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Yao H, Luo L, Li R, Zhao Y, Zhang L, Pešić M, Cai L, Li L. New insight into the role of SMAD4 mutation/deficiency in the prognosis and therapeutic resistance of pancreatic ductal adenocarcinomas. Biochim Biophys Acta Rev Cancer 2024; 1879:189220. [PMID: 39571764 DOI: 10.1016/j.bbcan.2024.189220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 10/03/2024] [Accepted: 11/11/2024] [Indexed: 11/29/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) patients have an unfavorable prognosis and disappointing treatment outcomes because of late diagnosis, high chemotherapy resistance, ineffective adjuvant chemotherapy, unavailable molecular targeted therapy, and profound immunosuppressive effects in the tumor microenvironment (TME). There are a variety of critical driver proteins, such as KRAS, TP53, PTEN and SMAD4, putatively involved in PDAC etiology. Current knowledge of their molecular mechanisms is still limited. SMAD4 gene alterations in ∼55 % of patients emphasize its key role in PDAC progression, metastasis, resistance and immunity. Despite extensive studies on the TGF-β/SMAD pathway, the impact of SMAD4 mutation/deficiency on PDAC prognosis and treatment, especially its mechanism in drug resistance, has not yet been elucidated. This review summarizes the latest advances in the effect of SMAD4 deficiency on the prognosis and therapeutic resistance of PDAC patients. It might be a predictive and prognostic biomarker or therapeutic target to achieve the desired clinical benefits. Moreover, we discuss potential strategies to implement targeted therapies in terms of SMAD4 genetic status.
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Affiliation(s)
- Hongjuan Yao
- State Key Laboratory of Respiratory Health and Multimorbidity; NHC Key Laboratory of Biotechnology for Microbial Drugs; Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, NO. 1 Tiantan Xili, Beijing 100050, China
| | - Liaoxin Luo
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325000, China
| | - Rui Li
- State Key Laboratory of Respiratory Health and Multimorbidity; NHC Key Laboratory of Biotechnology for Microbial Drugs; Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, NO. 1 Tiantan Xili, Beijing 100050, China
| | - Yelin Zhao
- State Key Laboratory of Respiratory Health and Multimorbidity; NHC Key Laboratory of Biotechnology for Microbial Drugs; Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, NO. 1 Tiantan Xili, Beijing 100050, China
| | - Li Zhang
- State Key Laboratory of Respiratory Health and Multimorbidity; NHC Key Laboratory of Biotechnology for Microbial Drugs; Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, NO. 1 Tiantan Xili, Beijing 100050, China
| | - Milica Pešić
- Department of Neurobiology, Institute for Biological Research, "Siniša Stanković"- National Institute of the Republic of Serbia, University of Belgrade, Despota Stefana 142, 11060 Belgrade, Serbia
| | - Lin Cai
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325000, China..
| | - Liang Li
- State Key Laboratory of Respiratory Health and Multimorbidity; NHC Key Laboratory of Biotechnology for Microbial Drugs; Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, NO. 1 Tiantan Xili, Beijing 100050, China.
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2
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Sebutsoe XM, Tsotetsi NJN, Jantjies ZE, Raphela-Choma PP, Choene MS, Motadi LR. Therapeutic Strategies in Advanced Cervical Cancer Detection, Prevention and Treatment. Onco Targets Ther 2024; 17:785-801. [PMID: 39345275 PMCID: PMC11439348 DOI: 10.2147/ott.s475132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 08/08/2024] [Indexed: 10/01/2024] Open
Abstract
Cervical cancer is ranked the fourth most common cause of cancer related deaths amongst women. The situation is particularly dire in low to lower middle-income countries. It continues to affect these countries due to poor vaccine coverage and screening. Cervical cancer is mostly detected in the advanced stages leading to poor outcomes. This review focuses on the progress made to date to improve early detection and targeted therapy using both circulating RNA. Vaccine has played a major role in cervical cancer control in vaccinated young woman in mainly developed countries yet in low-income countries with challenges of 3 dose vaccination affordability, cervical cancer continues to be the second most deadly amongst women. In this review, we show the progress made in reducing cervical cancer using vaccination that in combination with other treatments that might improve survival in cervical cancer. We further show with both miRNA and siRNA that targeted therapy and specific markers might be ideal for early detection of cervical cancer in low-income countries. These markers are either upregulated or down regulated in cancer providing clue to the stage of the cancer.
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Affiliation(s)
- Xolisiwe M Sebutsoe
- Department of Biochemistry C2 Lab, University of Johannesburg, Auckland Park Kingsway Campus, Johannesburg, South Africa
| | | | - Zodwa Edith Jantjies
- Department of Biochemistry C2 Lab, University of Johannesburg, Auckland Park Kingsway Campus, Johannesburg, South Africa
| | - Portia Pheladi Raphela-Choma
- Department of Biochemistry C2 Lab, University of Johannesburg, Auckland Park Kingsway Campus, Johannesburg, South Africa
| | - Mpho S Choene
- Department of Biochemistry C2 Lab, University of Johannesburg, Auckland Park Kingsway Campus, Johannesburg, South Africa
| | - Lesetja R Motadi
- Department of Biochemistry C2 Lab, University of Johannesburg, Auckland Park Kingsway Campus, Johannesburg, South Africa
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Przybyszewski O, Mik M, Nowicki M, Kusiński M, Mikołajczyk-Solińska M, Śliwińska A. Using microRNAs Networks to Understand Pancreatic Cancer-A Literature Review. Biomedicines 2024; 12:1713. [PMID: 39200178 PMCID: PMC11351910 DOI: 10.3390/biomedicines12081713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 07/26/2024] [Accepted: 07/28/2024] [Indexed: 09/02/2024] Open
Abstract
Pancreatic cancer is a severe disease, challenging to diagnose and treat, and thereby characterized by a poor prognosis and a high mortality rate. Pancreatic ductal adenocarcinoma (PDAC) represents approximately 90% of pancreatic cancer cases, while other cases include neuroendocrine carcinoma. Despite the growing knowledge of the pathophysiology of this cancer, the mortality rate caused by it has not been effectively reduced. Recently, microRNAs have aroused great interest among scientists and clinicians, as they are negative regulators of gene expression, which participate in many processes, including those related to the development of pancreatic cancer. The aim of this review is to show how microRNAs (miRNAs) affect key signaling pathways and related cellular processes in pancreatic cancer development, progression, diagnosis and treatment. We included the results of in vitro studies, animal model of pancreatic cancer and those performed on blood, saliva and tumor tissue isolated from patients suffering from PDAC. Our investigation identified numerous dysregulated miRNAs involved in KRAS, JAK/STAT, PI3/AKT, Wnt/β-catenin and TGF-β signaling pathways participating in cell cycle control, proliferation, differentiation, apoptosis and metastasis. Moreover, some miRNAs (miRNA-23a, miRNA-24, miRNA-29c, miRNA-216a) seem to be engaged in a crosstalk between signaling pathways. Evidence concerning the utility of microRNAs in the diagnosis and therapy of this cancer is poor. Therefore, despite growing knowledge of the involvement of miRNAs in several processes associated with pancreatic cancer, we are beginning to recognize and understand their role and usefulness in clinical practice.
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Affiliation(s)
- Oskar Przybyszewski
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska St., 92-213 Lodz, Poland
| | - Michał Mik
- Department of General and Colorectal Surgery, Medical University of Lodz, 113 Stefana Żeromskiego St., 90-549 Lodz, Poland; (M.M.); (M.N.)
| | - Michał Nowicki
- Department of General and Colorectal Surgery, Medical University of Lodz, 113 Stefana Żeromskiego St., 90-549 Lodz, Poland; (M.M.); (M.N.)
| | - Michał Kusiński
- Department of Endocrinological, General and Oncological Surgery, Medical University of Lodz, 62 Pabianicka St., 93-513 Lodz, Poland;
| | - Melania Mikołajczyk-Solińska
- Department of Internal Medicine, Diabetology and Clinical Pharmacology, Medical University of Lodz, 251 Pomorska St., 92-213 Lodz, Poland;
| | - Agnieszka Śliwińska
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska St., 92-213 Lodz, Poland
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Girolimetti G, Pelisenco IA, Eusebi LH, Ricci C, Cavina B, Kurelac I, Verri T, Calcagnile M, Alifano P, Salvi A, Bucci C, Guerra F. Dysregulation of a Subset of Circulating and Vesicle-Associated miRNA in Pancreatic Cancer. Noncoding RNA 2024; 10:29. [PMID: 38804361 PMCID: PMC11130804 DOI: 10.3390/ncrna10030029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 04/14/2024] [Accepted: 04/26/2024] [Indexed: 05/29/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive neoplasia, characterized by early metastasis, low diagnostic rates at early stages, resistance to drugs, and poor prognosis. There is an urgent need to better characterize this disease in order to identify efficient diagnostic/prognostic biomarkers. Since microRNAs (miRNAs) contribute to oncogenesis and metastasis formation in PDAC, they are considered potential candidates for fulfilling this task. In this work, the levels of two miRNA subsets (involved in chemoresistance or with oncogenic/tumor suppressing functions) were investigated in a panel of PDAC cell lines and liquid biopsies of a small cohort of patients. We used RT-qPCR and droplet digital PCR (ddPCR) to measure the amounts of cellular- and vesicle-associated, and circulating miRNAs. We found that both PDAC cell lines, also after gemcitabine treatment, and patients showed low amounts of cellular-and vesicle-associated miR-155-5p, compared to controls. Interestingly, we did not find any differences when we analyzed circulating miR-155-5p. Furthermore, vesicle-related miR-27a-3p increased in cancer patients compared to the controls, while circulating let-7a-5p, miR-221-3p, miR-23b-3p and miR-193a-3p presented as dysregulated in patients compared to healthy individuals. Our results highlight the potential clinical significance of these analyzed miRNAs as non-invasive diagnostic molecular tools to characterize PDAC.
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Affiliation(s)
- Giulia Girolimetti
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Provinciale Lecce-Monteroni 165, 73100 Lecce, Italy; (G.G.); (T.V.); (M.C.); (F.G.)
| | - Iulia Andreea Pelisenco
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy; (I.A.P.); (A.S.)
| | - Leonardo Henry Eusebi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.H.E.); (C.R.); (B.C.); (I.K.)
- Gastroenterology Unit, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Claudio Ricci
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.H.E.); (C.R.); (B.C.); (I.K.)
- Pancreatic Surgery Unit, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Beatrice Cavina
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.H.E.); (C.R.); (B.C.); (I.K.)
- Centre for Applied Biomedical Research (CRBA), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Ivana Kurelac
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.H.E.); (C.R.); (B.C.); (I.K.)
- Centre for Applied Biomedical Research (CRBA), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Tiziano Verri
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Provinciale Lecce-Monteroni 165, 73100 Lecce, Italy; (G.G.); (T.V.); (M.C.); (F.G.)
| | - Matteo Calcagnile
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Provinciale Lecce-Monteroni 165, 73100 Lecce, Italy; (G.G.); (T.V.); (M.C.); (F.G.)
| | - Pietro Alifano
- Department of Experimental Medicine (DiMeS), University of Salento, Via Provinciale Lecce-Monteroni 165, 73100 Lecce, Italy;
| | - Alessandro Salvi
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy; (I.A.P.); (A.S.)
| | - Cecilia Bucci
- Department of Experimental Medicine (DiMeS), University of Salento, Via Provinciale Lecce-Monteroni 165, 73100 Lecce, Italy;
| | - Flora Guerra
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Provinciale Lecce-Monteroni 165, 73100 Lecce, Italy; (G.G.); (T.V.); (M.C.); (F.G.)
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Wei H, Li X, Liu F, Li Y, Luo B, Huang X, Chen H, Wen B, Ma P. Curcumin inhibits the development of colorectal cancer via regulating the USP4/LAMP3 pathway. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:1749-1762. [PMID: 37728623 DOI: 10.1007/s00210-023-02721-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 09/13/2023] [Indexed: 09/21/2023]
Abstract
In this study, we aimed to explore the effects of curcumin on the progression of colorectal cancer and its underlying mechanisms involved. Cell proliferation, apoptosis and invasion were determined through CCK-8 assay, colony formation assay, EdU assay, flow cytometry, and transwell invasion assay, respectively. The protein expression of Bax, MMP2, USP4 and LAMP3 was measured using western blot. Pearson correlation coefficient was used to evaluate the relationship between USP4 and LAMP3. Co-IP was also conducted to determine the interaction between USP4 and LAMP3. Xenograft tumor model was established to explore the role of curcumin in colorectal cancer in vivo. IHC was utilized to measure the expression of Bax, MMP2, USP4 and LAMP3 in tumor tissues from mice. Curcumin significantly accelerated cell apoptosis, and inhibited cell proliferation and invasion in LoVo and HCT-116 cells. LAMP3 was augmented in colorectal cancer tissues and cells, and curcumin could reduce the expression of LAMP3. Curcumin decreased LAMP3 expression to exhibit the inhibition role in the progression of colorectal cancer. USP4 interacted with LAMP3, and positively regulated LAMP3 expression in colorectal cancer cells. LAMP3 overexpression could reverse the suppressive effects of USP4 knockdown on the development of colorectal cancer. Curcumin downregulated USP4 to impeded the progression of colorectal cancer via repressing LAMP3 expression. In addition, curcumin obviously restrained tumor growth in mice through downregulating USP4 and LAMP3 expression. These data indicated that curcumin exert the anti-tumor effects on the development of colorectal cancer through modulating the USP4/LAMP3 pathway.
