accepted: 05/21/2018] [Indexed: 12/11/2022] Open
Abstract
Antiestrogen resistance is a major challenge encountered during the treatment of estrogen receptor alpha positive (ERα+) breast cancer. A better understanding of signaling pathways and downstream transcription factors and their targets may identify key molecules that can overcome antiestrogen resistance in breast cancer. An aberrant expression of miR-22 has been demonstrated in breast cancer; however, its contribution to breast cancer resistance to fulvestrant, an antiestrogen drug, remains unknown. In this study, we demonstrated a moderate elevation in miR-22 expression in the 182R-6 fulvestrant-resistant breast cancer line we used as a model system, and this elevation was positively correlated with the expression of the miRNA biogenesis enzymes AGO2 and Dicer. The level of phosphorylated HER2/neu at Tyr877 was also upregulated in these cells, whereas the level of RelA/p65 phosphorylated at Ser536 (p-p65) was downregulated. Knockdown of HER2/neu led to an induction of p-p65 and a reduction in miR-22 levels. Luciferase assays identified two NF-κB binding motifs in the miR-22 promoter that contributed to transcriptional repression of miR-22. Activation of RelA/p65, triggered by LPS, attenuated miR-22 expression, but this expression was restored by sc-514, a selective IKKβ inhibitor. Inhibition of miR-22 suppressed cell proliferation, induced apoptosis and caused cell cycle S-phase arrest, whereas enhancing expression of p21Cip1/Waf1 and p27Kip1. Surprisingly, ectopic expression of miR-22 also suppressed cell proliferation, induced apoptosis, caused S-phase arrest, and promoted the expression of p21Cip1/Waf1 and p27Kip1. Ectopic overexpression of miR-22 repressed the expression of FOXP1 and HDAC4, leading to a marked induction of acetylation of HDAC4 target histones. Conversely, inhibition of miR-22 promoted the expression of both FOXP1 and HDAC4, without the expected attenuation of histone acetylation. Instead, p53 acetylation at lysine 382 was unexpectedly upregulated. Taken together, our findings demonstrated, for the first time, that HER2 activation dephosphorylates RelA/p65 at Ser536. This dephosphoryalted p65 may be pivotal in transactivation of miR-22. Both increased and decreased miR-22 expression cause resensitization of fulvestrant-resistant breast cancer cells to fulvestrant. HER2/NF-κB (p65)/miR-22/HDAC4/p21 and HER2/NF-κB (p65)/miR-22/Ac-p53/p21 signaling circuits may therefore confer this dual role on miR-22 through constitutive transactivation of p21.
Collapse
|
|
22
|
Hahne JC, Valeri N. Non-Coding RNAs and Resistance to Anticancer Drugs in Gastrointestinal Tumors. Front Oncol 2018; 8:226. [PMID: 29967761 PMCID: PMC6015885 DOI: 10.3389/fonc.2018.00226] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 05/31/2018] [Indexed: 12/12/2022] Open
Abstract
Non-coding RNAs are important regulators of gene expression and transcription. It is well established that impaired non-coding RNA expression especially the one of long non-coding RNAs and microRNAs is involved in a number of pathological conditions including cancer. Non-coding RNAs are responsible for the development of resistance to anticancer treatments as they regulate drug resistance-related genes, affect intracellular drug concentrations, induce alternative signaling pathways, alter drug efficiency via blocking cell cycle regulation, and DNA damage response. Furthermore, they can prevent therapeutic-induced cell death and promote epithelial-mesenchymal transition (EMT) and elicit non-cell autonomous mechanisms of resistance. In this review, we summarize the role of non-coding RNAs for different mechanisms resulting in drug resistance (e.g., drug transport, drug metabolism, cell cycle regulation, regulation of apoptotic pathways, cancer stem cells, and EMT) in the context of gastrointestinal cancers.
Collapse
Affiliation(s)
- Jens C. Hahne
- Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom
| | - Nicola Valeri
- Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom
- Department of Medicine, The Royal Marsden NHS Trust, London, United Kingdom
| |
Collapse
|
|
23
|
Zekri ARN, El-Sisi ER, Youssef ASED, Kamel MM, Nassar A, Ahmed OS, El Kassas M, Barakat AB, Abd El-Motaleb AI, Bahnassy AA. MicroRNA Signatures for circulating CD133-positive cells in hepatocellular carcinoma with HCV infection. PLoS One 2018; 13:e0193709. [PMID: 29534065 PMCID: PMC5849309 DOI: 10.1371/journal.pone.0193709] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 02/19/2018] [Indexed: 02/07/2023] Open
Abstract
AIM Molecular characterization of the CD133+ stem cells associated with hepatocarinogensis through identifying the expression patterns of specific microRNAs (miRNAs). METHODS We investigated the expression pattern of 13 miRNAs in purified CD133+ cells separated from the peripheral blood of healthy volunteers, chronic hepatitis C (CHC), liver cirrhosis (LC) and hepatocellular carcinoma (HCC) patients a long with bone marrow samples from the healthy volunteers and the LC patients using custom miScript miRNA PCR array. RESULTS The differential expression of the 13 studied miRNAs in CD133+ cells separated from the HCC patients' peripheral blood compared to the controls revealed that miR-602, miR-181b, miR-101, miR-122, miR-192, miR-125a-5p, and miR-221 were significantly up regulated (fold change = 1.8, 1.7, 2, 5.4, 1.6, 2.9 & 1.5 P value = 0.039, 0.0019, 0.0013, 0.0370, 00024, 0.000044 &0.000007 respectively). As for the HCC group compared to the CHC group; miR-602, miR-122, miR-181b, miR-125a-5p, and miR-192 were significantly up regulated (fold change = 13, 3.1, 2.8, 1.6 & 1.56, P value = 0.01, 0.001, 0.000004, 0.002 & 0.007 respectively). Upon comparing the HCC group to the LC group; miR-199a-3p, miR-192, miR-122, miR-181b, miR-224, miR-125a-5p, and miR-885-5p were significantly up regulated (fold change = 5, 6.7, 2.3, 3, 2.5, 4.2 & 39.5 P value = 0.001025, 0.000024, 0.000472, 0.000278, 0.000004, 0.000075 & 0.0000001 respectively) whereas miR-22 was significantly down regulated (fold change = 0.57 P value = 0.00002). Only, miR-192, miR-122, miR-181b and miR-125a-5p were significant common miRNAs in CD133+ cells of the HCC group compared to the other non-malignant groups. CONCLUSION We identified a miRNA panel comprised of four miRNAs (miR-192, miR-122, miR-181b and miR-125a-5p) that may serve as a molecular tool for characterization of the CD133+ cells associated with different stages of hepatocarinogensis. This panel may aid in developing a new target therapy specific for those CD133+ cells.
