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Zakari S, Niels NK, Olagunju GV, Nnaji PC, Ogunniyi O, Tebamifor M, Israel EN, Atawodi SE, Ogunlana OO. Emerging biomarkers for non-invasive diagnosis and treatment of cancer: a systematic review. Front Oncol 2024; 14:1405267. [PMID: 39132504 PMCID: PMC11313249 DOI: 10.3389/fonc.2024.1405267] [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: 03/22/2024] [Accepted: 07/05/2024] [Indexed: 08/13/2024] Open
Abstract
Cancer remains a global health challenge, necessitating continuous advancements in diagnostic and treatment strategies. This review focuses on the utility of non-invasive biomarkers in cancer diagnosis and treatment, their role in early detection, disease monitoring, and personalized therapeutic interventions. Through a systematic review of the literature, we identified 45 relevant studies that highlight the potential of these biomarkers across various cancer types, such as breast, prostate, lung, and colorectal cancers. The non-invasive biomarkers discussed include liquid biopsies, epigenetic markers, non-coding RNAs, exosomal cargo, and metabolites. Notably, liquid biopsies, particularly those based on circulating tumour DNA (ctDNA), have emerged as the most promising method for early, non-invasive cancer detection due to their ability to provide comprehensive genetic and epigenetic information from easily accessible blood samples. This review demonstrates how non-invasive biomarkers can facilitate early cancer detection, accurate subtyping, and tailored treatment strategies, thereby improving patient outcomes. It underscores the transformative potential of non-invasive biomarkers in oncology, highlighting their application for enhancing early detection, survival rates, and treatment precision in cancer care. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023474749 PROSPERO, identifier CRD42023474749.
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Affiliation(s)
- Suleiman Zakari
- Department of Biochemistry, College of Science and Technology, Covenant University, Ota, Ogun State, Nigeria
- Covenant Applied Informatics and Communication - Africa Centre of Excellence (CApIC-ACE), Covenant University, Ota, Ogun State, Nigeria
- Department of Biochemistry, College of Medicine, Federal University of Health Sciences Otukpo, Otukpo, Benue State, Nigeria
| | - Nguedia K. Niels
- Department of Biochemistry, College of Science and Technology, Covenant University, Ota, Ogun State, Nigeria
- Covenant Applied Informatics and Communication - Africa Centre of Excellence (CApIC-ACE), Covenant University, Ota, Ogun State, Nigeria
- Biotechnology Centre, University of Yaounde I, Yaounde, Cameroon
| | - Grace V. Olagunju
- Department of Molecular Biology, New Mexico State University, Las Cruces, NM, United States
| | - Precious C. Nnaji
- Department of Biochemistry, College of Science and Technology, Covenant University, Ota, Ogun State, Nigeria
| | - Oluwabusayo Ogunniyi
- Department of Biochemistry, College of Science and Technology, Covenant University, Ota, Ogun State, Nigeria
| | - Mercy Tebamifor
- Department of Biochemistry, College of Science and Technology, Covenant University, Ota, Ogun State, Nigeria
- Covenant Applied Informatics and Communication - Africa Centre of Excellence (CApIC-ACE), Covenant University, Ota, Ogun State, Nigeria
| | - Emmanuel N. Israel
- Department of Biochemistry, College of Science and Technology, Covenant University, Ota, Ogun State, Nigeria
- Covenant Applied Informatics and Communication - Africa Centre of Excellence (CApIC-ACE), Covenant University, Ota, Ogun State, Nigeria
| | - Sunday E. Atawodi
- Department of Biochemistry, Federal University Lokoja, Lokoja, Kogi State, Nigeria
| | - Olubanke Olujoke Ogunlana
- Department of Biochemistry, College of Science and Technology, Covenant University, Ota, Ogun State, Nigeria
- Covenant Applied Informatics and Communication - Africa Centre of Excellence (CApIC-ACE), Covenant University, Ota, Ogun State, Nigeria