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Affiliation(s)
- Hai Wei
- Department of Gastrointestinal Surgery, Nanyang First People's Hospital, Nanyang, 473000, China
| | - Xianzhe Li
- Department of General Surgery, Nanshi Hospital, Nanyang, 473065, China
| | - Fu Liu
- Department of Gastrointestinal Surgery, Nanyang First People's Hospital, Nanyang, 473000, China
| | - Yuan Li
- Department of Gastrointestinal Surgery, Nanyang First People's Hospital, Nanyang, 473000, China
| | - Bin Luo
- Department of Gastrointestinal Surgery, Nanyang First People's Hospital, Nanyang, 473000, China
| | - Xin Huang
- Department of Gastrointestinal Surgery, Nanyang First People's Hospital, Nanyang, 473000, China
| | - Hang Chen
- Department of Gastrointestinal Surgery, Nanyang First People's Hospital, Nanyang, 473000, China
| | - Bo Wen
- Department of Gastrointestinal Surgery, Nanyang First People's Hospital, Nanyang, 473000, China
| | - Pei Ma
- Department of Gastrointestinal Surgery, Nanyang First People's Hospital, Nanyang, 473000, China.
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Shen Y, Zhou L, Xu M, Tan Z, Yao K, Wang W. MED1 induces M2 polarization of tumor-associated macrophages to aggravate breast cancer. Genes Genomics 2023; 45:1517-1525. [PMID: 37594664 DOI: 10.1007/s13258-023-01435-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 07/12/2023] [Indexed: 08/19/2023]
Abstract
BACKGROUND Breast cancer is a common malignant tumor in female, and its 5-year survival rate remains low. The correlation between mediator subunit 1 (MED1) gene and macrophage phenotypic transformation may be a key factor affecting the therapeutic effect on cancer. OBJECTIVE The present study intended to explore the role of MED1 in macrophage polarization and its further influence on the malignant behaviors of breast cancer. METHODS Bioinformatics analysis was carried out to predict the expression pattern of MED1 in breast cancer. Flow cytometry was conducted to detect the effect of MED1 overexpression or silencing on macrophage polarization. ELISA was applied to analyze the effect of abnormal MED1 expression on cytokine secretion of macrophages. CCK-8, colony formation, Transwell and scratch healing assays were applied to investigate the effects of macrophage conditioned medium on the malignant behaviors of breast cancer cells. RESULTS MED1 expression was prominently increased in M2 macrophages, and overexpression of MED1 significantly increased M2 polarization of tumor-associated macrophages (TAMs) and IL-10 cytokine level. Meanwhile, M2 macrophages with MED1 overexpression could significantly promote the malignant behaviors of breast cancer cells. Dasatinib rescue experiment further confirmed that MED1-induced M2 macrophage polarization could facilitate the malignant progression of breast cancer cells. CONCLUSION In summary, MED1 could induce M2 macrophage polarization and thus regulate the malignant behaviors of breast cancer cells.
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Affiliation(s)
- Ye Shen
- Department of General Surgery, Shanghai Fengxian District Central Hospital, No. 6600 Nanfeng Road, Fengxian District, Shanghai, 201499, China
| | - Lianming Zhou
- Department of General Surgery, Shanghai Fengxian District Central Hospital, No. 6600 Nanfeng Road, Fengxian District, Shanghai, 201499, China
| | - Meiyu Xu
- Department of General Surgery, Shanghai Fengxian District Central Hospital, No. 6600 Nanfeng Road, Fengxian District, Shanghai, 201499, China
| | - Zhanhai Tan
- Department of General Surgery, Shanghai Fengxian District Central Hospital, No. 6600 Nanfeng Road, Fengxian District, Shanghai, 201499, China
| | - Kai Yao
- Department of General Surgery, Shanghai Fengxian District Central Hospital, No. 6600 Nanfeng Road, Fengxian District, Shanghai, 201499, China
| | - Wenjie Wang
- Department of General Surgery, Shanghai Fengxian District Central Hospital, No. 6600 Nanfeng Road, Fengxian District, Shanghai, 201499, China.
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Zhai C, Liu B, Kan F, Zhai S, Zhang R. MicroRNA‑27a‑3p regulates the proliferation and chemotaxis of pulmonary macrophages in non‑small cell lung carcinoma tissues through CXCL2. Oncol Lett 2023; 26:492. [PMID: 37854860 PMCID: PMC10579986 DOI: 10.3892/ol.2023.14079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 04/26/2022] [Indexed: 10/20/2023] Open
Abstract
The present study aimed to investigate microRNA (miRNA)-27a-3p expression in the pulmonary macrophages and peripheral blood of patients with early non-small cell lung carcinoma (NSCLC) and its regulatory effect on the infiltration of pulmonary macrophages into cancer tissues and invasion of NSCLC cells. Blood specimens were withdrawn from 36 patients with NSCLC and 29 healthy subjects. NSCLC tissues and cancer-adjacent tissues were both obtained from patients with NSCLC; furthermore, certain tissue samples were used to extract macrophages. The levels of miRNA-27a-3p and C-X-C motif ligand chemokine 2 (CXCL2) mRNA were detected by reverse transcription-quantitative PCR and the levels of CXCL2 protein were measured by ELISA and western blot analysis. A dual-luciferase reporter assay was performed to determine the interactions between miRNA and mRNA. An MTT assay was employed to examine the viability of transfected cells and macrophages and a Transwell assay was performed to assess chemotaxis. The differential expression of miRNA-27a-3p in NSCLC tissues, pulmonary macrophages and peripheral blood indicated that miRNA-27a-3p exerted different roles in these specimens. CXCL2 was upregulated in NSCLC tissues at both transcriptional and translational levels. In addition, the untranslated region of CXCL2 was confirmed to be directly targeted by miRNA-27a-3p prior to its transcriptional activation. Furthermore, miRNA-27a-3p regulated CXCL2 expression, thereby affecting the proliferation of human pulmonary macrophages. The present study highlights that miRNA-27a-3p expression in the pulmonary macrophages and peripheral blood of patients with NSCLC is downregulated, while its target gene CXCL2 is upregulated. miRNA-27a-3p may regulate the viability and chemotaxis of macrophages in tumor tissues of patients with NSCLC through CXCL2 and is expected to become a genetic marker of this disease.
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Affiliation(s)
- Congying Zhai
- Department of Pulmonary and Critical Care Medicine, Zibo First Hospital, Zibo, Shandong 255200, P.R. China
| | - Baoliang Liu
- Department of Pulmonary and Critical Care Medicine, Zibo First Hospital, Zibo, Shandong 255200, P.R. China
| | - Fanggong Kan
- Department of Oncology, Zibo First Hospital, Zibo, Shandong 255200, P.R. China
| | - Shuhui Zhai
- Department of Clinical Medicine, Jining Medical College, Jining, Shandong 272067, P.R. China
| | - Ronghua Zhang
- Department of Pulmonary and Critical Care Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250013, P.R. China
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Tuly KF, Hossen MB, Islam MA, Kibria MK, Alam MS, Harun-Or-Roshid M, Begum AA, Hasan S, Mahumud RA, Mollah MNH. Robust Identification of Differential Gene Expression Patterns from Multiple Transcriptomics Datasets for Early Diagnosis, Prognosis, and Therapies for Breast Cancer. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1705. [PMID: 37893423 PMCID: PMC10608013 DOI: 10.3390/medicina59101705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 09/07/2023] [Accepted: 09/20/2023] [Indexed: 10/29/2023]
Abstract
Background and Objectives: Breast cancer (BC) is one of the major causes of cancer-related death in women globally. Proper identification of BC-causing hub genes (HubGs) for prognosis, diagnosis, and therapies at an earlier stage may reduce such death rates. However, most of the previous studies detected HubGs through non-robust statistical approaches that are sensitive to outlying observations. Therefore, the main objectives of this study were to explore BC-causing potential HubGs from robustness viewpoints, highlighting their early prognostic, diagnostic, and therapeutic performance. Materials and Methods: Integrated robust statistics and bioinformatics methods and databases were used to obtain the required results. Results: We robustly identified 46 common differentially expressed genes (cDEGs) between BC and control samples from three microarrays (GSE26910, GSE42568, and GSE65194) and one scRNA-seq (GSE235168) dataset. Then, we identified eight cDEGs (COL11A1, COL10A1, CD36, ACACB, CD24, PLK1, UBE2C, and PDK4) as the BC-causing HubGs by the protein-protein interaction (PPI) network analysis of cDEGs. The performance of BC and survival probability prediction models with the expressions of HubGs from two independent datasets (GSE45827 and GSE54002) and the TCGA (The Cancer Genome Atlas) database showed that our proposed HubGs might be considered as diagnostic and prognostic biomarkers, where two genes, COL11A1 and CD24, exhibit better performance. The expression analysis of HubGs by Box plots with the TCGA database in different stages of BC progression indicated their early diagnosis and prognosis ability. The HubGs set enrichment analysis with GO (Gene ontology) terms and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways disclosed some BC-causing biological processes, molecular functions, and pathways. Finally, we suggested the top-ranked six drug molecules (Suramin, Rifaximin, Telmisartan, Tukysa Tucatinib, Lynparza Olaparib, and TG.02) for the treatment of BC by molecular docking analysis with the proposed HubGs-mediated receptors. Molecular docking analysis results also showed that these drug molecules may inhibit cancer-related post-translational modification (PTM) sites (Succinylation, phosphorylation, and ubiquitination) of hub proteins. Conclusions: This study's findings might be valuable resources for diagnosis, prognosis, and therapies at an earlier stage of BC.
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Affiliation(s)
- Khanis Farhana Tuly
- Bioinformatics Lab, Department of Statistics, University of Rajshahi, Rajshahi 6205, Bangladesh; (K.F.T.); (M.B.H.); (M.A.I.); (M.K.K.); (M.S.A.); (M.H.-O.-R.); (A.A.B.)
| | - Md. Bayazid Hossen
- Bioinformatics Lab, Department of Statistics, University of Rajshahi, Rajshahi 6205, Bangladesh; (K.F.T.); (M.B.H.); (M.A.I.); (M.K.K.); (M.S.A.); (M.H.-O.-R.); (A.A.B.)
| | - Md. Ariful Islam
- Bioinformatics Lab, Department of Statistics, University of Rajshahi, Rajshahi 6205, Bangladesh; (K.F.T.); (M.B.H.); (M.A.I.); (M.K.K.); (M.S.A.); (M.H.-O.-R.); (A.A.B.)
| | - Md. Kaderi Kibria
- Bioinformatics Lab, Department of Statistics, University of Rajshahi, Rajshahi 6205, Bangladesh; (K.F.T.); (M.B.H.); (M.A.I.); (M.K.K.); (M.S.A.); (M.H.-O.-R.); (A.A.B.)
- Department of Statistics, Hajee Mohammad Danesh Science & Technology University, Dinajpur 5200, Bangladesh
| | - Md. Shahin Alam
- Bioinformatics Lab, Department of Statistics, University of Rajshahi, Rajshahi 6205, Bangladesh; (K.F.T.); (M.B.H.); (M.A.I.); (M.K.K.); (M.S.A.); (M.H.-O.-R.); (A.A.B.)
| | - Md. Harun-Or-Roshid
- Bioinformatics Lab, Department of Statistics, University of Rajshahi, Rajshahi 6205, Bangladesh; (K.F.T.); (M.B.H.); (M.A.I.); (M.K.K.); (M.S.A.); (M.H.-O.-R.); (A.A.B.)
| | - Anjuman Ara Begum
- Bioinformatics Lab, Department of Statistics, University of Rajshahi, Rajshahi 6205, Bangladesh; (K.F.T.); (M.B.H.); (M.A.I.); (M.K.K.); (M.S.A.); (M.H.-O.-R.); (A.A.B.)
| | - Sohel Hasan
- Molecular and Biomedical Health Science Lab, Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi 6205, Bangladesh;
| | - Rashidul Alam Mahumud
- NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia;
| | - Md. Nurul Haque Mollah
- Bioinformatics Lab, Department of Statistics, University of Rajshahi, Rajshahi 6205, Bangladesh; (K.F.T.); (M.B.H.); (M.A.I.); (M.K.K.); (M.S.A.); (M.H.-O.-R.); (A.A.B.)
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Izdebska WM, Daniluk J, Niklinski J. Microbiome and MicroRNA or Long Non-Coding RNA-Two Modern Approaches to Understanding Pancreatic Ductal Adenocarcinoma. J Clin Med 2023; 12:5643. [PMID: 37685710 PMCID: PMC10488817 DOI: 10.3390/jcm12175643] [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: 07/21/2023] [Revised: 08/18/2023] [Accepted: 08/19/2023] [Indexed: 09/10/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of humans' most common and fatal neoplasms. Nowadays, a number of PDAC studies are being conducted in two different fields: non-coding RNA (especially microRNA and long non-coding RNA) and microbiota. It has been recently discovered that not only does miRNA affect particular bacteria in the gut microbiome that can promote carcinogenesis in the pancreas, but the microbiome also has a visible impact on the miRNA. This suggests that it is possible to use the combined impact of the microbiome and noncoding RNA to suppress the development of PDAC. Nevertheless, insufficient research has focused on bounding both approaches to the diagnosis, treatment, and prevention of pancreatic ductal adenocarcinoma. In this article, we summarize the recent literature on the molecular basis of carcinogenesis in the pancreas, the two-sided impact of particular types of non-coding RNA and the pancreatic cancer microbiome, and possible medical implications of the discovered phenomenon.