Collapse
Affiliation(s)
- Abdel-Rahman N. Zekri
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Enas Reda El-Sisi
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Amira Salah El-Din Youssef
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Mahmoud M. Kamel
- Clinical Pathology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Auhood Nassar
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Ola Sayed Ahmed
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
- Photobiology and Molecular Biology Department, Laser Institute for Research and Applications (LIRA), Beni-Suef University, Beni Suef, Egypt
| | - Mohamed El Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Helwan, Egypt
| | | | | | - Abeer A. Bahnassy
- Tissue Culture and Cytogenetics Unit, Pathology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| |
Collapse
|
|
24
|
Liu Y, Chen X, Cheng R, Yang F, Yu M, Wang C, Cui S, Hong Y, Liang H, Liu M, Zhao C, Ding M, Sun W, Liu Z, Sun F, Zhang C, Zhou Z, Jiang X, Chen X. The Jun/miR-22/HuR regulatory axis contributes to tumourigenesis in colorectal cancer. Mol Cancer 2018; 17:11. [PMID: 29351796 PMCID: PMC5775639 DOI: 10.1186/s12943-017-0751-3] [Citation(s) in RCA: 98] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 12/26/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a severe health problem worldwide. Clarifying the mechanisms for the deregulation of oncogenes and tumour suppressors in CRC is vital for its diagnosis, treatment, prognosis and prevention. Hu antigen R (HuR), which is highly upregulated in CRC, functions as a pivotal oncogene to promote CRC progression. However, the underlying cause of its dysregulation is poorly understood. METHODS In CRC tissue sample pairs, HuR protein levels were measured by Western blot and immunohistochemical (IHC) staining, respectively. HuR mRNA levels were also monitored by qRT-PCR. Combining meta-analysis and microRNA (miRNA) target prediction software, we predicted miRNAs that targeted HuR. Pull-down assay, Western blot and luciferase assay were utilized to demonstrate the direct binding of miR-22 on HuR's 3'-UTR. The biological effects of HuR and miR-22 were investigated both in vitro by CCK-8, EdU and Transwell assays and in vivo by a xenograft mice model. JASPAR and SABiosciences were used to predict transcriptional factors that could affect miR-22. Luciferase assay was used to explore the validity of putative Jun binding sites for miR-22 regulation. ChIP assay was performed to test the Jun's occupancy on the C17orf91 promoter. RESULTS We observed a significant upregulation of HuR in CRC tissue pairs and confirmed the oncogenic function of HuR both in vitro and in vivo. We found that an important tumour-suppressive miRNA, miR-22, was significantly downregulated in CRC tissues and inversely correlated with HuR in both CRC tissues and CRC cell lines. We demonstrated that miR-22 directly bound to the 3'-UTR of HuR and led to inhibition of HuR protein, which repressed CRC proliferation and migration in vitro and decelerated CRC xenografted tumour growth in vivo. Furthermore, we found that the onco-transcription factor Jun could inhibit the transcription of miR-22. CONCLUSIONS Our findings highlight the critical roles of the Jun/miR-22/HuR regulatory axis in CRC progression and may provide attractive potential targets for CRC prevention and treatment.
Collapse
Affiliation(s)
- Yanqing Liu
- State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210046, China
| | - Xiaorui Chen
- State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210046, China
| | - Rongjie Cheng
- State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210046, China
| | - Fei Yang
- State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210046, China
| | - Mengchao Yu
- State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210046, China
| | - Chen Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210046, China
| | - Shufang Cui
- State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210046, China
| | - Yeting Hong
- State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210046, China
| | - Hongwei Liang
- State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210046, China
| | - Minghui Liu
- State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210046, China
| | - Chihao Zhao
- State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210046, China
| | - Meng Ding
- State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210046, China
| | - Wu Sun
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - Zhijian Liu
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, 210008, China
| | - Feng Sun
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, 210008, China
| | - Chenyu Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210046, China
| | - Zhen Zhou
- State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210046, China.
| | - Xiaohong Jiang
- State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210046, China.
| | - Xi Chen
- State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210046, China.
| |
Collapse
|
|
25
|
Wang J, Li XM, Bai Z, Chi BX, Wei Y, Chen X. Curcumol induces cell cycle arrest in colon cancer cells via reactive oxygen species and Akt/ GSK3β/cyclin D1 pathway. JOURNAL OF ETHNOPHARMACOLOGY 2018; 210:1-9. [PMID: 28684297 DOI: 10.1016/j.jep.2017.06.037] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Revised: 02/10/2017] [Accepted: 06/10/2017] [Indexed: 06/07/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Curcuma kwangsiensis S. G. Lee & C. F. Liang (Guangxi ezhu, in Chinese) belongs to the Zingiberaceae family, has been used as a traditionally Chinese medicine nearly 2000 year. Curcumol is one of the guaiane-type sesquiterpenoid hemiketal isolated from medicine plant Curcuma kwangsiensis S. G. Lee & C. F. Liang, which has been reported possesses anti-cancer effects. Our previous study found that the most contribution to inhibit nasopharyngeal carcinoma cell growth was curcumol. AIM OF THE STUDY To assess the effect of curcumol on cell cycle arrest against human colon cancer cells (CRC) cells (LoVo and SW480) and explore its mechanism in vitro and in vivo. MATERIALS AND METHODS Curcumol was dissolved in absolute ethyl alcohol. The concentration of absolute ethyl alcohol in the control group or in experimental samples was always 1/500 (v/v) of the final medium volume. LoVo and SW480 cells were treated with different concentrations of curcumol (0, 53, 106, 212 and 424μM). And then the cell cycle of each group was examined by flow cytometry. The protein levels of PI3K, p-Akt, cyclin D1, cyclin E, CDK2, CDK4 and GSK3β were determined by Western blot. The mRNA expression of PI3K, Akt, cyclin D1, CDK4, P27, p21, and P16 in the treated cells were analyzed by real-time RT-PCR. In addition, the antitumor activity of curcumol was evaluated in nude mice bearing orthotopic tumor implants. RESULTS Curcumol induced cell cycle arrest in G1/S phase. RT-qPCR and Western blot data showed that curcumol enhanced the expression of GSK3β, P27, p21 and P16, and decreased the levels of PI3K, phosphorylated Akt (p-Akt), cyclin D1, CDK4, cyclin E and CDK2. Furthermore, curcumol induced reactive oxygen species (ROS) generation in LoVo cells, and ROS scavenger N-acetylcysteine (NAC) significantly reversed curcumol-induced cell growth inhibition. Besides, curcumol also prevented the growth of human colon cancer cells xenografts in nude mouse, accompanied by the reduction of PI3K, Akt, cyclin D1, CDK4, cycln E and significant increase of GSK3β. CONCLUSIONS Curcumol caused cell cycle arrest at the G0/G1 phase by ROS production and Akt/ GSK3β/cyclin D1 pathways inactivation, indicating the potential of curcumol in the prevention of colon cancer carcinogenesis.
Collapse
Affiliation(s)
- Juan Wang
- Xiangya Hospital Central South University, Chang sha 410008, China; College of Pharmacy, Guilin Medical University, Guilin 541004, China
| | - Xu-Mei Li
- College of Pharmacy, Guilin Medical University, Guilin 541004, China
| | - Zhun Bai
- Intensive Care Unit, Zhuzhou Central Hospital, Zhuzhou 412007, China
| | - Bi-Xia Chi
- Digestive System Department, The Frist People's Hospital of YueYang, Yueyang 414000, China
| | - Yan Wei
- College of Pharmacy, Guilin Medical University, Guilin 541004, China
| | - Xu Chen
- College of Pharmacy, Guilin Medical University, Guilin 541004, China.
| |
Collapse
|
|
26
|
Li J, Li B, Ren C, Chen Y, Guo X, Zhou L, Peng Z, Tang Y, Chen Y, Liu W, Zhu B, Wang L, Liu X, Shi X, Peng Z. The clinical significance of circulating GPC1 positive exosomes and its regulative miRNAs in colon cancer patients. Oncotarget 2017; 8:101189-101202. [PMID: 29254156 PMCID: PMC5731866 DOI: 10.18632/oncotarget.20516] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 08/06/2017] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Recent study found an increased level of glypican-1 positive (GPC1+) plasma exosomes in patients with stage II CRC, but decreased levels of plasma miR-96-5p and miR-149. This study further investigated the clinical significance of plasma GPC1+ exosomes and plasma miR-96-5p and miR-149 levels in stage III CRC patients. To study the effect of these microRNAs on GPC1+ plasma exosomes, we isolated and purified exosomes and overexpressed human GPC1 and the microRNAs miR-96-5p and miR-149 by adenovirus vectors. Overexpression of GPC1 activated epithelial-mesenchymal transition (EMT) which then increased invasion and migration in HT29 and HCT-116 colon cancer cells. In contrast, silencing GPC1 expression and overexpressing miR-96-5p and miR-149 significantly inactivated EMT and decreased invasion and migration of HT29 and HCT-116 cells. miR-96-5p and miR-149 inhibitors significantly increased invasion and migration of HT29 and HCT-116 cells. Our results indicate that high levels of circulating GPC1 positive exosomes before and after surgery as well as low circulating miR-96-5p and miR-149 before surgery indicated a severe clinical status and poor prognosis in stage III colon cancer patients. We conclude that GPC1 can be a biomarker for relapse of stage III CRC and may be involved in EMT activation, invasion, and migration of colorectal cancer cells.