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Patil N, Abdelrahim OG, Leupold JH, Allgayer H. JAK1 Is a Novel Target of Tumor- and Invasion-Suppressive microRNA 494-5p in Colorectal Cancer. Cancers (Basel) 2023; 16:24. [PMID: 38201452 PMCID: PMC10778350 DOI: 10.3390/cancers16010024] [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: 11/27/2023] [Revised: 12/12/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
MiR-494-5p expression has been suggested to be associated with colorectal cancer (CRC) and its metastases in our previous studies. However, functional investigations on the molecule-mediating actions of this miR in CRC are lacking. In silico analysis in the present study revealed a putative binding sequence within the 3'UTR of JAK1. Overexpression of miR-494-5p in cultured CRC significantly reduced the luciferase activity of a reporter plasmid containing the wild-type JAK1-3'UTR, which was abolished by seed sequence mutation. Furthermore, the overexpression of miR-494-5p in CRC cell lines led to a significant reduction in JAK1 expression, proliferation, in vitro migration, and invasion. These effects were abolished by co-transfection with a specific double-stranded RNA that inhibits endogenous miR-494-5p. Moreover, IL-4-induced migration, invasion, and phosphorylation of JAK1, STAT6, and AKT proteins were reduced after an overexpression of this miR, suggesting that this miR affects one of the most essential pathways in CRC. A Kaplan-Meier plotter analysis revealed that patients with high JAK1 expression show reduced survival. Together, these data suggest that miR-494-5p physically inhibits the expression of JAK1 at the translational level as well as in migration and invasion, supporting the hypothesis of miR-494-5p as an early tumor suppressor and inhibitor of early steps of metastasis in CRC.
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Affiliation(s)
| | | | | | - Heike Allgayer
- Correspondence: ; Tel.: +49-(0)621-383-71630 or +49-(0)621-383-71635; Fax: +49-(0)621-383-71631
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Wang YX, Cui L, Wu WB, Quinn MJ, Menon R, Zhao JR, Zhang HJ. Downregulation of PDCD4 by deSUMOylation associates with the progression of gestational trophoblastic disease. Placenta 2022; 130:17-24. [PMID: 36370491 DOI: 10.1016/j.placenta.2022.10.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 10/17/2022] [Accepted: 10/29/2022] [Indexed: 11/06/2022]
Abstract
INTRODUCTION Gestational trophoblastic disease (GTD) encompasses a range of trophoblastic disorders from hydatidiform mole (HM), to malignant gestational trophoblastic neoplasia (GTN). The exact molecular mechanisms of GTN remain unknown. Dysregulation and dysfunction of programmed cell death 4 (PDCD4)have been observed in many cancers. The roles of PDCD4 in GTD have not been previously reported. METHODS A total of 161 cases of formalin-fixed, paraffin-embedded trophoblast blocks, and 36 cases of fresh trophoblast tissues were collected, including normal first trimester placentas, HM, and invasive HM. Choriocarcinoma cells JAR and JEG-3 were employed. The expressions of PDCD4 and small ubiquitin-like modifier 2/3 (SUMO2/3) were examined by immunohistochemistry, quantitative reverse transcription PCR and Western blotting in trophoblastic tissues and cells. The relationship between SUMOylation and PDCD4 was investigated. The effects of PDCD4 on proliferation, invasion, and migration of choriocarcinoma cells were evaluated by Cell Counting Kit-8 and transwell assays post siRNA transfection. Extracellular Matrix & Adhesion Profiler PCR Array was used to screen the downstream molecules of PDCD4. RESULTS PDCD4 was significantly repressed in HM tissues. Loss of PDCD4 expression was demonstrated in 90% invasive HMs. Choriocarcinoma cells also displayed with suppressed PDCD4 expression. The varied expression of PDCD4 was paralleled by SUMO2/3. Inhibition of SUMOylation reduced the expression of PDCD4. Silencing of PDCD4promoted proliferation/migration/invasion, upregulatedMMP3/MMP8/ITGB2, and downregulated TIMP1/TIMP2 in choriocarcinoma cells. DISCUSSION Our results suggest that reduced SUMOylation is one reason for suppressed PDCD4 in GTD. Loss of PDCD4 likely determines the malignant phenotype of GTN by dysregulating some members of the MMPs/TIMPs/integrins complex.