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Affiliation(s)
- Wiktoria Maria Izdebska
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Jaroslaw Daniluk
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Jacek Niklinski
- Department of Clinical Molecular Biology, Medical University of Bialystok, 15-089 Bialystok, Poland
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10
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Zhao Y, Qin C, Zhao B, Wang Y, Li Z, Li T, Yang X, Wang W. Pancreatic cancer stemness: dynamic status in malignant progression. J Exp Clin Cancer Res 2023; 42:122. [PMID: 37173787 PMCID: PMC10182699 DOI: 10.1186/s13046-023-02693-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 04/30/2023] [Indexed: 05/15/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most aggressive malignancies worldwide. Increasing evidence suggests that the capacity for self-renewal, proliferation, and differentiation of pancreatic cancer stem cells (PCSCs) contribute to major challenges with current PC therapies, causing metastasis and therapeutic resistance, leading to recurrence and death in patients. The concept that PCSCs are characterized by their high plasticity and self-renewal capacities is central to this review. We focused specifically on the regulation of PCSCs, such as stemness-related signaling pathways, stimuli in tumor cells and the tumor microenvironment (TME), as well as the development of innovative stemness-targeted therapies. Understanding the biological behavior of PCSCs with plasticity and the molecular mechanisms regulating PC stemness will help to identify new treatment strategies to treat this horrible disease.
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Affiliation(s)
- Yutong Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Cheng Qin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Bangbo Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Yuanyang Wang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Zeru Li
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Tianyu Li
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Xiaoying Yang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Weibin Wang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China.
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China.
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China.
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11
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Potential Impact of PI3K-AKT Signaling Pathway Genes, KLF-14, MDM4, miRNAs 27a, miRNA-196a Genetic Alterations in the Predisposition and Progression of Breast Cancer Patients. Cancers (Basel) 2023; 15:cancers15041281. [PMID: 36831624 PMCID: PMC9954638 DOI: 10.3390/cancers15041281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/07/2023] [Accepted: 02/13/2023] [Indexed: 02/19/2023] Open
Abstract
Genome-wide association studies have reported link between SNPs and risk of breast cancer. This study investigated the association of the selected gene variants by predicting them as possible target genes. Molecular technique advances with the availability of whole-exome sequencing (WES), now offer opportunities for simultaneous investigations of many genes. The experimental protocol for PI3K, AKT-1, KLF-14, MDM4, miRNAs 27a, and miR-196a genotyping was done by ARMS-PCR and sanger sequencing. The novel and known gene variants were studied by Whole-exome sequencing using Illumina NovaSeq 6000 platform. This case control study reports significant association between BC patients, healthy controls with the polymorphic variants of PI3K C > T, AKT-1 G > A KLF 14 C > T, MDM4 A > G, miR-27a A > G, miR-196a-2 C > T genes (p < 0.05). MDM4 A > G genotypes were strongly associated with BC predisposition with OR 2.08 & 2.15, p < 0.05) in codominant and dominant models respectively. MDM4 A allele show the same effective (OR1.76, p < 0.05) whereas it remains protective in recessive model for BC risk. AKT1G > A genotypes were strongly associated with the BC susceptibility in all genetic models whereas PI3K C > T genotypes were associated with breast cancer predisposition in recessive model OR 6.96. Polymorphic variants of KLF-14 A > G, MDM4G > A, MiR-27aA >G, miR-196a-C > T were strongly associated with stage, tamoxifen treatment. Risk variants have been reported by whole exome sequencing in our BC patients. It was concluded that a strong association between the PI3K-AKT signaling pathway gene variants with the breast cancer susceptibility and progression. Similarly, KLF 14-AA, MDM4-GA, miR27a-GG and miR-196a-CT gene variants were associated with the higher risk probability of BC and were strongly correlated with staging of the BC patients. This study also reported Low, novel, and intermediate-genetic-risk variants of PI3K, AKT-1, MDM4G & KLF-14 by utilizing whole-exome sequencing. These variants should be further investigated in larger cohorts' studies.
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12
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Poormolaie N, Mohammadi M, Mir A, Asadi M, Kararoudi AN, Vahedian V, Maroufi NF, Rashidi M. Xanthomicrol: Effective therapy for cancer treatment. Toxicol Rep 2023; 10:436-440. [PMID: 37102154 PMCID: PMC10123071 DOI: 10.1016/j.toxrep.2023.02.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 02/13/2023] [Accepted: 02/20/2023] [Indexed: 02/24/2023] Open
Abstract
Cancer treatment is one of the main challenges of global health. For decades, researchers have been trying to find anti-cancer compounds with minimal side effects. In recent years, flavonoids, as a group of polyphenolic compounds, have attracted the attention of researchers due to their beneficial effects on health. Xanthomicrol is one of the flavonoids that has the ability to inhibit growth, proliferation, survival and cell invasion and ultimately tumor progression. Xanthomicrol, as active anti-cancer compounds, can be effective in the prevention and treatment of cancer. Therefore, the use of flavonoids can be suggested as a treatment along with other medicinal agents. It is obvious that additional investigations in cellular levels and animal models are still needed. In this review article, the effects of xanthomicrol on various cancers have been reviewed.
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13
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Wang Y, Wang G, Liu X, Yun D, Cui Q, Wu X, Lu W, Yang X, Zhang M. Inhibition of APLN suppresses cell proliferation and migration and promotes cell apoptosis in esophageal cancer cells <em>in vitro</em>, through activating PI3K/mTOR signaling pathway. Eur J Histochem 2022; 66. [PMID: 35920446 PMCID: PMC9422863 DOI: 10.4081/ejh.2022.3336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 07/13/2022] [Indexed: 11/23/2022] Open
Abstract
Esophageal cancer is the sixth leading cause of cancer mortalities globally with a high incidence rate. Apelin (APLN) plays regulatory roles in different organs. However, its role in esophageal cancer remains unknown. Therefore, our study aims to explore the effect of APLN on esophageal cancer. One hundred and eighty-four (184) esophageal tumor tissues samples from patients with esophageal cancer, and 11 esophageal tissues samples from healthy volunteers were analyzed for the expression of APLN. APLN was highly expressed in the tumor of patients with esophageal cancer and esophageal cancer cells. Patients with high expressions of APLN had a lower survival rate than the ones with low to medium expressions of APLN. Human esophageal carcinoma cell lines, TE-1 and ECA-109 cells were transfected with APLN siRNA to knockdown APLN, or transfected with pcDNA-APLN to overexpress APLN. Inhibition of APLN by siRNA-APLN reduced proliferative, migrative, and invasive abilities of esophageal cancer cells and promoted cell apoptosis, which could be all restored by pcDNA-APLN. Moreover, knocking down APLN by siRNA-APLN suppressed the PI3K/mTOR signaling pathway. These findings identify that APLN inhibition might ameliorate esophageal cancer through activating the PI3K/mTOR signaling pathway, thus APLN could be a potential target for esophageal cancer.
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Affiliation(s)
- Yuhan Wang
- Department of Integrated Traditional Chinese and Western Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University.
| | - Gang Wang
- Pharmacy Department, Puai District of Huangshi Central Hospital. Wuhan.
| | - Xiaojun Liu
- Pharmacy Department, Puai District of Huangshi Central Hospital, Wuhan.
| | - Dong Yun
- Department of Integrated Traditional Chinese and Western Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University.
| | - Qing Cui
- Department of Integrated Traditional Chinese and Western Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University.
| | - Xiaoting Wu
- Shanghai Jiao Tong University School of Medicine.
| | - Wenfeng Lu
- Department of Integrated Traditional Chinese and Western Medicine, Zhongshan Hospital, Fudan University.
| | - Xiwen Yang
- Shanghai Literature Institute of Traditional Chinese Medicine.
| | - Ming Zhang
- Department of Integrated Traditional Chinese and Western Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University.
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14
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Hsa_circ_0000994 Inhibits Pancreatic Cancer Progression by Clearing Immune-Related miR-27a and miR-27b. JOURNAL OF ONCOLOGY 2022; 2022:7274794. [PMID: 35669238 PMCID: PMC9166970 DOI: 10.1155/2022/7274794] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 04/26/2022] [Accepted: 04/27/2022] [Indexed: 11/23/2022]
Abstract
Pancreatic cancer (PC) is a common cause of cancer death. Although more and more evidences suggest that circular RNAs (circRNAs) are associated with the development of cancer, the biological function of circRNAs in PC has not been fully explored. Based on previous studies, Hsa_circ_0000994 was screened out, and its clinical significance, functional role, and mechanism in PC are poorly studied. In various cell lines, 50 PC tissues, and an equal number of normal tissues, RT-qPCR was used to identify expression level of Hsa_circ_0000994. The impact of Hsa_circ_0000994 on metastasis, cell proliferation, and apoptosis was detected using functional loss and functional gain tests. An animal study was also conducted. Underlying mechanisms of Hsa_circ_0000994 were revealed by luciferase reporter gene detection. Hsa_circ_0000994 was lowly expressed in PC tissues as well as various PC cell lines, and this low expression was closely related to cancer. In terms of functional testing, Hsa_circ_0000994 suppressed core ability of PC cells, including proliferation, migration, and invasion ability. Xenotransplantation studies further confirmed the effect of Hsa_circ_0000994 in promoting cell growth. Mechanically, Hsa_circ_0000994 inhibited miR-27a and miR-27b. Hsa_circ_0000994 inhibited the cancer cells through the effect on miR-27a and miR-27b. In summary, a circRNA with tumor suppressor effects on PC has been elucidated.
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15
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Dai H, Abdullah R, Wu X, Li F, Ma Y, Lu A, Zhang G. Pancreatic Cancer: Nucleic Acid Drug Discovery and Targeted Therapy. Front Cell Dev Biol 2022; 10:855474. [PMID: 35652096 PMCID: PMC9149368 DOI: 10.3389/fcell.2022.855474] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 04/07/2022] [Indexed: 12/20/2022] Open
Abstract
Pancreatic cancer (PC) is one of the most lethal cancers with an almost 10% 5-year survival rate. Because PC is implicated in high heterogeneity, desmoplastic tumor-microenvironment, and inefficient drug-penetration, the chemotherapeutic strategy currently recommended for the treatment of PC has limited clinical benefit. Nucleic acid-based targeting therapies have become strong competitors in the realm of drug discovery and targeted therapy. A vast evidence has demonstrated that antibody-based or alternatively aptamer-based strategy largely contributed to the elevated drug accumulation in tumors with reduced systematic cytotoxicity. This review describes the advanced progress of antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), messenger RNA (mRNAs), and aptamer-drug conjugates (ApDCs) in the treatment of PC, revealing the bright application and development direction in PC therapy.
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Affiliation(s)
- Hong Dai
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
| | - Razack Abdullah
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute for the Advancement of Chinese medicine (IACM) .Ltd, Shatin, Hong Kong SAR, China
| | - Xiaoqiu Wu
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
| | - Fangfei Li
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, Shenzhen, China
| | - Yuan Ma
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, Shenzhen, China
| | - Aiping Lu
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, Shenzhen, China
| | - Ge Zhang
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, Shenzhen, China
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16
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Gouhar SA, Abo-Elfadl MT, Gamal-Eldeen AM, El-Daly SM. Involvement of miRNAs in response to oxidative stress induced by the steroidal glycoalkaloid α-solanine in hepatocellular carcinoma cells. ENVIRONMENTAL TOXICOLOGY 2022; 37:212-223. [PMID: 34655286 DOI: 10.1002/tox.23390] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 09/28/2021] [Accepted: 10/05/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND α-Solanine is a natural toxic glycoalkaloid produced in some species of the Solanaceae family with antiproliferative activity in various cancers. OBJECTIVE This study aimed to investigate the effect of α-solanine on the oxidative stress status in human hepatocellular carcinoma HepG2 cells and to evaluate its influence on microRNAs (miRNAs) associated with oxidative stress and NF-κB regulation. METHODS The prooxidant effect of α-solanine was tested by the decay rate of the fluorescent probe, β-phycoerythrin, and by measuring malondialdehyde, reduced Glutathione, catalase, and superoxide dismutase following treatment of HepG2 cells with low doses of α-solanine. Immunocytochemical techniques were used to detect mitochondrial membrane potential (ΔΨm) and NF-κB protein. The gene expression of NF-κB and miRNAs was evaluated by real-time PCR. RESULTS α-Solanine is a prooxidant that causes a rapid decay in the fluorescence intensity of β-phycoerythrin. It induces oxidative stress-related alterations such as increased lipid peroxidation and reduced antioxidant markers. Oxidative stress induced by α-solanine was mediated by decreased ΔΨm, increased NF-κB expression, upregulation of miRNAs that control oxidative stress by regulating the NF-κB pathway, and downregulation of oncogenic miRNAs that inhibit the NF-κB pathway. CONCLUSION α-Solanine-induced oxidative stress is mediated by alterations in the NF-κB pathway with a detected crosstalk between α-solanine treatment and the expression of oxidative stress-responsive miRNAs.