Collapse
Affiliation(s)
- Jian Li
- Hepatobiliary and Enteric Surgery Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Bo Li
- Department of Pathology, Xiangya Medical School, Central South University, Changsha, Hunan 410078, China
| | - Caiping Ren
- Cancer Research Institute, Xiangya Hospital, Collaborative Innovation Center for Cancer Medicine, Key Laboratory for Carcinogenesis of Chinese Ministry of Health, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
| | - Yuxiang Chen
- School of Pharmaceutical Science, Central South University, Changsha, Hunan 410013, China
| | - Xiong Guo
- Hepatobiliary and Enteric Surgery Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Lin Zhou
- Hepatobiliary and Enteric Surgery Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Zha Peng
- Hepatobiliary and Enteric Surgery Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yaping Tang
- Hepatobiliary and Enteric Surgery Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yang Chen
- Hepatobiliary and Enteric Surgery Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Weidong Liu
- Cancer Research Institute, Xiangya Hospital, Collaborative Innovation Center for Cancer Medicine, Key Laboratory for Carcinogenesis of Chinese Ministry of Health, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
| | - Bin Zhu
- Cancer Research Institute, Xiangya Hospital, Collaborative Innovation Center for Cancer Medicine, Key Laboratory for Carcinogenesis of Chinese Ministry of Health, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
| | - Lei Wang
- Cancer Research Institute, Xiangya Hospital, Collaborative Innovation Center for Cancer Medicine, Key Laboratory for Carcinogenesis of Chinese Ministry of Health, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
| | - Xuxu Liu
- Cancer Research Institute, Xiangya Hospital, Collaborative Innovation Center for Cancer Medicine, Key Laboratory for Carcinogenesis of Chinese Ministry of Health, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
| | - Xiao Shi
- Cancer Research Institute, Xiangya Hospital, Collaborative Innovation Center for Cancer Medicine, Key Laboratory for Carcinogenesis of Chinese Ministry of Health, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
| | - Zixuan Peng
- Cancer Research Institute, Xiangya Hospital, Collaborative Innovation Center for Cancer Medicine, Key Laboratory for Carcinogenesis of Chinese Ministry of Health, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
| |
Collapse
|
|
27
|
Zeng Q, Liu J, Cao P, Li J, Liu X, Fan X, Liu L, Cheng Y, Xiong W, Li J, Bo H, Zhu Y, Yang F, Hu J, Zhou M, Zhou Y, Zou Q, Zhou J, Cao K. Inhibition of REDD1 Sensitizes Bladder Urothelial Carcinoma to Paclitaxel by Inhibiting Autophagy. Clin Cancer Res 2017; 24:445-459. [PMID: 29084921 DOI: 10.1158/1078-0432.ccr-17-0419] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 06/26/2017] [Accepted: 10/24/2017] [Indexed: 11/16/2022]
Abstract
Purpose: Regulated in development and DNA damage response-1 (REDD1) is a stress-related protein and is involved in the progression of cancer. The role and regulatory mechanism of REDD1 in bladder urothelial carcinoma (BUC), however, is yet unidentified.Experimental Design: The expression of REDD1 in BUC was detected by Western blot analysis and immunohistochemistry (IHC). The correlation between REDD1 expression and clinical features in patients with BUC were assessed. The effects of REDD1 on cellular proliferation, apoptosis, autophagy, and paclitaxel sensitivity were determined both in vitro and in vivo Then the targeted-regulating mechanism of REDD1 by miRNAs was explored.Results: Here the significant increase of REDD1 expression is detected in BUC tissue, and REDD1 is first reported as an independent prognostic factor in patients with BUC. Silencing REDD1 expression in T24 and EJ cells decreased cell proliferation, increased apoptosis, and decreased autophagy, whereas the ectopic expression of REDD1 in RT4 and BIU87 cells had the opposite effect. In addition, the REDD1-mediated proliferation, apoptosis, and autophagy are found to be negatively regulated by miR-22 in vitro, which intensify the paclitaxel sensitivity via inhibition of the well-acknowledged REDD1-EEF2K-autophagy axis. AKT/mTOR signaling initially activated or inhibited in response to silencing or enhancing REDD1 expression and then recovered rapidly. Finally, the inhibited REDD1 expression by either RNAi or miR-22 sensitizes BUC tumor cells to paclitaxel in a subcutaneous transplant carcinoma model in vivoConclusions: REDD1 is confirmed as an oncogene in BUC, and antagonizing REDD1 could be a potential therapeutic strategy to sensitize BUC cells to paclitaxel. Clin Cancer Res; 24(2); 445-59. ©2017 AACR.
Collapse
Affiliation(s)
- Qinghai Zeng
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Jianye Liu
- Department of Urology, Third Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Peiguo Cao
- Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Jingjing Li
- Department of Plastic Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Xiaoming Liu
- Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Xiaojun Fan
- Research Service Office, Third Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Ling Liu
- Outpatient service office, Third Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Yan Cheng
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, P.R. China
| | - Wei Xiong
- Cancer Research Institute and Key Laboratory of Carcinogenesis of Ministry of Health, Central South University, Changsha, Hunan, P.R. China
| | - Jigang Li
- Department of Pathology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P.R. China
| | - Hao Bo
- Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, Hunan, P.R. China
| | - Yuxing Zhu
- Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Fei Yang
- School of Public Health, Central South University, Changsha, Hunan, P.R. China
| | - Jun Hu
- Department of Tissue-bank, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P.R. China
| | - Ming Zhou
- Cancer Research Institute and Key Laboratory of Carcinogenesis of Ministry of Health, Central South University, Changsha, Hunan, P.R. China
| | - Yanhong Zhou
- Cancer Research Institute and Key Laboratory of Carcinogenesis of Ministry of Health, Central South University, Changsha, Hunan, P.R. China
| | - Qiong Zou
- Department of Pathology, Third Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Jianda Zhou
- Department of Plastic Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Ke Cao
- Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China.
| |
Collapse
|
|
28
|
Chen Z, Shen A, Liu L, Chen Y, Chu J, Cai Q, Qi F, Sferra TJ, Peng J. Pien Tze Huang induces apoptosis and inhibits proliferation of 5-fluorouracil-resistant colorectal carcinoma cells via increasing miR-22 expression. Exp Ther Med 2017; 14:3533-3540. [PMID: 29042944 PMCID: PMC5639424 DOI: 10.3892/etm.2017.4951] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2016] [Accepted: 07/01/2017] [Indexed: 12/23/2022] Open
Abstract
The well-known traditional Chinese medicine formula Pien Tze Huang (PZH) has long been used to treat various malignancies, including colorectal cancer (CRC). It was recently reported that PZH possesses the ability to overcome multidrug resistance in CRC cells. In the present study, a 5-fluorouracil (5-FU) resistant human CRC cell line (HCT-8/5-FU) was used to further evaluate the effect of PZH on chemotherapy (chemo)-resistance and investigate the mechanisms through which this occurs. The results identified that PZH significantly reduced the viability and cell density of HCT-8/5-FU cells in a dose- and time-dependent manner (P<0.05). PZH inhibited cell survival, reduced the proportion of cells in S-phase, and suppressed the expression of pro-proliferative proteins cyclin D1 and cyclin-dependent kinase 4. In addition, PZH treatment induced nuclear condensation and fragmentation, activated caspase-9 and -3 and increased the pro-apoptotic Bcl-2-associated X protein/B-cell lymphoma 2 protein ratio. Furthermore, PZH treatment upregulated the expression of microRNA-22 (miR-22) and downregulated the expression of c-Myc (a target gene of miR-22). In conclusion, the findings from the present study suggest that PZH can overcome chemo-resistance in cancer cells, likely through increasing miR-22 expression, and by reversing the imbalance between levels of proliferation and apoptosis.