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Affiliation(s)
- Ya-Xin Wang
- Departments of Pathology, International Peace Maternity and Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China; Department of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Ling Cui
- Departments of Pathology, International Peace Maternity and Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Wei-Bin Wu
- Department of Biobank, International Peace Maternity and Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Martin John Quinn
- Departments of Pathology, International Peace Maternity and Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Ramkumar Menon
- Division of Basic and Translational Research, Department of Obstetrics and Gynaecology, The University of Texas Medical Branch at Galveston, Galveston, TX, USA
| | - Jiu-Ru Zhao
- Department of Biobank, International Peace Maternity and Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
| | - Hui-Juan Zhang
- Departments of Pathology, International Peace Maternity and Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
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Ferris WF. The Role and Interactions of Programmed Cell Death 4 and its Regulation by microRNA in Transformed Cells of the Gastrointestinal Tract. Front Oncol 2022; 12:903374. [PMID: 35847932 PMCID: PMC9277020 DOI: 10.3389/fonc.2022.903374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 05/30/2022] [Indexed: 11/26/2022] Open
Abstract
Data from GLOBOCAN 2020 estimates that there were 19.3 million new cases of cancer and 10.0 million cancer-related deaths in 2020 and that this is predicted to increase by 47% in 2040. The combined burden of cancers of the gastrointestinal (GI) tract, including oesophageal-, gastric- and colorectal cancers, resulted in 22.6% of the cancer-related deaths in 2020 and 18.7% of new diagnosed cases. Understanding the aetiology of GI tract cancers should have a major impact on future therapies and lessen this substantial burden of disease. Many cancers of the GI tract have suppression of the tumour suppressor Programmed Cell Death 4 (PDCD4) and this has been linked to the expression of microRNAs which bind to the untranslated region of PDCD4 mRNA and either inhibit translation or target the mRNA for degradation. This review highlights the properties of PDCD4 and documents the evidence for the regulation of PDCD4 expression by microRNAs in cancers of the GI tract.
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Gurer HG, Gursoy OO, Eren CY, Sezer CV. ANTITUMOR EFFECTS OF TURMERIC ON OVCAR-3 OVARIAN CANCER CELL LİNES. Anticancer Agents Med Chem 2022; 22:2896-2901. [PMID: 35473538 DOI: 10.2174/1871520622666220426103332] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 02/23/2022] [Accepted: 02/23/2022] [Indexed: 11/22/2022]
Abstract
INTRODUCTION Ovarian cancer is the deadliest gynecological malignancy, usually not detected until the late stages. In vitro cell culture is a method used to study the behavior of cells in a controlled environment. Turmeric has attracted the attention of scientists due to its anticancer potential. MATERIAL-METHOD OVCAR-3 cells were cultured in RPMI medium with 100 units/mL-100 μg/mL of penicillin-streptomycin and 10% foetal bovine serum in a CO2 incubator. Turmeric extract was diluted in DMSO. Different concentrations of turmeric extract were prepared. Annexin-V staining was performed to test the translocation of phosphatidylserine to the outer side of the cell membrane as a clear indicator of apoptosis. RESULTS Turmeric extract significantly reduced the viability of OVCAR-3 cells both in 24 and 48 hours of exposure. OVCAR-3 cells treated with IC50 concentration of turmeric extract for 24 hours. 82.60% of cells were viable. The percentages of dead, early apoptotic and late apoptotic cells were detected to be 0.80%, 9.70% and 6.90%, respectively. Untreated OVCAR-3 cells have migration ability. OVCAR-3 cells exposed to an IC50 concentration of turmeric extract for 24 hours did not close the scratch area. CONCLUSION In this research anticancer effects of turmeric have been demonstrated by different analysis methods.</p>.