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Affiliation(s)
- Shaimaa A Gouhar
- Medical Biochemistry Department, Medical Research Division, National Research Centre, Cairo, Egypt
| | - Mahmoud T Abo-Elfadl
- Biochemistry Department, Genetic Engineering and Biotechnology Research Division, National Research Centre, Cairo, Egypt
- Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt
| | - Amira M Gamal-Eldeen
- Biochemistry Department, Genetic Engineering and Biotechnology Research Division, National Research Centre, Cairo, Egypt
- Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt
| | - Sherien M El-Daly
- Medical Biochemistry Department, Medical Research Division, National Research Centre, Cairo, Egypt
- Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt
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17
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Song G, Dong H, Ma D, Wang H, Ren X, Qu Y, Wu H, Zhu J, Song W, Meng Y, Wang L, Liu T, Shen X, Zhao Y, Zhu C. Tetrahedral Framework Nucleic Acid Delivered RNA Therapeutics Significantly Attenuate Pancreatic Cancer Progression via Inhibition of CTR1-Dependent Copper Absorption. ACS APPLIED MATERIALS & INTERFACES 2021; 13:46334-46342. [PMID: 34549583 DOI: 10.1021/acsami.1c13091] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Copper is vital for various life processes, whereas severely toxic at excess level. Intracellular copper homeostasis is strictly controlled by a set of transporters and chaperones encoded by the copper homeostasis genes. Increasing evidence has shown that copper is usually overloaded in multiple malignancies, including pancreatic cancer, which has an extremely poor prognosis. Recently, silencing the SLC31A1 gene, which encodes a major transmembrane copper transporter (CTR1), has been demonstrated to be an effective means for reducing the malignant degree of pancreatic cancer by downregulating the cellular copper levels. Herein, we utilized tetrahedral framework nucleic acids (tFNAs) as vehicles to overcome the biological barriers for delivering small molecular RNAs and efficiently transferred two kinds of CTR1 mRNA-targeted RNA therapeutics, siCTR1 or miR-124, into PANC-1 cells. Both therapeutic tFNAs, termed t-siCTR1 and t-miR-124, prevented copper intake more effective than the free RNA therapeutics via efficiently suppressing the expression of CTR1, thereby significantly attenuating the progression of PANC-1 cells. In this study, therapeutic tFNAs are constructed to target metal ion transporters for the first time, which may provide an effective strategy for future treatment of other metal metabolism disorders.
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Affiliation(s)
- Guangqi Song
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Haisi Dong
- Clinical Medical College, Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Danhui Ma
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Heming Wang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Xinran Ren
- Clinical Medical College, Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China
- School of Pharmaceutical Science, Jilin University, Changchun 130021, China
| | - Yishen Qu
- Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China
| | - Hao Wu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Jimin Zhu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Wu Song
- Clinical Medical College, Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Ying Meng
- Clinical Medical College, Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Li Wang
- Clinical Medical College, Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Taotao Liu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Xizhong Shen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Yicheng Zhao
- Clinical Medical College, Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Changfeng Zhu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
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18
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Chen X, Liu F, Xue Q, Weng X, Xu F. Metastatic pancreatic cancer: Mechanisms and detection (Review). Oncol Rep 2021; 46:231. [PMID: 34498718 PMCID: PMC8444192 DOI: 10.3892/or.2021.8182] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 08/19/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer (PC) is a lethal malignancy. Its prevalence rate remains low but continues to grow each year. Among all stages of PC, metastatic PC is defined as late-stage (stage IV) PC and has an even higher fatality rate. Patients with PC do not have any specific clinical manifestations. Most cases are inoperable at the time-point of diagnosis. Prognosis is also poor even with curative-intent surgery. Complications during surgery, postoperative pancreatic fistula and recurrence with metastatic foci make the management of metastatic PC difficult. While extensive efforts were made to improve survival outcomes, further elucidation of the molecular mechanisms of metastasis poses a formidable challenge. The present review provided an overview of the mechanisms of metastatic PC, summarizing currently known signaling pathways (e.g. epithelial-mesenchymal transition, NF-κB and KRAS), imaging that may be utilized for early detection and biomarkers (e.g. carbohydrate antigen 19-9, prostate cancer-associated transcript-1, F-box/LRR-repeat protein 7 and tumor stroma), giving insight into promising therapeutic targets.
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Affiliation(s)
- Xiangling Chen
- Department of Public Health, Chengdu Medical College, Chengdu, Sichuan 610500, P.R. China
| | - Fangfang Liu
- Department of Art, Art College, Southwest Minzu University, Chengdu, Sichuan 610041, P.R. China
| | - Qingping Xue
- Department of Public Health, Chengdu Medical College, Chengdu, Sichuan 610500, P.R. China
| | - Xiechuan Weng
- Department of Neuroscience, Beijing Institute of Basic Medical Sciences, Beijing 100850, P.R. China
| | - Fan Xu
- Department of Public Health, Chengdu Medical College, Chengdu, Sichuan 610500, P.R. China
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19
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Mortoglou M, Tabin ZK, Arisan ED, Kocher HM, Uysal-Onganer P. Non-coding RNAs in pancreatic ductal adenocarcinoma: New approaches for better diagnosis and therapy. Transl Oncol 2021; 14:101090. [PMID: 33831655 PMCID: PMC8042452 DOI: 10.1016/j.tranon.2021.101090] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 03/14/2021] [Accepted: 03/26/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with a 5-year survival rate less than 8%, which has remained unchanged over the last 50 years. Early detection is particularly difficult due to the lack of disease-specific symptoms and a reliable biomarker. Multimodality treatment including chemotherapy, radiotherapy (used sparingly) and surgery has become the standard of care for patients with PDAC. Carbohydrate antigen 19-9 (CA 19-9) is the most common diagnostic biomarker; however, it is not specific enough especially for asymptomatic patients. Non-coding RNAs are often deregulated in human malignancies and shown to be involved in cancer-related mechanisms such as cell growth, differentiation, and cell death. Several micro, long non-coding and circular RNAs have been reported to date which are involved in PDAC. Aim of this review is to discuss the roles and functions of non-coding RNAs in diagnosis and treatments of PDAC.
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Affiliation(s)
- Maria Mortoglou
- Cancer Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK.
| | - Zoey Kathleen Tabin
- Cancer Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK.
| | - E Damla Arisan
- Institution of Biotechnology, Gebze Technical University, Gebze, Turkey.
| | - Hemant M Kocher
- Centre for Tumour Biology, Barts Cancer Institute-a CRUK Centre of Excellence, Queen Mary University London, London EC1M 6BQ, UK.
| | - Pinar Uysal-Onganer
- Cancer Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK.
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20
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Romano R, Picca A, Eusebi LHU, Marzetti E, Calvani R, Moro L, Bucci C, Guerra F. Extracellular Vesicles and Pancreatic Cancer: Insights on the Roles of miRNA, lncRNA, and Protein Cargos in Cancer Progression. Cells 2021; 10:1361. [PMID: 34205944 PMCID: PMC8226820 DOI: 10.3390/cells10061361] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 05/28/2021] [Accepted: 05/29/2021] [Indexed: 01/18/2023] Open
Abstract
Pancreatic cancer (PC) is among the most devastating digestive tract cancers worldwide. This cancer is characterized by poor diagnostic detection, lack of therapy, and difficulty in predicting tumorigenesis progression. Although mutations of key oncogenes and oncosuppressor involved in tumor growth and in immunosurveillance escape are known, the underlying mechanisms that orchestrate PC initiation and progression are poorly understood or still under debate. In recent years, the attention of many researchers has been concentrated on the role of extracellular vesicles and of a particular subset of extracellular vesicles, known as exosomes. Literature data report that these nanovesicles are able to deliver their cargos to recipient cells playing key roles in the pathogenesis and progression of many pancreatic precancerous conditions. In this review, we have summarized and discussed principal cargos of extracellular vesicles characterized in PC, such as miRNAs, lncRNAs, and several proteins, to offer a systematic overview of their function in PC progression. The study of extracellular vesicles is allowing to understand that investigation of their secretion and analysis of their content might represent a new and potential diagnostic and prognostic tools for PC.
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Affiliation(s)
- Roberta Romano
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy;
| | - Anna Picca
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy; (A.P.); (E.M.); (R.C.)
- Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institute and Stockholm University, 171 77 Stockholm, Sweden
| | - Leonardo Henry Umberto Eusebi
- Gastroenterology and Endoscopy Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Gastroenterology and Endoscopy Unit, Sant’Orsola University Hospital, 40138 Bologna, Italy
| | - Emanuele Marzetti
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy; (A.P.); (E.M.); (R.C.)
- Institute of Internal Medicine and Geriatrics, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Riccardo Calvani
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy; (A.P.); (E.M.); (R.C.)
- Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institute and Stockholm University, 171 77 Stockholm, Sweden
| | - Loredana Moro
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA; or
- Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, 70126 Bari, Italy
| | - Cecilia Bucci
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy;
| | - Flora Guerra
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy;
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21
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Baghbani E, Noorolyai S, Duijf PHG, Silvestris N, Kolahian S, Hashemzadeh S, Baghbanzadeh Kojabad A, FallahVazirabad A, Baradaran B. The impact of microRNAs on myeloid-derived suppressor cells in cancer. Hum Immunol 2021; 82:668-678. [PMID: 34020831 DOI: 10.1016/j.humimm.2021.04.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 04/28/2021] [Accepted: 04/28/2021] [Indexed: 02/08/2023]
Abstract
Inflammation promotes cancer development. To a large extent, this can be attributed to the recruitment of myeloid-derived suppressor cells (MDSCs) to tumors. These cells are known for establishing an immunosuppressive tumor microenvironment by suppressing T cell activities. However, MDSCs also promote metastasis and angiogenesis. Critically, as small non-coding RNAs that regulate gene expression, microRNAs (miRNAs) control MDSC activities. In this review, we discuss how miRNA networks regulate key MDSC signaling pathways, how they shape MDSC development, differentiation and activation, and how this impacts tumor development. By targeting the expression of miRNAs in MDSCs, we can alter their main signaling pathways. In turn, this can compromise their ability to promote multiple hallmarks of cancer. Therefore, this may represent a new powerful strategy for cancer immunotherapy.
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Affiliation(s)
- Elham Baghbani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saeed Noorolyai
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Pascal H G Duijf
- Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Australia; University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia
| | - Nicola Silvestris
- IRCCS Bari, Italy. Medical Oncology Unit-IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, Bari, Italy, Department of Biomedical Sciences and Human Oncology DIMO-University of Bari, Bari, Italy
| | - Saeed Kolahian
- Department of Experimental and Clinical Pharmacology and Pharmacogenomics, Division of Pharmacogenomics, University of Tübingen, Tübingen, Germany; Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany; Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Marburg, Germany
| | - Shahryar Hashemzadeh
- General and Vascular Surgery Department, Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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22
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and invasive type of pancreatic cancer (PCa) and is expected to be the second most common cause of cancer-associated deaths. The high mortality rate is due to the asymptomatic progression of the clinical features until the advanced stages of the disease and the limited effectiveness of the current therapeutics. Aberrant expression of several microRNAs (miRs/miRNAs) has been related to PDAC progression and thus they could be potential early diagnostic, prognostic, and/or therapeutic predictors for PDAC. miRs are small (18 to 24 nucleotides long) non-coding RNAs, which regulate the expression of key genes by targeting their 3′-untranslated mRNA region. Increased evidence has also suggested that the chemoresistance of PDAC cells is associated with metabolic alterations. Metabolic stress and the dysfunctionality of systems to compensate for the altered metabolic status of PDAC cells is the foundation for cellular damage. Current data have implicated multiple systems as hallmarks of PDAC development, such as glutamine redox imbalance, oxidative stress, and mitochondrial dysfunction. Hence, both the aberrant expression of miRs and dysregulation in metabolism can have unfavorable effects in several biological processes, such as apoptosis, cell proliferation, growth, survival, stress response, angiogenesis, chemoresistance, invasion, and migration. Therefore, due to these dismal statistics, it is crucial to develop beneficial therapeutic strategies based on an improved understanding of the biology of both miRs and metabolic mediators. This review focuses on miR-mediated pathways and therapeutic resistance mechanisms in PDAC and evaluates the impact of metabolic alterations in the progression of PDAC.
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Therapeutic Approaches for Metastases from Colorectal Cancer and Pancreatic Ductal Carcinoma. Pharmaceutics 2021; 13:pharmaceutics13010103. [PMID: 33466892 PMCID: PMC7830403 DOI: 10.3390/pharmaceutics13010103] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 01/05/2021] [Accepted: 01/05/2021] [Indexed: 12/12/2022] Open
Abstract
Metastasis is the process of dissemination of a tumor, whereby cells from the primary site dislodge and find their way to other tissues where secondary tumors establish. Metastasis is the primary cause of death related to cancer. This process warrants changes in original tumoral cells and their microenvironment to establish a metastatic niche. Traditionally, cancer therapy has focused on metastasis prevention by systematic treatments or direct surgical re-sectioning. However, metastasis can still occur. More recently, new therapies direct their attention to targeting cancer stem cells. As they propose, these cells could be the orchestrators of the metastatic niche. In this review, we describe conventional and novel developments in cancer therapeutics for liver and lung metastasis. We further discuss the resistance mechanisms of targeted therapy, the advantages, and disadvantages of diverse treatment approaches, and future novel strategies to enhance cancer prognosis.