Collapse
Affiliation(s)
- Zhaorong Chen
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Aling Shen
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Liya Liu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Youqin Chen
- Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Jianfeng Chu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Qiaoyan Cai
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Fei Qi
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Thomas Joseph Sferra
- Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Jun Peng
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| |
Collapse
|
|
29
|
Zhang Y, Wang J. MicroRNAs are important regulators of drug resistance in colorectal cancer. Biol Chem 2017; 398:929-938. [PMID: 28095367 PMCID: PMC5911396 DOI: 10.1515/hsz-2016-0308] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 01/08/2017] [Indexed: 12/13/2022]
Abstract
Despite of continuous development of cancer treatment over the past decades, drug resistance is still one of the major hurdles of effective therapy for advanced colorectal cancer (CRC) worldwide and the understanding of its underlying mechanisms remains limited. Data which have emerged suggests that many microRNAs (miRNAs) may contribute to drug resistance in CRC. Major findings on miRNA functions in drug resistance of CRC are systemically reviewed here, with the goal of providing new updates to broaden our comprehension of its mechanisms and evidence to utilize miRNAs as potential therapeutic targets for CRC treatment.
Collapse
|
|
30
|
Li B, Li B, Sun H, Zhang H. The predicted target gene validation, function, and prognosis studies of miRNA-22 in colorectal cancer tissue. Tumour Biol 2017; 39:1010428317692257. [PMID: 28347238 DOI: 10.1177/1010428317692257] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
MicroRNAs are known as small, non-coding, and single-stranded RNAs which can regulate cell proliferation, differentiation, and apoptosis and involve in the development of tumors. In this study, colorectal cancer tissue morphological change in different prognosis in patients was observed by hematoxylin and eosin staining. Thereafter, differentially expressed miR-22 and TIAM1 gene were detected using quantitative polymerase chain reaction and western blot in different colorectal cancer tissues. Meanwhile, luciferase reporter gene system was used to verify the relationship between miR-22 and TIAM1. Eventually, the survival curve was plotted according to follow-up records of patients with colorectal cancer and the expression levels of miR-22 and TIAM1 in different tumor tissues. The hematoxylin and eosin results showed the poor pathological features in the 1-year survival group. The expression level of miR-22 was upregulated and TIAM1 was inhibited, correlating with the extension of patients' survival time. Our results indicated that miR-22 and TIAM1 might play a regulatory role in the occurrence and development of colorectal cancer which were consistent with the survival curve analysis results. Furthermore, the luciferase in miR-22 co-transfected with pmiR-RB-REPORT- TIAM1 group was significantly lower than pmiR-RB-REPORT- TIAM1-mut and Si groups. Collectively, these data suggest that miR-22 may suppress the expression of its target gene TIAM1. The low miR-22 level or the high TIAM1 level will indicate the poor prognosis in colorectal cancer patients.
Collapse
Affiliation(s)
- Bo Li
- 1 Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, P.R. China
| | - Bai Li
- 2 Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Jilin University, Changchun, P.R. China
| | - Hongyan Sun
- 3 Department of Tissue Bank, China-Japan Union Hospital of Jilin University, Changchun, P.R. China
| | - Haishan Zhang
- 1 Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, P.R. China
| |
Collapse
|
|
31
|
Li J, Chen Y, Guo X, Zhou L, Jia Z, Peng Z, Tang Y, Liu W, Zhu B, Wang L, Ren C. GPC1 exosome and its regulatory miRNAs are specific markers for the detection and target therapy of colorectal cancer. J Cell Mol Med 2017; 21:838-847. [PMID: 28233416 PMCID: PMC5387162 DOI: 10.1111/jcmm.12941] [Citation(s) in RCA: 132] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 06/29/2016] [Indexed: 12/20/2022] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. However, a biomarker for a sensitive and simple diagnostic test and highly effective target therapy of CRC is still clinically unavailable. This study is to investigate the evidence and significance of plasma GPC1 positive exosomes as a biomarker of CRC. Results showed that GPC1+ exosomes were successfully isolated from tissues and plasma. The percentage of GPC1+ exosomes and the GPC1 protein expression in exosomes from tumour tissues and plasma of CRC patients before surgical treatment was significantly elevated compared to that in the peritumoural tissues and the plasma of healthy controls. miR-96-5p and miR-149 expression in tumour tissues and plasma of CRC patients as well as in the GPC1+ exosomes from CRC patients were significantly decreased compared to that in the peritumoural tissues and the plasma of healthy controls. Two months after surgical treatment, levels of all tested markers significantly normalized. Overexpression of miR-96-5p and miR-149 significantly decreased GPC1 expression in HT-29 and HCT-116 cells, xenograft tumours, plasma in mice bearing HT-29 and HCT-116 tumours, and the secretion of GPC1+ exosomes from the HT-29 and HCT-116 cells and xenograft tumours. Overexpression of miR-96-5p and miR-149 significantly decreased cell viability and increased cell apoptosis in HT-29 and HCT-116 cells, and inhibited the growth of xenograft HT-29 and HCT-116 tumours. In conclusion, the increased plasma GPC1+ exosomes and reduced plasma miR-96-5p and miR-149 expression are specific markers for the diagnosis of CRC and targets for the therapy of CRC.
Collapse
Affiliation(s)
- Jian Li
- Hepatobiliary and Enteric Surgery Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuxiang Chen
- School of Pharmaceutical Science, Central South University, Changsha, Hunan, China
| | - Xiong Guo
- Hepatobiliary and Enteric Surgery Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lin Zhou
- Hepatobiliary and Enteric Surgery Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zeming Jia
- Hepatobiliary and Enteric Surgery Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zha Peng
- Hepatobiliary and Enteric Surgery Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yaping Tang
- Hepatobiliary and Enteric Surgery Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Weidong Liu
- Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, Key Laboratory for Carcinogenesis of Chinese Ministry of Health, School of Basic Medical Science, Central South University, Changsha, Hunan, China
| | - Bin Zhu
- Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, Key Laboratory for Carcinogenesis of Chinese Ministry of Health, School of Basic Medical Science, Central South University, Changsha, Hunan, China
| | - Lei Wang
- Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, Key Laboratory for Carcinogenesis of Chinese Ministry of Health, School of Basic Medical Science, Central South University, Changsha, Hunan, China
| | - Caiping Ren
- Cancer Research Institute, Collaborative Innovation Center for Cancer Medicine, Key Laboratory for Carcinogenesis of Chinese Ministry of Health, School of Basic Medical Science, Central South University, Changsha, Hunan, China
| |
Collapse
|
|
32
|
Gu W, Zhan H, Zhou XY, Yao L, Yan M, Chen A, Liu J, Ren X, Zhang X, Liu JX, Liu G. MicroRNA-22 regulates inflammation and angiogenesisviatargeting VE-cadherin. FEBS Lett 2017; 591:513-526. [DOI: 10.1002/1873-3468.12565] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 01/08/2017] [Accepted: 01/10/2017] [Indexed: 11/10/2022]
Affiliation(s)
- Wei Gu
- Department of Basic Veterinary Medicine; College of Animal Science and Veterinary Medicine; Huazhong Agricultural University; Wuhan Hubei China
| | - Huihui Zhan
- Department of Basic Veterinary Medicine; College of Animal Science and Veterinary Medicine; Huazhong Agricultural University; Wuhan Hubei China
| | - Xin-Ying Zhou
- Key Laboratory of Fresh Water Animal Breeding; College of Fisheries; Huazhong Agricultural University; Wuhan Hubei China
| | - Lun Yao
- Department of Basic Veterinary Medicine; College of Animal Science and Veterinary Medicine; Huazhong Agricultural University; Wuhan Hubei China
| | - Meiping Yan
- Department of Basic Veterinary Medicine; College of Animal Science and Veterinary Medicine; Huazhong Agricultural University; Wuhan Hubei China
| | - Ao Chen
- Department of Basic Veterinary Medicine; College of Animal Science and Veterinary Medicine; Huazhong Agricultural University; Wuhan Hubei China
| | - Jie Liu
- Department of Basic Veterinary Medicine; College of Animal Science and Veterinary Medicine; Huazhong Agricultural University; Wuhan Hubei China
| | - Xiaojiao Ren
- Department of Basic Veterinary Medicine; College of Animal Science and Veterinary Medicine; Huazhong Agricultural University; Wuhan Hubei China
| | - Xinhua Zhang
- Department of Basic Veterinary Medicine; College of Animal Science and Veterinary Medicine; Huazhong Agricultural University; Wuhan Hubei China
| | - Jing-Xia Liu
- Key Laboratory of Fresh Water Animal Breeding; College of Fisheries; Huazhong Agricultural University; Wuhan Hubei China
| | - Guoquan Liu
- Department of Basic Veterinary Medicine; College of Animal Science and Veterinary Medicine; Huazhong Agricultural University; Wuhan Hubei China
| |
Collapse
|
|
33
|
An X, Sarmiento C, Tan T, Zhu H. Regulation of multidrug resistance by microRNAs in anti-cancer therapy. Acta Pharm Sin B 2017; 7:38-51. [PMID: 28119807 PMCID: PMC5237711 DOI: 10.1016/j.apsb.2016.09.002] [Citation(s) in RCA: 151] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 05/30/2016] [Accepted: 07/06/2016] [Indexed: 12/31/2022] Open
Abstract
Multidrug resistance (MDR) remains a major clinical obstacle to successful cancer treatment. Although diverse mechanisms of MDR have been well elucidated, such as dysregulation of drugs transporters, defects of apoptosis and autophagy machinery, alterations of drug metabolism and drug targets, disrupti on of redox homeostasis, the exact mechanisms of MDR in a specific cancer patient and the cross-talk among these different mechanisms and how they are regulated are poorly understood. MicroRNAs (miRNAs) are a new class of small noncoding RNAs that could control the global activity of the cell by post-transcriptionally regulating a large variety of target genes and proteins expression. Accumulating evidence shows that miRNAs play a key regulatory role in MDR through modulating various drug resistant mechanisms mentioned above, thereby holding much promise for developing novel and more effective individualized therapies for cancer treatment. This review summarizes the various MDR mechanisms and mainly focuses on the role of miRNAs in regulating MDR in cancer treatment.