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Affiliation(s)
- Hulusi Goktug Gurer
- Eskisehir Acibadem Hospital, Obstetrics and Gynecology Clinic, Eskisehir, Turkey
| | - Ozlem Ozgur Gursoy
- Eskisehir Acibadem Hospital, Obstetrics and Gynecology Clinic, Eskisehir, Turkey
| | - Ceren Yildiz Eren
- Eskisehir Acibadem Hospital, Obstetrics and Gynecology Clinic, Eskisehir, Turkey
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Du X, Osoro EK, Chen Q, Yan X, Gao D, Wu L, Ren J, Feng L, Wu N, Lu K, Yang X, Zhong B, Han Y, Zhang F, Li D, Lan X, Lu S. Pdcd4 promotes lipid deposition by attenuating PPARα-mediated fatty acid oxidation in hepatocytes. Mol Cell Endocrinol 2022; 545:111562. [PMID: 35051553 DOI: 10.1016/j.mce.2022.111562] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 01/11/2022] [Accepted: 01/13/2022] [Indexed: 11/21/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in hepatocytes. The involvement of programmed cell death 4 (Pdcd4) in inflammation and metabolic diseases has been widely reported. However, the precise regulatory role of Pdcd4 in hepatocytic lipid metabolism and NAFLD is not well known. RESEARCH DESIGN AND METHODS We established a high-fat diet-induced NAFLD (HFD-NAFLD) rat model and a free fatty acids (FFAs)-treated cell model, and analyzed the expression and distribution of PDCD4. The lentivirus for Pdcd4 knockout and the vector for Pdcd4 overexpression were used to alter Pdcd4 expression in BRL 3A cells. Thereafter, lipid accumulation, FA metabolic gene expression, and peroxisome proliferator-activated receptor alpha (Pparα)-dependent peroxisomal β-oxidation-related gene expression, especially that of the critical transcription factors and enzymes acyl-CoA oxidases 1-3 (Acox1-3), were detected both at the mRNA and protein levels. RESULTS PDCD4 expression increased and it was mainly distributed in hepatocyte nuclei of the HFD-NAFLD rats. as well as the FFAs-treated CBRH-7919 and BRL 3A cell lines. Pdcd4 knockout significantly suppressed FFAs-induced lipid accumulation, and Pdcd4 overexpression accelerated FFAs-induced lipid accumulation in hepatocytes. Mechanistically, Pdcd4 negatively regulated the expression Pparα and Acox1-3. In addition, rescue experiments confirmed that Pparα knockdown could attenuate the expression of Acox1-3 in Pdcd4 knockout cells, which ultimately restored lipid deposition to normal levels. PPARα expression decreased in the liver of the HFD-NAFLD rats. The enrichment of PDCD4 in hepatocyte nuclei correlated with lower PPARα expression after FFAs treatment in vitro. CONCLUSION Our results indicate that the abundance of PDCD4 under high-fat conditions facilitates hepatocellular lipid accumulation by decreasing PPARα-dependent FA peroxisomal β-oxidation.
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Affiliation(s)
- Xiaojuan Du
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Beijing, China
| | - Ezra Kombo Osoro
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Beijing, China
| | - Qian Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Beijing, China
| | - Xiaofei Yan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Beijing, China
| | - Dan Gao
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China
| | - Litao Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Beijing, China
| | - Jiajun Ren
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Beijing, China
| | - Lina Feng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Beijing, China
| | - Nan Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Beijing, China
| | - Kaikai Lu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Beijing, China
| | - Xudong Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Beijing, China
| | - Bo Zhong
- Department of Pediatrics, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China
| | - Yan Han
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Beijing, China
| | - Fujun Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Beijing, China
| | - Dongmin Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Beijing, China
| | - Xi Lan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Beijing, China.
| | - Shemin Lu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Beijing, China.