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24
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Sun W, Ren Y, Lu Z, Zhao X. The potential roles of exosomes in pancreatic cancer initiation and metastasis. Mol Cancer 2020; 19:135. [PMID: 32878635 PMCID: PMC7466807 DOI: 10.1186/s12943-020-01255-w] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 08/25/2020] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer (PaCa) is an insidious and highly metastatic malignancy, with a 5-year survival rate of less than 5%. So far, the pathogenesis and progression mechanisms of PaCa have been poorly characterized. Exosomes correspond to a class of extracellular nanovesicles, produced by a broad range of human somatic and cancerous cells. These particular nanovesicles are mainly composed by proteins, genetic substances and lipids, which mediate signal transduction and material transport. A large number of studies have indicated that exosomes may play decisive roles in the occurrence and metastatic progression of PaCa. This article summarizes the specific functions of exosomes and their underlying molecular mechanisms in mediating the initiation and metastatic capability of PaCa.
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Affiliation(s)
- Wei Sun
- Department of Radiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Ying Ren
- Department of Radiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Zaiming Lu
- Department of Radiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Xiangxuan Zhao
- Department of Radiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China.
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25
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Abstract
PURPOSE Esophageal squamous cell carcinoma (ESCC) is one of the predominant types of esophageal cancer with poor prognosis which shows high prevalence in eastern countries. Studying microRNAs that were considered for their capabilities such as tissue-specific expression and involvement in different cell features may be informative in the field of diagnostic and prognostic tumor markers. The expression levels of miR-27a and miR-24-2 have been reported to be dysregulated in various cancers and contribute in tumorigenesis and progression; thus, evaluating their expressional behavior and its association with tumor states alteration in ESCC could potentially be helpful. METHODS The study was conducted on 30 fresh specimens including tumor and normal counterparts' tissues of ESCC. After the extraction of total RNA, complementary DNA synthesis was performed by the use of linear specific primers. Eventually, real-time polymerase chain reaction was carried out for the measurement of microRNAs expression level. RESULTS According to the obtained data, miR 27a and miR-24-2 were significantly upregulated (~2.5 fold, p < 0.05) in tumor specimens compared with their normal adjacent tissue; Moreover, upregulation of miR-27a and 24-2 showed cooperative relationship while analyzed. However, there was no correlation between clinicopathological features and microRNAs upregulation. CONCLUSIONS The results of this study show that miR-27a and miR-24-2 cooperatively upregulate in ESCC and suggest that these microRNAs can be introduced as a candidate for further study in the field of screening and prognostic biomarkers.
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26
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Li X, Zhou S, Fan T, Feng X. lncRNA DGCR 5/miR‑27a‑3p/BNIP3 promotes cell apoptosis in pancreatic cancer by regulating the p38 MAPK pathway. Int J Mol Med 2020; 46:729-739. [PMID: 32626951 PMCID: PMC7307863 DOI: 10.3892/ijmm.2020.4632] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 04/14/2020] [Indexed: 12/13/2022] Open
Abstract
Long non‑coding RNA (lncRNA) DGCR5 has been identified as a tumor suppressor in several types of cancer. However, its biological functions in pancreatic cancer (PaCa) have not yet been fully elucidated. The present study was designed to investigate the role of lncRNA DGCR5 in the regulation of PaCa cell apoptosis. For this purpose, lncRNA DGCR5, miR‑27a‑3p and Bcl‑2/adenovirus E1B‑19kDa‑interacting protein 3 (BNIP3) expression levels were examined by reverse transcription‑quantitative (RT‑qPCR) and western blot analysis, respectively. RNA pull‑down assay was used to verify DGCR5 as a target of miR‑27a‑3p and dual luciferase reporter assay was used to clarify whether miR‑27a‑3p targets the BNIP3 3' UTR. In addition, PaCa cell apoptosis was assessed by flow cytometry. Recombinant plasmids and cell transfection were performed to modulate the endogenous expression of related genes. Thereafter, the role of DGCR5 in PaCa was analyzed using a nude mouse model of PaCa. lncRNA DGCR5 was found to be downregulated in PaCa tissues and cells. DGCR5 functioned as a decoy of miR‑27a‑3p, and BNIP3 was negatively regulated by miR‑27a‑3p. Following the transfection of DGCR5 plasmid into PaCa cells, the expression of miR‑27a‑3p was downregulated, and this downregulation was reversed following transfection with miR‑27a‑3p mimic. In addition, DGCR5 regulated the BNIP3 and p38 MAPK pathways via miR‑27a‑3p and promoted PaCa cell apoptosis via the miR‑27a‑3p/BNIP3 pathway. The results of in vivo experiments also indicated the positive effects of DGCR5 on a nude mouse model of PaCa. On the whole, the findings of the present study indicate that lncRNA DGCR5 upregulates the BNIP3 and p38 MAPK pathways via miR‑27a‑3p to promote PaCa cell apoptosis, thereby attenuating PaCa development.
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Affiliation(s)
- Xianjie Li
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Medical School, Ningbo University, Ningbo, Zhejiang 315020, P.R. China
| | - Shanxue Zhou
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Medical School, Ningbo University, Ningbo, Zhejiang 315020, P.R. China
| | - Tianyi Fan
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Medical School, Ningbo University, Ningbo, Zhejiang 315020, P.R. China
| | - Xuefeng Feng
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Medical School, Ningbo University, Ningbo, Zhejiang 315020, P.R. China
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Shang D, Xie C, Hu J, Tan J, Yuan Y, Liu Z, Yang Z. Pancreatic cancer cell-derived exosomal microRNA-27a promotes angiogenesis of human microvascular endothelial cells in pancreatic cancer via BTG2. J Cell Mol Med 2020; 24:588-604. [PMID: 31724333 PMCID: PMC6933412 DOI: 10.1111/jcmm.14766] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 08/14/2019] [Accepted: 09/17/2019] [Indexed: 01/06/2023] Open
Abstract
Pancreatic cancer (PC) remains a primary cause of cancer-related deaths worldwide. Existing literature has highlighted the oncogenic role of microRNA-27a (miR-27a) in multiple cancers. Hence, the current study aimed to clarify the potential therapeutic role of PC cell-derived exosomal miR-27a in human microvascular endothelial cell (HMVEC) angiogenesis in PC. Initially, differentially expressed genes (DEGs) and miRs related to PC were identified by microarray analysis. Microarray analysis provided data predicting the interaction between miR-27a and BTG2 in PC, which was further verified by the elevation or depletion of miR-27a. Next, the expression of miR-27a and BTG2 in the PC tissues was quantified. HMVECs were exposed to exosomes derived from PC cell line PANC-1 to investigate the effects associated with PC cell-derived exosomes carrying miR-27a on HMVEC proliferation, invasion and angiogenesis. Finally, the effect of miR-27a on tumorigenesis and microvessel density (MVD) was analysed after xenograft tumour inoculation in nude mice. Our results revealed that miR-27a was highly expressed, while BTG2 was poorly expressed in both PC tissues and cell lines. miR-27a targeted BTG2. Moreover, miR-27a silencing inhibited PC cell proliferation and invasion, and promoted apoptosis through the elevation of BTG2. The in vitro assays revealed that PC cell-derived exosomes carrying miR-27a stimulated HMVEC proliferation, invasion and angiogenesis, while this effect was reversed in the HMVECs cultured with medium containing GW4869-treated PANC-1 cells. Furthermore, in vivo experiment revealed that miR-27a knockdown suppressed tumorigenesis and MVD. Taken together, cell-derived exosomes carrying miR-27a promotes HMVEC angiogenesis via BTG2 in PC.
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Affiliation(s)
- Dan Shang
- Department of Vascular SurgeryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Chao Xie
- Department of Hepatobiliary and Pancreatic SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Pancreatic Surgery CenterZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Jin Hu
- Department of Pancreatic SurgeryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Jinru Tan
- Department of Pancreatic SurgeryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Yufeng Yuan
- Department of Hepatobiliary and Pancreatic SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Zhisu Liu
- Department of Hepatobiliary and Pancreatic SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Zhiyong Yang
- Department of Hepatobiliary and Pancreatic SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Pancreatic Surgery CenterZhongnan Hospital of Wuhan UniversityWuhanChina
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28
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Tang W, Xu H, Ma D, Ma R, Wu J, Yu X, Feng J, Liu Q. Pre-miR-27a rs895819 polymorphism and risk of diffuse large B-cell lymphoma. J Clin Lab Anal 2019; 34:e23088. [PMID: 31797450 PMCID: PMC7083450 DOI: 10.1002/jcla.23088] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 09/09/2019] [Accepted: 09/14/2019] [Indexed: 12/13/2022] Open
Abstract
Background Recently, several studies have investigated the relationship between Pre‐miR‐27a rs895819 polymorphism and risk of various cancers. However, the relationship between rs895819 and diffuse large B‐cell lymphoma (DLBCL) has not been well known. Methods In this study, we conducted a case‐control study to explore the role of Pre‐miR‐27a rs895819 in risk of DLBCL. The PCR‐TaqMan and luciferase assays and in vitro experiments were used to evaluate polymorphism function. Results As a result, we found subjects carrying with rs895819 AG/GG genotype had a significantly decreased risk when compared with those carrying the AA genotype. Further qPCR assay showed that the DLBCL patients carrying AG/GG genotypes showed a lower level of mature miR‐27a when compared with patients carrying AA genotype. Moreover, miR‐27a levels were upregulated in DLBCL tissues compared with normal lymphoid tissues. Further in vitro experiments showed that miR‐27a might function as an oncogene through target TGFBR1. In addition, TGFBR1 overexpression rescues effects of miR‐27a inhibitor on DLBCL cells phenotypes. Conclusions In conclusion, these findings indicate that rs895819 A > G might reduce the expression of mature miR‐27a, and leading a higher level of TGFBR1, ultimately inhibiting the development of DLBCL.
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Affiliation(s)
- Weiyan Tang
- The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Haonan Xu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Dawei Ma
- The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Rong Ma
- The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Jianqiu Wu
- The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Xinnian Yu
- The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Jifeng Feng
- The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Qizhan Liu
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer, Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
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29
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Yang D, Hu Z, Xu J, Tang Y, Wang Y, Cai Q, Zhu Z. MiR-760 enhances sensitivity of pancreatic cancer cells to gemcitabine through modulating Integrin β1. Biosci Rep 2019; 39:BSR20192358. [PMID: 31693728 PMCID: PMC6863763 DOI: 10.1042/bsr20192358] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 09/10/2019] [Accepted: 09/25/2019] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer (PC) is the most lethal tumor type among human diseases, with low survival rate. The investigation of potent molecular mechanisms involved in PC is still obscure owing to its drug resistance. The purpose of the present study is to disclose the underlying mechanism participating in PC progression and drug therapy, reversing the unpromising treatment outcome. In our research, microRNA-760 (miR-760) was first revealed to be lowly expressed in PC cells. And up-regulation of miR-760 could further suppress PC cell proliferation and boost cell apoptosis, as well as improve gemcitabine sensitivity of PC cells through gain-of-function assays. Besides, RNA-binding protein (RBP) MOV10 interacted with and stabilized Integrin β1 (ITGB1). Furtherly, miR-760 was proved to target Moloney leukemia virus 10 (MOV10) mRNA to decrease MOV10 protein expression, thus promoting the destabilization of ITGB1. At last, rescue experiments validated that up-regulation of ITGB1 remedied the miR-760 overexpression-caused inhibition on biological activities and gemcitabine resistance of PC cells. To summarize, the current inspection demonstrated that miR-760 enhances sensitivity of PC cells to gemcitabine through modulating MOV10-stablized ITGB1, highlighting the role of miR-760/MOV10/ITGB1 pathway in the drug therapy for PC patients.
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Affiliation(s)
- Dejun Yang
- Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Zunqi Hu
- Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Jiapeng Xu
- Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Yuan Tang
- Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Yu Wang
- Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Qingping Cai
- Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Zhenxin Zhu
- Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
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30
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Zhang P, Fu H, Du S, Wang F, Yang J, Cai W, Liu D. Click RNA for Rapid Capture and Identification of Intracellular MicroRNA Targets. Anal Chem 2019; 91:15740-15747. [PMID: 31714070 DOI: 10.1021/acs.analchem.9b03943] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Rapid capture and identification of the intracellular target genes of microRNAs (miRNAs) are the key to understanding miRNA functions and development of RNA-based therapeutics. However, developing biochemical tools that can fish out the target genes of miRNAs in live cells is a significant technical challenge. Here, we report a remarkably simple yet powerful technology capable of loading virtually any miRNA into Ago2 of the RNA-induced silencing complexes (RISCs). This surprising discovery enables rapid capture and identification of target mRNAs and long noncoding RNAs. It is achieved by linking dibenzocyclooctyne (DBCO), a classical chemical moiety in copper-free click chemistry, to the 3' end of miRNAs. DBCO serves as a high-affinity tag to the Ago2 protein, thus boosting the formation of RISCs with miRNA target genes in living cells. Upon cell lysing, DBCO's routine function in click chemistry allows rapid enrichment of target genes for analysis without the need of additional molecular handles. A series of miR-21 and miR-27a target genes that were previously unknown were pulled down from various cell lines and identified with qRT-PCR, demonstrating the utility of this innovative technology in both transcriptomic research and RNA-based studies.