Collapse
Affiliation(s)
- Xin An
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Cesar Sarmiento
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Tao Tan
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
- Corresponding authors..
| | - Hua Zhu
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
- Corresponding authors..
| |
Collapse
|
|
34
|
Wang J, Li Y, Ding M, Zhang H, Xu X, Tang J. Molecular mechanisms and clinical applications of miR-22 in regulating malignant progression in human cancer (Review). Int J Oncol 2016; 50:345-355. [PMID: 28000852 PMCID: PMC5238783 DOI: 10.3892/ijo.2016.3811] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Accepted: 12/07/2016] [Indexed: 12/31/2022] Open
Abstract
miRNAs (microRNAs) have been validated to play fateful roles in the occurrence and development of cancers by post-transcriptionally targeting 3′-untranslated regions of the downstream gene mRNAs to repress mRNA expression. Mounting investigations forcefully document that not only does miR-22 biologically impinge on the processes of senescence, energy supply, angiogenesis, EMT (epithelial-mesenchymal transition), proliferation, migration, invasion, metastasis and apoptosis, but also it genetically or epigenetically exerts dual (inhibitory/promoting cancer) effects in various cancers via CNAs (copy number alterations), SNPs (single nucleotide polymorphisms), methylation, acetylation and even more momentously hydroxymethylation. Additionally, miR-22 expression may fluctuate with cancer progression in the body fluids of cancer patients and miR-22 could amplify its inhibitory or promoting effects through partaking in positive or negative feedback loops and interplaying with many other related miRNAs in the cascade of events, making it possible for miR-22 to be a promising and complementary or even independent cancer biomarker in some cancers and engendering profound influences on the early diagnosis, therapeutics, supervising curative effects and prognosis.
Collapse
Affiliation(s)
- Jingyu Wang
- Department of Pathology, The First Hospital of Jiaxing, Zhejiang, P.R. China
| | - Yuan Li
- Department of Pediatrics, The Affiliated Children's Hospital, Zhejiang University School of Medicine, Hangzhou, P.R. China
| | - Meiman Ding
- The Criminal Investigation Detachment of Jiaxing Public Security Bureau, Hangzhou, Zhejiang, P.R. China
| | - Honghe Zhang
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| | - Xiaoming Xu
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| | - Jinlong Tang
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| |
Collapse
|
|
35
|
MicroRNA-497 inhibits tumor growth and increases chemosensitivity to 5-fluorouracil treatment by targeting KSR1. Oncotarget 2016; 7:2660-71. [PMID: 26673620 PMCID: PMC4823062 DOI: 10.18632/oncotarget.6545] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 11/16/2015] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading cancer-related causes of death in the world. Recently, downregulation of microRNA-497 (miR-497) has been observed in CRC tissues. In this study, we found that miR-497 expression levels were downregulated in human CRC specimens compared to the adjacent normal tissues. MiR-497 expression levels were strongly correlated with clinical stages and lymph node metastases. Furthermore, kinase suppressor of ras 1 (KSR1), a known oncogene, was a direct target of miR-497, and KSR1 expression levels were inversely correlated with miR-497 expression levels in human CRC specimens. Overexpression of miR-497 inhibited cell proliferation, migration, invasion and increased chemosensitivity to 5-fluorouracil treatment, whereas forced expression of KSR1 had the opposite effect. Taken together, these results revealed that lower miR-497 levels in human CRC tissues induce KSR1 expression which is associated with CRC cancer occurrence, advanced stages, metastasis and chemoresistance. Lower miR-497 levels may be a potential biomarker for CRC advanced stages and treatment response.
Collapse
|
|
36
|
Tumor suppressor genes and their underlying interactions in paclitaxel resistance in cancer therapy. Cancer Cell Int 2016; 16:13. [PMID: 26900348 PMCID: PMC4761208 DOI: 10.1186/s12935-016-0290-9] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 02/12/2016] [Indexed: 01/01/2023] Open
Abstract
Objectives Paclitaxel (PTX) is frequently used in the clinical treatment of solid tumors. But the PTX-resistance is a great obstacle in cancer treatment. Exploration of the mechanisms of drug resistance suggests that tumor suppressor genes (TSGs) play a key role in the response of chemotherapeutic drugs. TSGs, a set of genes that are often inactivated in cancers, can regulate various biological processes. In this study, an overview of the contribution of TSGs to PTX resistance and their underlying relationship in cancers are reported by using GeneMANIA, a web-based tool for gene/protein function prediction. Methods Using PubMed online database and Google web site, the terms “paclitaxel resistance” or “taxol resistance” or “drug resistance” or “chemotherapy resistance”, and “cancer” or “carcinoma”, and “tumor suppressor genes” or “TSGs” or “negative regulated protein” or “antioncogenes” were searched and analyzed. GeneMANIA data base was used to predict gene/protein interactions and functions. Results We identified 22 TSGs involved in PTX resistance, including BRCA1, TP53, PTEN, APC, CDKN1A, CDKN2A, HIN-1, RASSF1, YAP, ING4, PLK2, FBW7, BLU, LZTS1, REST, FADD, PDCD4, TGFBI, ING1, Bax, PinX1 and hEx. The TSGs were found to have direct and indirect relationships with each other, and thus they could contribute to PTX resistance as a group. The varied expression status and regulation function of the TSGs on cell cycle in different cancers might play an important role in PTX resistance. Conclusion A further understanding of the roles of tumor suppressor genes in drug resistance is an important step to overcome chemotherapy tolerance. Tumor suppressor gene therapy targets the altered genes and signaling pathways and can be a new strategy to reverse chemotherapy resistance.
Collapse
|
|
37
|
|
|
38
|
Abstract
Non-coding RNAs have received a lot of attention in recent years, with especial focus on microRNAs (miRNAs), so much so that in the just over two decades since the first miRNA, Lin4, was described, almost 40,000 publications about miRNAs have been generated. Less than 500 of these focus on sarcoma, and only a fraction of those on sarcomas of childhood specifically, with some of these representing observational studies and others containing functionally validated data. This is a group of cancers for which prognosis is often poor and therapeutic options limited, and it is especially in these areas that strides in understanding the role of non-coding RNAs and miRNAs in particular are to be welcomed. This review deals with the main forms of pediatric sarcoma, exploring what is known about the diagnostic and prognostic profiles of miRNAs in these tumours and where novel therapeutic options might present themselves for further exploration.
Collapse
Affiliation(s)
- Lorna C Kelly
- The National Children's Research Centre, Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
| | - Antonio Lázaro
- The National Children's Research Centre, Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
| | - Maureen J O'Sullivan
- The National Children's Research Centre, Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
- Histology Laboratory, Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
- Trinity College, University of Dublin, Dublin 2, Ireland.
| |
Collapse
|
|
39
|
A better experimental method to detect the sensitivity of cancer cells to anticancer drugs after adenovirus-mediated introduction of two kinds of p53 in vivo. Anticancer Drugs 2015; 26:852-9. [PMID: 26164152 PMCID: PMC4521903 DOI: 10.1097/cad.0000000000000259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
p53 plays an important role in drug responses by regulating cell cycle progression and inducing programmed cell death. The C-terminal of p53 self-regulates the protein negatively; however, whether it affects the sensitivity of cancer cells to anticancer drugs is unclear. In this study, two experimental methods were used to compare the sensitivity to anticancer drugs of human lung 801D cancer cells transfected with adenovirus bearing either full-length p53 or the deleted-C-terminal p53 in vivo. Adenovirus-mediated deliveries of full-length or deleted-C-terminal p53 were performed after development of tumors (the first method) or by infection into cells before xenotransplantation (the second method). The results showed that infection with the deleted-C-terminal p53 increased 801D cell sensitivity to anticancer drugs in the second, but not in the first method, as indicated by greater tumor-inhibition rates. In addition, compared with the first method, the second method resulted in viruses with more uniformly infected cells and the infection rates between groups were similar. This yielded smaller within-group variations and greater uniformity among transplanted tumors. The second method could circumvent the difficulties associated with intratumoral injection.
Collapse
|
|
40
|
MicroRNAs in tumor angiogenesis. Life Sci 2015; 136:28-35. [PMID: 26144623 DOI: 10.1016/j.lfs.2015.06.025] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 06/03/2015] [Accepted: 06/30/2015] [Indexed: 01/07/2023]
Abstract
As it is necessary for tumor growth, angiogenesis has been an attractive target for drug therapy. Accumulating evidences indicate that microRNAs (miRNAs), which are short non-coding RNAs, delicately regulate the angiogenic signals through targeting angiogenic factors and protein kinases. They can modulate pro-angiogenic signals induced by vascular endothelial growth factor (VEGF) and anti-angiogenic signals induced by thrombospondin-1 (TSP-1), and therefore promote or inhibit tumor angiogenesis. Receptor tyrosine kinases (RTKs) and hypoxia inducible factor (HIF) are also targeted by miRNAs. Moreover, miRNAs crosstalk with reactive oxygen species (ROS) influencing tumor angiogenesis. It is critical to understand the role of miRNAs in tumor angiogenesis due to their therapeutic potential to improve outcome for cancer patients. The following review discusses the current state of knowledge related to tumor angiogenesis-regulatory miRNAs and their targets.
Collapse
|
|
41
|
Downregulation of miR-22 acts as an unfavorable prognostic biomarker in osteosarcoma. Tumour Biol 2015; 36:7891-5. [PMID: 25953260 DOI: 10.1007/s13277-015-3379-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Accepted: 03/24/2015] [Indexed: 12/25/2022] Open
Abstract
miRNA-22 (miR-22) has been showed to involve in a variety of cancers; however, the association between miR-22 expression level and the prognosis of osteosarcoma is also poorly unknown. Fifty-two patients with surgically resected paired osteosarcoma and non-neoplastic disease between 2008 and 2014 were involved in this study. Real-time PCR was performed to examine the expression level of miR-22 in osteosarcoma tissues and noncancerous bone tissues. Then the association between miR-22 expression and clinical-pathological parameters were further evaluated. Kaplan-Meier analysis and Cox proportional hazards regression models were explored to reveal the correlations of miR-22 expression with survival of patients. The results indicated that miR-22 was downregulated in osteosarcoma tissues in comparison with noncancerous bone tissues. In addition, there is statistically significance between miR-22 expression level and recurrence, metastasis, and chemotherapy response. The patients with lower miR-22 expression level had both poorer overall survival and disease-free survival. The multivariant analysis revealed that the miR-22 expression level and metastasis status are independent prognosis factors for osteosarcoma. In conclusion, miR-22 was downregulated in osteosarcoma and its expression level was correlated with a variety of important clinical-pathological parameters. Moreover, miR-22 may serve as a promising biomarker for predicting the prognosis of osteosarcoma.
Collapse
|
|
42
|
Wu XN, Ye YX, Niu JW, Li Y, Li X, You X, Chen H, Zhao LD, Zeng XF, Zhang FC, Tang FL, He W, Cao XT, Zhang X, Lipsky PE. Defective PTEN regulation contributes to B cell hyperresponsiveness in systemic lupus erythematosus. Sci Transl Med 2015; 6:246ra99. [PMID: 25101889 DOI: 10.1126/scitranslmed.3009131] [Citation(s) in RCA: 126] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
PTEN regulates normal signaling through the B cell receptor (BCR). In systemic lupus erythematosus (SLE), enhanced BCR signaling contributes to increased B cell activity, but the role of PTEN in human SLE has remained unclear. We performed fluorescence-activated cell sorting analysis in B cells from SLE patients and found that all SLE B cell subsets, except for memory B cells, showed decreased expression of PTEN compared with B cells from healthy controls. Moreover, the level of PTEN expression was inversely correlated with disease activity. We then explored the mechanisms governing PTEN regulation in SLE B cells. Notably, in normal but not SLE B cells, interleukin-21 (IL-21) induced PTEN expression and suppressed Akt phosphorylation induced by anti-immunoglobulin M and CD40L stimulation. However, this deficit was not primarily at the signaling or the transcriptional level, because IL-21-induced STAT3 (signal transducer and activator of transcription 3) phosphorylation was intact and IL-21 up-regulated PTEN mRNA in SLE B cells. Therefore, we examined the expression of candidate microRNAs (miRs) that could regulate PTEN: SLE B cells were found to express increased levels of miR-7, miR-21, and miR-22. These miRs down-regulated the expression of PTEN, and IL-21 stimulation increased the expression of miR-7 and miR-22 in both normal and SLE B cells. Indeed, a miR-7 antagomir corrected PTEN-related abnormalities in SLE B cells in a manner dependent on PTEN. Therefore, defective miR-7 regulation of PTEN contributes to B cell hyperresponsiveness in SLE and could be a new target of therapeutic intervention.
Collapse
Affiliation(s)
- Xiang-ni Wu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yan-xia Ye
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Jing-wen Niu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yang Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xin Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xin You
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Hua Chen
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Li-dan Zhao
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xiao-feng Zeng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Feng-chun Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Fu-lin Tang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Wei He
- Department of Immunology, School of Basic Medicine, Peking Union Medical College, and Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Xue-tao Cao
- Department of Immunology, School of Basic Medicine, Peking Union Medical College, and Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Xuan Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
| | - Peter E Lipsky
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. Formerly National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
| |
Collapse
|
|
43
|
Qu J, Zhao L, Zhang P, Wang J, Xu N, Mi W, Jiang X, Zhang C, Qu J. MicroRNA-195 chemosensitizes colon cancer cells to the chemotherapeutic drug doxorubicin by targeting the first binding site of BCL2L2 mRNA. J Cell Physiol 2015; 230:535-45. [PMID: 23526568 DOI: 10.1002/jcp.24366] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2012] [Accepted: 03/04/2013] [Indexed: 01/07/2023]
Abstract
The mechanisms underlying doxorubicin (Dox) resistance in colon cancer cells are not fully understood. MicroRNA (miRNA) play important roles in tumorigenesis and drug resistance. However, the relationship between miRNA and Dox resistance in colon cancer cells has not been previously explored. In this study, we utilized microRNA array and real-time PCR to verify that miR-127, miR-195, miR-22, miR-137 were significantly down-regulated, while miR-21, miR-592 were up-regulated in both HT29/DOX and LOVO/DOX cell lines. In vitro cell viability assay showed that knockdown of miR-195 in HT29 and LOVO cells caused a marked inhibition of Dox-induced cytotoxicity. Moreover, we explored that miR-195 is involved in repression of BCL2L2 expression through targeting its 3'-untranslated region, especially the first binding site within its mRNA. Furthermore, down-regulation of miR-195 conferred DOX resistance in parental cells and reduced cell apoptosis activity, while over-expression of miR-195 sensitized resistant cells to DOX and enhanced cell apoptosis activity, all of which can be partly rescued by BCL2L2 siRNA and cDNA expression. These results may have implications for therapeutic strategies aiming to overcome colon cancer cell resistance to Dox.