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Affiliation(s)
- Pengjuan Zhang
- College of Chemistry, Research Center for Analytical Sciences, State Key Laboratory of Medicinal Chemical Biology, and Tianjin Key Laboratory of Molecular Recognition and Biosensing , Nankai University , Tianjin 300071 , China.,Hebei University of Environmental Engineering , Qinhuangdao 066102 , Hebei , China
| | - Haohao Fu
- College of Chemistry, Research Center for Analytical Sciences, State Key Laboratory of Medicinal Chemical Biology, and Tianjin Key Laboratory of Molecular Recognition and Biosensing , Nankai University , Tianjin 300071 , China
| | - Shuangli Du
- College of Chemistry, Research Center for Analytical Sciences, State Key Laboratory of Medicinal Chemical Biology, and Tianjin Key Laboratory of Molecular Recognition and Biosensing , Nankai University , Tianjin 300071 , China
| | - Fengchao Wang
- College of Chemistry, Research Center for Analytical Sciences, State Key Laboratory of Medicinal Chemical Biology, and Tianjin Key Laboratory of Molecular Recognition and Biosensing , Nankai University , Tianjin 300071 , China
| | - Jie Yang
- College of Chemistry, Research Center for Analytical Sciences, State Key Laboratory of Medicinal Chemical Biology, and Tianjin Key Laboratory of Molecular Recognition and Biosensing , Nankai University , Tianjin 300071 , China
| | - Wensheng Cai
- College of Chemistry, Research Center for Analytical Sciences, State Key Laboratory of Medicinal Chemical Biology, and Tianjin Key Laboratory of Molecular Recognition and Biosensing , Nankai University , Tianjin 300071 , China
| | - Dingbin Liu
- College of Chemistry, Research Center for Analytical Sciences, State Key Laboratory of Medicinal Chemical Biology, and Tianjin Key Laboratory of Molecular Recognition and Biosensing , Nankai University , Tianjin 300071 , China
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31
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Rawat M, Kadian K, Gupta Y, Kumar A, Chain PSG, Kovbasnjuk O, Kumar S, Parasher G. MicroRNA in Pancreatic Cancer: From Biology to Therapeutic Potential. Genes (Basel) 2019; 10:genes10100752. [PMID: 31557962 PMCID: PMC6827136 DOI: 10.3390/genes10100752] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 09/19/2019] [Accepted: 09/20/2019] [Indexed: 12/20/2022] Open
Abstract
Pancreatic cancer is one of the most aggressive malignancies, accounting for more than 45,750 deaths annually in the U.S. alone. The aggressive nature and late diagnosis of pancreatic cancer, coupled with the limitations of existing chemotherapy, present the pressing need for the development of novel therapeutic strategies. Recent reports have demonstrated a critical role of microRNAs (miRNAs) in the initiation, progression, and metastasis of cancer. Furthermore, aberrant expressions of miRNAs have often been associated with the cause and consequence of pancreatic cancer, emphasizing the possible use of miRNAs in the effective management of pancreatic cancer patients. In this review, we provide a brief overview of miRNA biogenesis and its role in fundamental cellular process and miRNA studies in pancreatic cancer patients and animal models. Subsequent sections narrate the role of miRNA in, (i) cell cycle and proliferation; (ii) apoptosis; (iii) invasions and metastasis; and (iv) various cellular signaling pathways. We also describe the role of miRNA's in pancreatic cancer; (i) diagnosis; (ii) prognosis and (iii) therapeutic intervention. Conclusion section describes the gist of review with future directions.
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Affiliation(s)
- Manmeet Rawat
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
| | - Kavita Kadian
- Department of Biotechnology, Kumaun University, Nainital, Uttarakhand 263001, India.
| | - Yash Gupta
- Department of Internal Medicine, Loyola University Medical Center, Chicago, IL 60153, USA.
| | - Anand Kumar
- Biosecurity and Public Health Group, Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
| | - Patrick S G Chain
- Biosecurity and Public Health Group, Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
| | - Olga Kovbasnjuk
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
| | - Suneel Kumar
- Department of Biomedical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
| | - Gulshan Parasher
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
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Zhao J, Du X, Wang M, Yang P, Zhang J. Salidroside mitigates hydrogen peroxide-induced injury by enhancement of microRNA-27a in human trabecular meshwork cells. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 47:1758-1765. [PMID: 31062616 DOI: 10.1080/21691401.2019.1608222] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Salidroside (Sal) exerted widely pharmacological effects in multitudinous diseases had been certified. The actual study clarified the protective activity of Sal in H2O2-injured human trabecular meshwork (HTM) cells. HTM cells were disposed with H2O2 to construct an oxidative damage model in vitro. Then, Sal was utilized to administrate HTM cells, and cell viability, apoptosis, apoptosis-interrelated proteins and ROS production were appraised using CCK-8, flow cytometry, western blot and DCFH-DA staining. MiR-27a inhibitor and its control were transfected into HTM cells, and the influences of miR-27a inhibition in HTM cells stimulated with H2O2 and Sal were detected. PI3K/AKT and Wnt/β-catenin pathways were ultimately investigated to uncover the underlying mechanism. We found that H2O2 evoked HTM cells oxidative damage, as evidenced by repressing cell viability, inducing apoptosis, activating cleaved-caspase-3/-9 expression and increasing ROS production. Sal significantly lightened H2O2-evoked oxidative damage in HTM cells. Additionally, miR-27a was up-regulated by Sal, and miR-27a suppression significantly reversed the protective effect of Sal on H2O2-injured HTM cells. Finally, Sal activated PI3K/AKT and Wnt/β-catenin pathways through enhancement of miR-27a in H2O2-injured HTM cells. In conclusion, these discoveries suggested that Sal could protect HTM cells against H2O2-evoked oxidative damage by activating PI3K/AKT and Wnt/β-catenin pathways through enhancement of miR-27a. Highlights H2O2 evokes HTM cells oxidative damage; Sal relieves H2O2-induced oxidative damage in HTM cells; Sal enhances miR-27a expression in H2O2-injured HTM cells; Repressed miR-27a reverses the protective impacts of Sal on H2O2-injured HTM cells; Sal activates PI3K/AKT and Wnt/β-catenin pathways by increasing miR-27a.
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Affiliation(s)
- Jun Zhao
- a Department of Ophthalmology , Linyi People's Hospital , Linyi , China
| | - Xiujuan Du
- b Department of Ophthalmology, Eye Institute of Shandong University of Traditional Chinese Medicine , Affiliated Eye Hospital of Shandong University of TCM , Jinan , China
| | - Meng Wang
- a Department of Ophthalmology , Linyi People's Hospital , Linyi , China
| | | | - Juanmei Zhang
- a Department of Ophthalmology , Linyi People's Hospital , Linyi , China
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Zhang Y, Yang J, Zhou X, Wang N, Li Z, Zhou Y, Feng J, Shen D, Zhao W. Knockdown of miR-222 inhibits inflammation and the apoptosis of LPS-stimulated human intervertebral disc nucleus pulposus cells. Int J Mol Med 2019; 44:1357-1365. [PMID: 31432092 PMCID: PMC6713428 DOI: 10.3892/ijmm.2019.4314] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 06/14/2019] [Indexed: 01/01/2023] Open
Abstract
It has been demonstrated that miR‑222 is upregulated in human intervertebral disc (IVD) degeneration tissues; however, the underlying mechanisms remain unclear. In this study, we aimed to elucidate the mechanisms of action of miR‑222 in IVD tissues. Nucleus pulposus (NP) cells were treated with lipopolysaccharide (LPS) to simulate IVD degeneration. The expression level of miR‑222 was detected by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) in cells and tissues. Cell apoptosis was analyzed by flow cytometry. Additionally, western blot analysis was used to determine the levels of Toll‑like receptor 4 (TLR4), Iκβ‑alpha (IκBα) and p65. Interleukin (IL)‑1β, tumor necrosis factor‑α (TNF‑α) and IL‑6 protein expression levels were determined by enzyme‑linked immunosorbent assay (ELISA). The target gene of miR‑222 was determined by TargetScan7.2 and dual luciferase reporter gene analysis. Western blot analysis and RT‑qPCR were used to determine the mRNA and protein levels of tissue inhibitor of metalloproteinase 3 (TIMP3). The mRNA expression level of miR‑222 was found to be increased in IVD tissues and in LPS‑stimulated cells, and its expression was positively associated with the clinical MRI grade. In vitro, apoptosis was promoted/inhibited by miR‑222 mimics/inhibitors. Transfection with miR‑222 mimics/inhibitors significantly increased/decreased the production of TNF‑α, IL‑1β and IL‑6 and suppressed/enhanced collagen II and aggrecan expression. The protein levels of TLR4, p‑IκΒα and p‑p65 were upregulated/downregulated by transfection with the mimics/inhibitors. In addition, it was demonstrated that TIMP3 was a direct target gene of miR‑222, and was negatively regulated by miR‑222 in NP cells. The silencing of TIMP3 reversed the inhibitory effects of miR‑222 inhibitor on cell apoptosis, which was induced by LPS. Thus, on the whole, the findings of this study demonstrate that miR‑222 functions as a promoter of IVD development, partly via the regulation of TIMP3.
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Affiliation(s)
- Yang Zhang
- Spine Division, Department of Orthopedics, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning 110024, P.R. China
| | - Jiujie Yang
- Spine Division, Department of Orthopedics, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning 110024, P.R. China
| | - Xiaoqing Zhou
- Spine Division, Department of Orthopedics, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning 110024, P.R. China
| | - Nan Wang
- Spine Division, Department of Orthopedics, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning 110024, P.R. China
| | - Zhi Li
- Spine Division, Department of Orthopedics, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning 110024, P.R. China
| | - Yubo Zhou
- Spine Division, Department of Orthopedics, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning 110024, P.R. China
| | - Jianzhou Feng
- Spine Division, Department of Orthopedics, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning 110024, P.R. China
| | - Dewei Shen
- Spine Division, Department of Orthopedics, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning 110024, P.R. China
| | - Wei Zhao
- Spine Division, Department of Orthopedics, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning 110024, P.R. China
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Abstract
OBJECTIVE The KRAS gene is the most frequently mutated gene in pancreatic cancer, and no successful anti-Ras therapy has been developed. Gastrin has been shown to stimulate pancreatic cancer in an autocrine fashion. We hypothesized that reactivation of the peptide gastrin collaborates with KRAS during pancreatic carcinogenesis. METHODS LSL-Kras; P48-Cre (KC) mutant KRAS transgenic mice were crossed with gastrin-KO (GKO) mice to develop GKO/KC mice. Pancreata were examined for 8 months for stage of pancreatic intraepithelial neoplasia lesions, inflammation, fibrosis, gastrin peptide, and microRNA expression. Pancreatic intraepithelial neoplasias from mice were collected by laser capture microdissection and subjected to reverse-phase protein microarray, for gastrin and protein kinases associated with signal transduction. Gastrin mRNA was measured by RNAseq in human pancreatic cancer tissues and compared to that in normal pancreas. RESULTS In the absence of gastrin, PanIN progression, inflammation, and fibrosis were significantly decreased and signal transduction was reversed to the canonical pathway with decreased KRAS. Gastrin re-expression in the PanINs was mediated by miR-27a. Gastrin mRNA expression was significantly increased in human pancreatic cancer samples compared to normal human pancreas controls. CONCLUSIONS This study supports the mitogenic role of gastrin in activation of KRAS during pancreatic carcinogenesis.
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Lv L, Zhang J, Tian F, Li X, Li D, Yu X. Arbutin protects HK-2 cells against high glucose-induced apoptosis and autophagy by up-regulating microRNA-27a. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 47:2940-2947. [PMID: 31319730 DOI: 10.1080/21691401.2019.1640231] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- Lina Lv
- Department of Nephrology, Jining No.1 People's Hospital, Jining, China
- Affiliated Jining No.1 People's Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Jing Zhang
- Department of Endocrinology, Jining No.1 People's Hospital, Jining, China
| | - Fengqun Tian
- Department of Nephrology, Jiaxiang County Medicine Hospital, Jiaxiang County, Jining, China
| | - Xia Li
- Department of Nephrology, Jining No.1 People's Hospital, Jining, China
| | - Dandan Li
- Department of Endocrinology, Jining No.1 People's Hospital, Jining, China
| | - Xiulian Yu
- Department of Nephrology, Jining No.1 People's Hospital, Jining, China
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Su C, Huang DP, Liu JW, Liu WY, Cao YO. miR-27a-3p regulates proliferation and apoptosis of colon cancer cells by potentially targeting BTG1. Oncol Lett 2019; 18:2825-2834. [PMID: 31452761 PMCID: PMC6676402 DOI: 10.3892/ol.2019.10629] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 05/13/2019] [Indexed: 01/16/2023] Open
Abstract
microRNA (miR/miRNA)-27a-3p has been reported to be abnormally expressed in various types of cancer, including colorectal cancer (CRC). B-cell translocation gene 1 (BTG1) has also been implicated with CRC. However, the association between miR-27a-3p and BTG1 in CRC, to the best of our knowledge, has not been investigated. In order to assess whether miR-27a-3p is associated with CRC, reverse transcription-quantitative PCR was performed on 20 paired CRC and paracancerous tissues for miRNA analysis. For the screening and validation of miR-27a-3p expression in colon cancer, several colon cancer cell lines (HCT-116, HCT8, SW480, HT29, LOVO and Caco2) and the normal colorectal epithelial cell line NCM460 were examined. The highest expression levels of miR-27a-3p were detected in the HCT-116, which was selected for further experimentation. The HCT-116 cells were divided into control, miR-27a-3p mimic and inhibitor groups, and cell proliferation was tested using an MTT assay. Additionally, miR-27a-3p inhibitor/mimic or BTG1 plasmid were transfected into the HCT-116 cells, and flow cytometry was performed to analyze cell cycle distributions. TUNEL analysis was performed to detect apoptosis. Protein levels of factors in the downstream signaling pathway mediated by miR-27a-3p [ERK/mitogen-activated extracellular signal-regulated kinase (MEK)] were detected. miR-27a-3p was revealed to be overexpressed in human CRC tissues and colon cancer cell lines. Knockdown of miR-27a-3p suppressed proliferation of HCT-116 cells and apoptosis was increased. It further markedly upregulated expression levels of BTG1 and inhibited activation of proteins of the ERK/MEK signaling pathway. In addition, overexpression of BTG1 in HCT-116 cells triggered G1/S phase cell cycle arrest and increased apoptosis via the ERK/MEK signaling pathway. In conclusion, the present study demonstrated that the effects of miR-27a-3p on colon cancer cell proliferation and apoptosis were similar to those of the tumor suppressor gene BTG1. The miR-27a-3p/BTG1 axis may have potential implications for diagnostic and therapeutic approaches in CRC.