Collapse
Affiliation(s)
- Juan Qu
- Department of Otolaryngology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Yang F, Hu Y, Liu HX, Wan YJY. MiR-22-silenced cyclin A expression in colon and liver cancer cells is regulated by bile acid receptor. J Biol Chem 2015; 290:6507-15. [PMID: 25596928 DOI: 10.1074/jbc.m114.620369] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Because of the significant tumor-suppressive role of microRNA-22 (miR-22), the current study was designed to understand the regulation of miR-22 and to identify additional downstream miR-22 targets in liver and colon cells. The data showed that miR-22 was transcriptionally regulated by bile acid receptor farnesoid X receptor (FXR) through direct binding to an invert repeat 1 motif located at -1012 to -1025 bp upstream from miR-22. Among the studied primary and secondary bile acids, chenodeoxycholic acid, which has the highest binding affinity to FXR, induced miR-22 level in both Huh7 liver and HCT116 colon cells in a dose- and time-dependent manner. In addition, cyclin A2 (CCNA2) was identified as a miR-22 novel target in liver and colon cancer cells. The sequence of miR-22, which is conserved in mice, rats, humans, and other mammalians, aligns with the sequence of 3'-UTR of CCNA2. Chenodeoxycholic acid treatment and miR-22 mimics reduced CCNA2 protein and increased the number of G0/G1 Huh7 and HCT116 cells. In FXR KO mice, reduction of miR-22 was accompanied by elevated hepatic and ileal CCNA2 protein, as well as an increased number of hepatic and colonic Ki-67-positive cells. In humans, the expression levels of miR-22 and CCNA2 are inversely correlated in liver and colon cancers. Taken together, our data showed that bile acid-activated FXR stimulates miR-22-silenced CCNA2, a novel pathway for FXR to exert its protective effect in the gastrointestinal tract.
Collapse
Affiliation(s)
- Fan Yang
- From the Department of Pathology and Laboratory Medicine, the University of California at Davis Medical Center, Sacramento, California 95817 and the Institute of Chinese Material Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203 China
| | - Ying Hu
- From the Department of Pathology and Laboratory Medicine, the University of California at Davis Medical Center, Sacramento, California 95817 and
| | - Hui-Xin Liu
- From the Department of Pathology and Laboratory Medicine, the University of California at Davis Medical Center, Sacramento, California 95817 and
| | - Yu-Jui Yvonne Wan
- From the Department of Pathology and Laboratory Medicine, the University of California at Davis Medical Center, Sacramento, California 95817 and the Institute of Chinese Material Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203 China
| |
Collapse
|
|
45
|
Ciccarelli M, Rusciano M, Sorriento D, Maione AS, Soprano M, Iaccarino G, Illario M. Messages from the Border: Novel Insights in Signal Transduction Pathways Involved in Tumor Invasion and Metastasis. ACTA ACUST UNITED AC 2015. [DOI: 10.4236/jct.2015.62022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
|
|
46
|
Liu K, Guo L, Guo Y, Zhou B, Li T, Yang H, Yin R, Xi T. AEG-1 3'-untranslated region functions as a ceRNA in inducing epithelial-mesenchymal transition of human non-small cell lung cancer by regulating miR-30a activity. Eur J Cell Biol 2014; 94:22-31. [PMID: 25484183 DOI: 10.1016/j.ejcb.2014.10.006] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Revised: 10/20/2014] [Accepted: 10/20/2014] [Indexed: 01/12/2023] Open
Abstract
Competitive endogenous messenger RNA regulates the transcription of other RNA moleculars through competing for the shared microRNAs. This study was carried out to explore the regulation of AEG-1 messenger RNA as a competitive endogenous RNA in the epithelial-mesenchymal transition and metastasis of lung tumor cells. It is shown that the epithelial-mesenchymal transition was associated with the down-regulation of miR-30a, up-regulation of AEG-1 and mesenchymal markers (Snail and Vimentin); miR-30a inhibited the metastasis of lung tumor A549 cells in vitro, whereas AEG-1 promoted it. These results suggested the potential linkage between miR-30a and genes (AEG-1, Snail and Vimentin) in the epithelial-mesenchymal transition and metastasis of lung tumor cell. It was verified later that the 3'-untranslated regions of AEG-1, Snail and Vimentin bind to miR-30a in A549 cells. Therefore, a competitive endogenous RNAs regulatory network among AEG-1, Snail and Vimentin mediated via competitive binding to miR-30a was proved. That is, the 3'-untranslated region of AEG-1, functioning as the competitive endogenous RNAs, indirectly regulated the expression of Vimentin and Snail in inducing epithelial-mesenchymal transition of human non-small cell lung cancer. In conclusion, our findings demonstrated a competitive endogenous RNAs regulatory network which will help understand the metastasis mechanisms of lung cancer and improve the prevention and treatment of lung cancer.
Collapse
Affiliation(s)
- Kunmei Liu
- School of Life Science and Technology, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009 Nanjing, China; Ningxia Key Laboratory of Cerebrocranial Diseases, School of Laboratory Medicine, Ningxia Medical University, Yinchuan 750004, China
| | - Le Guo
- Ningxia Key Laboratory of Cerebrocranial Diseases, School of Laboratory Medicine, Ningxia Medical University, Yinchuan 750004, China.
| | - Yongjian Guo
- School of Life Science and Technology, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009 Nanjing, China
| | - Bo Zhou
- School of Life Science and Technology, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009 Nanjing, China
| | - Tong Li
- School of Life Science and Technology, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009 Nanjing, China
| | - Hua Yang
- Ningxia Key Laboratory of Cerebrocranial Diseases, School of Laboratory Medicine, Ningxia Medical University, Yinchuan 750004, China
| | - Runting Yin
- Medical School of Nantong University, Nantong University, Nantong 226001, China
| | - Tao Xi
- School of Life Science and Technology, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009 Nanjing, China.
| |
Collapse
|
|
47
|
Zhang H, Tang J, Li C, Kong J, Wang J, Wu Y, Xu E, Lai M. MiR-22 regulates 5-FU sensitivity by inhibiting autophagy and promoting apoptosis in colorectal cancer cells. Cancer Lett 2014; 356:781-90. [PMID: 25449431 DOI: 10.1016/j.canlet.2014.10.029] [Citation(s) in RCA: 122] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Revised: 10/26/2014] [Accepted: 10/27/2014] [Indexed: 01/08/2023]
Abstract
Autophagy has become one of the most important mechanisms of chemotherapy resistance by supporting the survival of tumor cells under metabolic and therapeutic stress. Here, we showed that miR-22 inhibited autophagy and promoted apoptosis to increase the sensitivity of colorectal cancer (CRC) cells to 5-fluorouracil (5-FU) treatment both in vitro and in vivo. B-cell translocation gene 1 (BTG1) was identified as a new target of miR-22, which could reverse the inhibition of autophagy induced by miR-22. Thus, miR-22 may function as an important switch between autophagy and apoptosis to regulate 5-FU sensitivity through post-transcriptional silencing of BTG1. Promisingly, miR-22 could be considered as both a predictor of 5-FU sensitivity for personalized treatment and a therapeutic target for colorectal cancer.
Collapse
Affiliation(s)
- Honghe Zhang
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, China
| | - Jinlong Tang
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, China; Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chen Li
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, China
| | - Jianlu Kong
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, China
| | - Jingyu Wang
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, China; Department of Pathology, The First Hospital of Jiaxing, Jiaxing, China
| | - Yihua Wu
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, China
| | - Enping Xu
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, China
| | - Maode Lai
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, China.
| |
Collapse
|
|
48
|
Donzelli S, Mori F, Biagioni F, Bellissimo T, Pulito C, Muti P, Strano S, Blandino G. MicroRNAs: short non-coding players in cancer chemoresistance. MOLECULAR AND CELLULAR THERAPIES 2014; 2:16. [PMID: 26056584 PMCID: PMC4451970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Accepted: 04/17/2014] [Indexed: 11/21/2023]
Abstract
Chemoresistance is one of the main problems in the therapy of cancer. There are a number of different molecular mechanisms through which a cancer cell acquires resistance to a specific treatment, such as alterations in drug uptake, drug metabolism and drug targets. There are several lines of evidence showing that miRNAs are involved in drug sensitivity of cancer cells in different tumor types and by different treatments. In this review, we provide an overview of the more recent and significant findings on the role of miRNAs in cancer cell drug resistance. In particular, we focus on specific miRNA mechanisms of action that in various steps lead from drug cell sensitivity to drug cell resistance. We also provide evidence on how miRNA profiling may unveil relevant predictive biomarkers for therapy outcomes.
Collapse
Affiliation(s)
- Sara Donzelli
- />Translational Oncogenomics Unit, Italian National Cancer Institute ‘Regina Elena’, Via Elio Chianesi 53, 00144 Rome, Italy
| | - Federica Mori
- />Molecular Chemoprevention Unit, Italian National Cancer Institute ‘Regina Elena’, Rome, Italy
| | - Francesca Biagioni
- />Translational Oncogenomics Unit, Italian National Cancer Institute ‘Regina Elena’, Via Elio Chianesi 53, 00144 Rome, Italy
| | - Teresa Bellissimo
- />Translational Oncogenomics Unit, Italian National Cancer Institute ‘Regina Elena’, Via Elio Chianesi 53, 00144 Rome, Italy
| | - Claudio Pulito
- />Molecular Chemoprevention Unit, Italian National Cancer Institute ‘Regina Elena’, Rome, Italy
| | - Paola Muti
- />Department of Oncology, Juravinski Cancer Center-McMaster University, Hamilton, Ontario Canada
| | - Sabrina Strano
- />Molecular Chemoprevention Unit, Italian National Cancer Institute ‘Regina Elena’, Rome, Italy
- />Department of Oncology, Juravinski Cancer Center-McMaster University, Hamilton, Ontario Canada
| | - Giovanni Blandino
- />Translational Oncogenomics Unit, Italian National Cancer Institute ‘Regina Elena’, Via Elio Chianesi 53, 00144 Rome, Italy
- />College of Agriculture and Environmental Sciences, Unisa, Florida campus, Johannesburg, South Africa
| |
Collapse
|
|
49
|
Donzelli S, Mori F, Biagioni F, Bellissimo T, Pulito C, Muti P, Strano S, Blandino G. MicroRNAs: short non-coding players in cancer chemoresistance. MOLECULAR AND CELLULAR THERAPIES 2014; 2:16. [PMID: 26056584 PMCID: PMC4451970 DOI: 10.1186/2052-8426-2-16] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Accepted: 04/17/2014] [Indexed: 12/18/2022]
Abstract
Chemoresistance is one of the main problems in the therapy of cancer. There are a number of different molecular mechanisms through which a cancer cell acquires resistance to a specific treatment, such as alterations in drug uptake, drug metabolism and drug targets. There are several lines of evidence showing that miRNAs are involved in drug sensitivity of cancer cells in different tumor types and by different treatments. In this review, we provide an overview of the more recent and significant findings on the role of miRNAs in cancer cell drug resistance. In particular, we focus on specific miRNA mechanisms of action that in various steps lead from drug cell sensitivity to drug cell resistance. We also provide evidence on how miRNA profiling may unveil relevant predictive biomarkers for therapy outcomes.
Collapse
Affiliation(s)
- Sara Donzelli
- Translational Oncogenomics Unit, Italian National Cancer Institute 'Regina Elena', Via Elio Chianesi 53, 00144 Rome, Italy
| | - Federica Mori
- Molecular Chemoprevention Unit, Italian National Cancer Institute 'Regina Elena', Rome, Italy
| | - Francesca Biagioni
- Translational Oncogenomics Unit, Italian National Cancer Institute 'Regina Elena', Via Elio Chianesi 53, 00144 Rome, Italy
| | - Teresa Bellissimo
- Translational Oncogenomics Unit, Italian National Cancer Institute 'Regina Elena', Via Elio Chianesi 53, 00144 Rome, Italy
| | - Claudio Pulito
- Molecular Chemoprevention Unit, Italian National Cancer Institute 'Regina Elena', Rome, Italy
| | - Paola Muti
- Department of Oncology, Juravinski Cancer Center-McMaster University, Hamilton, Ontario Canada
| | - Sabrina Strano
- Molecular Chemoprevention Unit, Italian National Cancer Institute 'Regina Elena', Rome, Italy ; Department of Oncology, Juravinski Cancer Center-McMaster University, Hamilton, Ontario Canada
| | - Giovanni Blandino
- Translational Oncogenomics Unit, Italian National Cancer Institute 'Regina Elena', Via Elio Chianesi 53, 00144 Rome, Italy ; College of Agriculture and Environmental Sciences, Unisa, Florida campus, Johannesburg, South Africa
| |
Collapse
|
|
50
|
Ye X, Bai W, Zhu H, Zhang X, Chen Y, Wang L, Yang A, Zhao J, Jia L. MiR-221 promotes trastuzumab-resistance and metastasis in HER2-positive breast cancers by targeting PTEN. BMB Rep 2014; 47:268-273. [PMID: 24286315 PMCID: PMC4163864 DOI: 10.5483/bmbrep.2014.47.5.165] [Citation(s) in RCA: 61] [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] [Received: 07/17/2013] [Revised: 07/31/2013] [Accepted: 08/22/2013] [Indexed: 12/15/2022] Open
Abstract
HER2-overexpressing breast cancers are characterized by frequent distant metastasis and often develop resistance after short-term effective treatment with the monoclonal antibody drug, trastuzumab. Here, we found that the oncogenic miRNA, miR-221, inhibited apoptosis, induced trastuzumab resistance and promoted metastasis of HER2-positive breast cancers. The tumor suppressor PTEN was identified as a miR-221 target; overexpression of PTEN abrogated the aforementioned miR-221-induced malignant phenotypes of the cells. These findings indicate that miR-221 may promote trastuzumab resistance and metastasis of HER2-positive breast cancers by targeting PTEN, suggesting its role as a potential biomarker for progression and poor prognosis, and as a novel target for trastuzumab-combined treatment of breast cancers.
Collapse
MESH Headings
- Antibodies, Monoclonal, Humanized/pharmacology
- Antineoplastic Agents/therapeutic use
- Apoptosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Breast Neoplasms/genetics
- Breast Neoplasms/metabolism
- Breast Neoplasms/therapy
- Cell Line, Tumor
- Drug Resistance, Neoplasm/genetics
- Female
- Humans
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Neoplasm Invasiveness/genetics
- Neoplasm Metastasis/genetics
- PTEN Phosphohydrolase/antagonists & inhibitors
- PTEN Phosphohydrolase/genetics
- RNA, Neoplasm/genetics
- RNA, Neoplasm/metabolism
- Receptor, ErbB-2/genetics
- Receptor, ErbB-2/metabolism
- Trastuzumab
Collapse
Affiliation(s)
- Xingming Ye
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular, Biology, Fourth Military Medical University, Xi’an 710032, China
- Fujian Provincial Cancer Hospital, the Teaching Hospital of Fujian Medical University, Fuzhou 350014, China
| | - Wendong Bai
- Department of Immunology, Fourth Military Medical University, Xi’an 710032, China
| | - Huayu Zhu
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular, Biology, Fourth Military Medical University, Xi’an 710032, China
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Xiao Zhang
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular, Biology, Fourth Military Medical University, Xi’an 710032, China
| | - Ying Chen
- Fujian Provincial Cancer Hospital, the Teaching Hospital of Fujian Medical University, Fuzhou 350014, China
| | - Lei Wang
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular, Biology, Fourth Military Medical University, Xi’an 710032, China
| | - Angang Yang
- Department of Immunology, Fourth Military Medical University, Xi’an 710032, China
| | - Jing Zhao
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular, Biology, Fourth Military Medical University, Xi’an 710032, China
| | - Lintao Jia
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular, Biology, Fourth Military Medical University, Xi’an 710032, China
| |
Collapse
|