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Affiliation(s)
- Chang Su
- Department of Surgery, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai 201199, P.R. China
| | - Dong-Ping Huang
- Department of Surgery, People's Hospital of Putuo District, Shanghai 200060, P.R. China
| | - Jian-Wen Liu
- Department of Molecular and Cellular Pharmacology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, P.R. China
| | - Wei-Yan Liu
- Department of Surgery, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai 201199, P.R. China
| | - Yi-Ou Cao
- Department of Surgery, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai 201199, P.R. China
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Silencing microRNA-27a inhibits proliferation and invasion of human osteosarcoma cells through the SFRP1-dependent Wnt/β-catenin signaling pathway. Biosci Rep 2019; 39:BSR20182366. [PMID: 31072914 PMCID: PMC6549093 DOI: 10.1042/bsr20182366] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 04/15/2019] [Accepted: 04/29/2019] [Indexed: 12/18/2022] Open
Abstract
Osteosarcoma is the most common malignant tumor of bone with a high potential for metastasis. Importantly, microRNA-27a (miR-27a) is involved in the progression of osteosarcoma. The present study aims to discuss the effects of miR-27a and its target gene secreted frizzled related protein 1 (SFRP1) on proliferation and invasion of human osteosarcoma cells via Wnt/β-catenin signaling pathway. The expression of miR-27a and SFRP1 in osteosarcoma tissues and cells was detected, followed by identification of their relations. Subsequently, miR-27a mimic, miR-27a inhibitor, or siRNA against SFRP1 were introduced into cells (HOS and U2OS) to investigate their role in cell proliferation and invasion. The expression of Wnt/β-catenin signaling pathway-related gene was analyzed to further uncover the regulatory mechanism of miR-27a. The osteosarcoma tissues and cells exhibited elevated miR-27 expression and reduced SFRP1 expression. SFRP1 was verified to be a target gene of miR-27a. Meanwhile, silenced miR-27a inhibited proliferation and invasion of human osteosarcoma cells. Finally, silencing miR-27a inhibited the activation of Wnt/β-catenin signaling pathway, evidenced by reduced β-catenin expression. Our study draws a conclusion that silencing miR-27a dampens osteosarcoma progression, which might be achieved through the inactivation of the Wnt/β-catenin signaling pathway by up-regulating SFRP1.
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MicroRNA-27a regulates the proliferation, chemosensitivity and invasion of human ovarian cancer cell lines by targeting Cullin 5. Arch Biochem Biophys 2019; 668:9-15. [DOI: 10.1016/j.abb.2019.04.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 04/13/2019] [Accepted: 04/27/2019] [Indexed: 12/30/2022]
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Luo B, Zhou Y, Lv H, Sun S, Tang W. MS-275 potentiates the effect of YM-155 in lung adenocarcinoma via survivin downregulation induced by miR-138 and miR-195. Thorac Cancer 2019; 10:1355-1368. [PMID: 31090206 PMCID: PMC6558485 DOI: 10.1111/1759-7714.13076] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 03/28/2019] [Accepted: 03/29/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND YM-155 has been proven to be an efficient antitumor suppressor in non-small cell lung cancer (NSCLC) cells. However, the suppressive effect of YM-155 on the expression of survivin is not sufficient and has a short half-life. MS-275, a histone deacetylase inhibitor, has significant antitumor capacity with a relatively long half-life. Our study explored whether MS-275 could enhance the inhibitory effect of YM-155 on LUAD proliferation. METHODS To investigate the synergistic effect of MS-275 and YM-155, we employed methyl thiazolyl tetrazolium and colony formation assays to access the inhibition effect of MS-275, YM-155, or a combination in A549 and HCC827 cell lines. We then detected the effect of MS-275 and YM-155 on the expression of survivin and pro-apoptotic proteins by Western blot and miR-138 or miR-195 expression by quantitative PCR. We also analyzed the methylation level of microRNAs (miRNAs) using methylation-sensitive quantitative PCR. Finally, we investigated the interaction between miRNAs and survivin by luciferase reporter assay. RESULTS MS-275 facilitated an inhibitory effect of YM-155 on lung adenocarcinoma cell proliferation. MS-275 can upregulate the level of acetylated H3, promote the degradation of DNA methyltransferases, and inhibit the methylation of miR-138 and miR-195 genes to elevate the expression of miR-138 and miR-195. Moreover, miR-138 and miR-195 showed a synergistic effect with YM-155 by directly binding to the 3 untranslated region of survivin to attenuate its expression. CONCLUSION For the first time, we report the synergistic effective of MS-275 and YM-155 and suggest a new direction for the future application of YM-155.
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Affiliation(s)
- Bai‐Ling Luo
- Respiratory DepartmentThe First Xiangya Hospital of Central South UniversityChangshaChina
| | - Yan Zhou
- Respiratory DepartmentThe First Xiangya Hospital of Central South UniversityChangshaChina
- Respiratory DepartmentThe Third Xiangya Hospital of Central South UniversityChangshaChina
| | - Hui Lv
- Department of Pathology, School of MedicineUniversity of Colorado Anschutz Medical CampusAurora, ColoradoUSA
| | - Sheng‐Hua Sun
- Respiratory DepartmentThe Third Xiangya Hospital of Central South UniversityChangshaChina
| | - Wen‐Xiang Tang
- Respiratory DepartmentThe Third Xiangya Hospital of Central South UniversityChangshaChina
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Yi J, Li S, Wang C, Cao N, Qu H, Cheng C, Wang Z, Wang L, Zhou L. Potential applications of polyphenols on main ncRNAs regulations as novel therapeutic strategy for cancer. Biomed Pharmacother 2019; 113:108703. [DOI: 10.1016/j.biopha.2019.108703] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Revised: 02/08/2019] [Accepted: 02/19/2019] [Indexed: 12/14/2022] Open
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Tang H, Xu X, Xiao W, Liao Y, Xiao X, Li L, Li K, Jia X, Feng H. Silencing of microRNA-27a facilitates autophagy and apoptosis of melanoma cells through the activation of the SYK-dependent mTOR signaling pathway. J Cell Biochem 2019; 120:13262-13274. [PMID: 30994959 DOI: 10.1002/jcb.28600] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 02/11/2019] [Indexed: 12/19/2022]
Abstract
Melanoma is considered as an aggressive neoplastic transformation and featured with high metastatic potential. Although some studies have provided targets for novel therapeutic interventions, clinical development of targeted drugs for melanoma still remains obscure. Therefore, this study aims to identify the role of microRNA-27a (miR-27a) in autophagy and apoptosis of melanoma cells in regulating spleen tyrosine kinase (SYK)-mediated the mammalian target of rapamycin (mTOR) signaling pathway. A microarray-based analysis was made to screen differentially expressed genes and predict target miRNA. Melanoma specimens were collected with pigmented nevus as a control. Melanoma cell line Mel-RM was treated with miR-27a inhibitor or pcDNA-SYK to prove their effects on autophagy and apoptosis of melanoma cells. The volume change and tumor mass of nude mice in each group were detected by the tumorigenesis assay. Microarray-based analysis results showed that SYK was lowly expressed in melanoma cells and may be regulated by miR-27a. Besides, miR-27a expression was increased whereas SYK expression was decreased in melanoma tissues. Meanwhile, miR-27a was positively correlated with tumor stage and lymph node metastasis of melanoma tissues. Furthermore, miR-27a targeted SYK and silencing of miR-27a or overexpression of SYK cells promoted autophagy and apoptosis of melanoma cells and reduced their tumorigenic ability in vivo. In conclusion, this study proves that silencing of miR-27a facilitates autophagy and apoptosis of melanoma cells by upregulating SYK expression and activating the mTOR signaling pathway. The finding offers new ideas for the clinical development of melanoma.
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Affiliation(s)
- Hua Tang
- Department of Dermatology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, P.R. China
| | - Xiaopeng Xu
- Department of Dermatology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, P.R. China
| | - Weirong Xiao
- Department of Dermatology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, P.R. China
| | - Yangying Liao
- Department of Dermatology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, P.R. China
| | - Xiao Xiao
- Department of Dermatology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, P.R. China
| | - Lan Li
- Department of Dermatology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, P.R. China
| | - Ke Li
- Department of Dermatology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, P.R. China
| | - Xiaomin Jia
- Department of Pathology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, P.R. China
| | - Hao Feng
- Department of Dermatology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, P.R. China
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Mukwaya A, Jensen L, Peebo B, Lagali N. MicroRNAs in the cornea: Role and implications for treatment of corneal neovascularization. Ocul Surf 2019; 17:400-411. [PMID: 30959113 DOI: 10.1016/j.jtos.2019.04.002] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 03/25/2019] [Accepted: 04/01/2019] [Indexed: 12/18/2022]
Abstract
With no safe and efficient approved therapy available for treating corneal neovascularization, the search for alternative and effective treatments is of great importance. Since the discovery of miRNAs as key regulators of gene expression, knowledge of their function in the eye has expanded continuously, facilitated by high throughput genomic tools such as microarrays and RNA sequencing. Recently, reports have emerged implicating miRNAs in pathological and developmental angiogenesis. This has led to the idea of targeting these regulatory molecules as a therapeutic approach for treating corneal neovascularization. With the growing volume of data generated from high throughput tools applied to study corneal neovascularization, we provide here a focused review of the known miRNAs related to corneal neovascularization, while presenting new experimental data and insights for future research and therapy development.
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Affiliation(s)
- Anthony Mukwaya
- Department of Ophthalmology, Institute for Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoping University, Linköping, Sweden
| | - Lasse Jensen
- Department of Medical and Health Sciences, Division of Cardiovascular Medicine, Linköping University, Linköping, Sweden
| | - Beatrice Peebo
- Department of Ophthalmology, Institute for Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoping University, Linköping, Sweden
| | - Neil Lagali
- Department of Ophthalmology, Institute for Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoping University, Linköping, Sweden; Department of Ophthalmology, Sørlandet Hospital Arendal, Arendal, Norway.
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Gao W, Lin S, Cheng C, Zhu A, Hu Y, Shi Z, Zhang X, Hong Z. Long non-coding RNA CASC2 regulates Sprouty2 via functioning as a competing endogenous RNA for miR-183 to modulate the sensitivity of prostate cancer cells to docetaxel. Arch Biochem Biophys 2019; 665:69-78. [DOI: 10.1016/j.abb.2018.01.013] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 01/13/2018] [Accepted: 01/21/2018] [Indexed: 02/01/2023]
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Li J, Yang R, Dong Y, Chen M, Wang Y, Wang G. Knockdown of FOXO3a induces epithelial-mesenchymal transition and promotes metastasis of pancreatic ductal adenocarcinoma by activation of the β-catenin/TCF4 pathway through SPRY2. J Exp Clin Cancer Res 2019; 38:38. [PMID: 30691517 PMCID: PMC6350320 DOI: 10.1186/s13046-019-1046-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 01/16/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Early invasion and metastasis are responsible for the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC), and epithelial-to-mesenchymal transition (EMT) is recognized as a crucial biological progress in driving tumor invasion and metastasis. The transcription factor FOXO3a is inactivated in various types of solid cancers and the loss of FOXO3a is associated with EMT and tumor metastasis. In this study, we sought to explore whether SPRY2, a regulator of receptor tyrosine kinase (RTK) signaling, is involved in FOXO3a-mediated EMT and metastasis in PDAC. METHODS Immunohistochemistry was performed in 130 paired PDAC tissues and paracarcinomatous pancreatic tissues. Cell proliferation and apoptosis were assessed by cell counting kit and flow cytometry, while cell migration and invasion were evaluated with wound healing and transwell assays. The changes in mRNA and protein levels were estimated by qRT-PCR and western blot. BALB/c nude mice xenograft model was established to evaluate tumorigenesis and metastasis in vivo. RESULTS FOXO3a expression was remarkably reduced in PDAC tissues, and correlated with metastasis-associated clinicopathologic characteristics and poor prognosis in patients with PDAC. In addition to the promotion of proliferation and suppression of apoptosis, knockdown of FOXO3a or SPRY2 induced EMT and promoted the migration and invasion of PDAC cells via activation of the β-catenin/TCF4 pathway. Moreover, silencing of SPRY2 reversed the suppressor effects induced by FOXO3a overexpression on EMT-associated migration and invasion of PDAC cells, while blockade of β-catenin reversed the effects of SPRY2 loss. FOXO3a knockdown decreased SPRY2 protein stability, whereas SPRY2 knockdown enhanced β-catenin protein stability. In vivo, FOXO3a knockdown promoted the tumorigenic ability and metastasis of PDAC cells. CONCLUSIONS Our study suggests that knockdown of FOXO3a induces EMT and promotes metastasis of PDAC by activation of the β-catenin/TCF4 pathway through SPRY2. Thus, FOXO3a may represent a candidate therapeutic target in PDAC.
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Affiliation(s)
- Jun Li
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Dadao, Wuhan, 430030, People's Republic of China
- Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Rumeng Yang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Dadao, Wuhan, 430030, People's Republic of China
- Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Yuting Dong
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Dadao, Wuhan, 430030, People's Republic of China
- Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Manyao Chen
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Dadao, Wuhan, 430030, People's Republic of China
- Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Yu Wang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Dadao, Wuhan, 430030, People's Republic of China.
| | - Guoping Wang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Dadao, Wuhan, 430030, People's Republic of China.
- Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
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Yang C, Chan KK, Xu G, Yin M, Lin G, Wang X, Lin WJ, Birowosuto MD, Zeng S, Ogi T, Okuyama K, Permatasari FA, Iskandar F, Chen CK, Yong KT. Biodegradable Polymer-Coated Multifunctional Graphene Quantum Dots for Light-Triggered Synergetic Therapy of Pancreatic Cancer. ACS APPLIED MATERIALS & INTERFACES 2019; 11:2768-2781. [PMID: 30589254 DOI: 10.1021/acsami.8b16168] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
In this work, we reported the synthesis of an engineered novel nanocarrier composed of biodegradable charged polyester vectors (BCPVs) and graphene quantum dots (GQDs) for pancreatic cancer (MiaPaCa-2 cells) therapy applications. Such a nanocarrier was utilized to co-load doxorubicin (DOX) and small interfering ribonucleic acid (siRNA), resulting in the formation of GQD/DOX/BCPV/siRNA nanocomplexes. The resulting nanocomplexes have demonstrated high stability in physiologically mimicking media, excellent K-ras downregulation activity, and effective bioactivity inhibition for MiaPaCa-2 cells. More importantly, laser light was used to generate heat for the nanocomplexes via the photothermal effect to damage the cells, which was further employed to trigger the release of payloads from the nanocomplexes. Such triggered release function greatly enhanced the anticancer activity of the nanocomplexes. Preliminary colony formation study also suggested that GQD/DOX/BCPV/siRNA nanocomplexes are qualified carrier candidates in subsequent in vivo tests.
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Affiliation(s)
| | - Kok Ken Chan
- School of Electrical and Electronic Engineering , Nanyang Technological University , Singapore 639798 , Singapore
| | | | - Mingjie Yin
- School of Electrical and Electronic Engineering , Nanyang Technological University , Singapore 639798 , Singapore
| | | | | | - Wei-Jen Lin
- Department of Fiber and Composite Materials , Feng Chia University , Taichung 40724 , Republic of China
| | - Muhammad Danang Birowosuto
- CINTRA CNRS/NTU/THALES UMI 3288 , Research Techno Plaza, 50 Nanyang Drive , Singapore 637553 , Singapore
| | - Shuwen Zeng
- CINTRA CNRS/NTU/THALES UMI 3288 , Research Techno Plaza, 50 Nanyang Drive , Singapore 637553 , Singapore
| | - Takashi Ogi
- Department of Chemical Engineering, Graduate School of Engineering , Hiroshima University , Higashi Hiroshima 7398527 , Japan
| | - Kikuo Okuyama
- Department of Chemical Engineering, Graduate School of Engineering , Hiroshima University , Higashi Hiroshima 7398527 , Japan
| | - Fitri Aulia Permatasari
- Department of Chemical Engineering, Graduate School of Engineering , Hiroshima University , Higashi Hiroshima 7398527 , Japan
- Department of Physics, Faculty of Mathematics and Natural Sciences , Institut Teknologi Bandung , Bandung 40132 , Indonesia
| | - Ferry Iskandar
- Department of Physics, Faculty of Mathematics and Natural Sciences , Institut Teknologi Bandung , Bandung 40132 , Indonesia
| | - Chih-Kuang Chen
- Department of Chemical and Materials Engineering , National Yunlin University of Science and Technology , Yunlin 64002 , Republic of China
| | - Ken-Tye Yong
- School of Electrical and Electronic Engineering , Nanyang Technological University , Singapore 639798 , Singapore
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46
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Wu J, Li H, Wang X, Zhang X, Liu W, Wang Y, Zhang Y, Pan H, Wang Q, Han Y. Effect of polysaccharide from Undaria pinnatifida on proliferation, migration and apoptosis of breast cancer cell MCF7. Int J Biol Macromol 2019; 121:734-742. [PMID: 30342943 DOI: 10.1016/j.ijbiomac.2018.10.086] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 09/28/2018] [Accepted: 10/14/2018] [Indexed: 02/04/2023]
Abstract
Sulfated polysaccharide from Undaria pinnatifida (SPUP) has significant anti-breast cancer activity. However, its anticarcinogenic mechanism still remains unclear. The aim of this article is to observe the effect of SPUP on proliferation, migration and apoptosis of human breast cancer cell line MCF7. Firstly, the effect of SPUP on proliferation was evaluated through MTT assay, plate clonality assay and immunofluorescence test of PCNA. The results showed that SPUP could significantly reduce MCF7 cells proliferation in a time- and dose-dependent manner. Based on transwell and scratch wound healing assays, then, inhibitory action of SPUP for MCF7 cells migration was observed. Finally, apoptosis and cycle arrest of SPUP for MCF7 cells also were found by the results from both flow cytometry analysis and Hoechst 33342 staining of apoptotic cells. Overall, these results showed anti-breast cancer mechanism of SPUP could be possibly related to inhibit migration, proliferation and induce apoptosis of cancer cells.
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Affiliation(s)
- Jun Wu
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, PR China; School of Chinese Medicine, Shandong College of Traditional Chinese Medicine, Yantai 264199, Shangdong, PR China
| | - Hailun Li
- Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an 223001, Jiangsu, PR China
| | - Xinyue Wang
- Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, PR China
| | - Xiaolei Zhang
- Jiangsu Vocational College of Nursing, Huai'an 223003, Jiangsu, China
| | - Weiping Liu
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, PR China
| | - Yumei Wang
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, PR China
| | - Yongbin Zhang
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, PR China
| | - Huafeng Pan
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, PR China
| | - Qi Wang
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, PR China.
| | - Yun Han
- School of Integrated Chinese and Western Medicine, Binzhou Medical University, Yantai 264003, Shangdong, PR China.
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Li X, Ma D, Zheng S, Fan J, Wang T, Dai Z, Zou X, Teng S, Zhang W. Assembly of a miRNA‐modified QCM sensor for miRNA recognition through response patterns. J Mol Recognit 2018; 32:e2772. [DOI: 10.1002/jmr.2772] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 10/28/2018] [Accepted: 10/29/2018] [Indexed: 12/28/2022]
Affiliation(s)
- Xue Li
- School of Chemistry and EnvironmentSouth China Normal University Guangzhou China
| | - Ding Ma
- School of Chemistry and EnvironmentSouth China Normal University Guangzhou China
| | - Sheng‐Run Zheng
- School of Chemistry and EnvironmentSouth China Normal University Guangzhou China
| | - Jun Fan
- School of Chemistry and EnvironmentSouth China Normal University Guangzhou China
| | - Tai Wang
- Research and Development DepartmentGuangzhou Research & Creativity Biotechnology Co. Ltd Guangzhou China
| | - Zong Dai
- School of ChemistrySun Yat‐sen University Guangzhou China
| | - Xiao‐Yong Zou
- School of ChemistrySun Yat‐sen University Guangzhou China
| | - Shao‐Hua Teng
- School of Computer Science and TechnologyGuangdong University of Technology Guangzhou China
| | - Wei‐Guang Zhang
- School of Chemistry and EnvironmentSouth China Normal University Guangzhou China
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48
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Li ZY, Sun XY. Molecular targets regulating invasion and metastasis of pancreatic cancer. Shijie Huaren Xiaohua Zazhi 2018; 26:1651-1659. [DOI: 10.11569/wcjd.v26.i28.1651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most malignant tumors of the digestive system. Invasion and metastasis are important biological characteristics of pancreatic cancer and contribute greatly to the poor prognosis of the patients. Many lines of evidence have recently revealed that many molecules, genes and proteins regulate the invasion and metastasis of pancreatic cancer cells. Therefore, exploration and a deep understanding of the molecular mechanism accounting for the invasion and metastasis of pancreatic cancer can help find novel pancreatic cancer biomarkers, improve early diagnosis, develop novel and effective treatment strategies, and predict the prognosis. This review summarizes the latest progress in the research of molecular targets for pancreatic cancer and the mechanisms by which they participate in the invasion and metastasis of this aggressive malignancy.
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Affiliation(s)
- Zi-Yi Li
- The Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Xue-Ying Sun
- The Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
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MiR-27a/b Regulates Liver Regeneration by Posttranscriptional Modification of Tmub1. Dig Dis Sci 2018; 63:2362-2372. [PMID: 29777440 DOI: 10.1007/s10620-018-5113-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 05/04/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Transmembrane and ubiquitin-like domain-containing 1 protein (Tmub1) negatively regulates liver regeneration. However, whether this regulation involves posttranscriptional modification of Tmub1 expression is unknown. AIM The aim of the study was to investigate whether microRNA (miR)-27a/b regulates posttranscriptional modification of Tmub1 and cell proliferation during liver regeneration. METHODS Tmub1 mRNA 3'-untranslated region (UTR) sequences were analyzed using online software. A luciferase assay was used to verify the relationship between miR-27a/b and the 3'-UTR of Tmub1. Rat partial hepatectomy models were used to investigate miR-27a/b and Tmub1 levels after partial hepatectomy. MiR-27a/b expression was down- and up-regulated with mimics and inhibitors, respectively, to observe the effects of miR-27a/b on Tmub1 expression. Quantitative RT-PCR and Western blot analyses were used to measure miR-27a/b and Tmub1 expression. Hepatocyte proliferation was measured using the CCK8 method for BRL-3A liver cells and proliferating cell nuclear antigen and histone H3 phosphorylation in the regenerating liver. RESULTS A potential binding site of miR-27a/b was found in the 3'-UTR sequence of Tmub1. Our luciferase assay confirmed that the Tmub1 mRNA 3'-UTR was the target of miR-27a/b. We observed a temporal correlation between miR-27a/b and Tmub1 expression during liver regeneration. MiR-27a/b down-regulated Tmub1 expression both in vivo and in vitro. MiR-27a/b regulated hepatocyte proliferation during liver regeneration. CONCLUSION MiR-27a/b regulates hepatocyte proliferation by controlling posttranscriptional modification of Tmub1 during liver regeneration.
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Song J, Zhang H, Sun Y, Guo R, Zhong D, Xu R, Song M. Omentin-1 protects renal function of mice with type 2 diabetic nephropathy via regulating miR-27a-Nrf2/Keap1 axis. Biomed Pharmacother 2018; 107:440-446. [PMID: 30103116 DOI: 10.1016/j.biopha.2018.08.002] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 08/01/2018] [Accepted: 08/03/2018] [Indexed: 12/21/2022] Open
Abstract
Omentin-1, a novel identified adipokine, always significantly decreases in patients with metabolic syndrome. However, the functional roles of omentin-1 in diabetic nephropathy (DN) remains largely unknown. In the present study, we found that omentin-1 treatment could improve renal function of type 2 diabetic db/db mice. ELISA assay and immunohistochemistry staining showed that omentin-1 reduced the productions of proinflammatory cytokines (IFN-γ, TNF-α, MCP-1 and IL-8), and improved oxidative stress level (CAT, MDA and SOD) in the kidney tissue, indicating omentin-1 could relieved the inflammatory response and suppressed oxidative stress. Mechanistic analysis demonstrated that omentin-1 down-regulated miR-27a expression, and subsequently inhibited oxidative stress and inflammation. Luciferase reporter assay and western blot further revealed that miR-27a directly targeted the 3' untranslated region (UTR) of nuclear factor erythroid 2-like 2 (Nrf2) and reduced its expression in type 2 DN. Taken together, these findings provide a new function of omentin-1 in renal protection and also delineate multiple potential targets for therapeutic intervention for type 2 DN.
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Affiliation(s)
- Juan Song
- Department of Emergency, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Hongxia Zhang
- Department of Endocrinology, Shanxi Province People's Hospital, Taiyuan 030012, China
| | - Yanni Sun
- Department of Emergency, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China.
| | - Ruimin Guo
- Department of Emergency, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Dongxiang Zhong
- Department of Emergency, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Runxi Xu
- Department of Emergency, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Meng Song
- Department of Emergency, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
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