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Demirkol Canlı S, Seza EG, Sheraj I, Gömçeli I, Turhan N, Carberry S, Prehn JHM, Güre AO, Banerjee S. Evaluation of an aldo-keto reductase gene signature with prognostic significance in colon cancer via activation of epithelial to mesenchymal transition and the p70S6K pathway. Carcinogenesis 2021; 41:1219-1228. [PMID: 32628753 DOI: 10.1093/carcin/bgaa072] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 06/04/2020] [Accepted: 07/02/2020] [Indexed: 12/24/2022] Open
Abstract
AKR1B1 and AKR1B10, members of the aldo-keto reductase family of enzymes that participate in the polyol pathway of aldehyde metabolism, are aberrantly expressed in colon cancer. We previously showed that high expression of AKR1B1 (AKR1B1HIGH) was associated with enhanced motility, inflammation and poor clinical outcome in colon cancer patients. Using publicly available datasets and ex vivo gene expression analysis (n = 51, Ankara cohort), we have validated our previous in silico finding that AKR1B1HIGH was associated with worse overall survival (OS) compared with patients with low expression of AKR1B1 (AKR1B1LOW) samples. A combined signature of AKR1B1HIGH and AKR1B10LOW was significantly associated with worse recurrence-free survival (RFS) in microsatellite stable (MSS) patients and in patients with distal colon tumors as well as a higher mesenchymal signature when compared with AKR1B1LOW/AKR1B10HIGH tumors. When the patients were stratified according to consensus molecular subtypes (CMS), AKR1B1HIGH/AKR1B10LOW samples were primarily classified as CMS4 with predominantly mesenchymal characteristics while AKR1B1LOW/AKR1B10HIGH samples were primarily classified as CMS3 which is associated with metabolic deregulation. Reverse Phase Protein Array carried out using protein samples from the Ankara cohort indicated that AKR1B1HIGH/AKR1B10LOW tumors showed aberrant activation of metabolic pathways. Western blot analysis of AKR1B1HIGH/AKR1B10LOW colon cancer cell lines also suggested aberrant activation of nutrient-sensing pathways. Collectively, our data suggest that the AKR1B1HIGH/AKR1B10LOW signature may be predictive of poor prognosis, aberrant activation of metabolic pathways, and can be considered as a novel biomarker for colon cancer prognostication.
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Affiliation(s)
- Seçil Demirkol Canlı
- Molecular Pathology Application and Research Center, Hacettepe University, Ankara, Turkey
| | - Esin Gülce Seza
- Department of Biological Sciences, Orta Dogu Teknik Universitesi, Ankara, Turkey
| | - Ilir Sheraj
- Department of Biological Sciences, Orta Dogu Teknik Universitesi, Ankara, Turkey
| | - Ismail Gömçeli
- Department of Gastroenterological Surgery, Antalya Education and Research Hospital, Antalya, Turkey
| | - Nesrin Turhan
- Department of Pathology, Ankara City Hospital, University of Health Science, Ankara, Turkey
| | - Steven Carberry
- Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Jochen H M Prehn
- Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Ali Osmay Güre
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
| | - Sreeparna Banerjee
- Department of Biological Sciences, Orta Dogu Teknik Universitesi, Ankara, Turkey.,Cancer Systems Biology Laboratory (CanSyl) Orta Dogu Teknik Universitesi, Ankara, Turkey
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Marongiu L, Burkard M, Venturelli S, Allgayer H. Dietary Modulation of Bacteriophages as an Additional Player in Inflammation and Cancer. Cancers (Basel) 2021; 13:cancers13092036. [PMID: 33922485 PMCID: PMC8122878 DOI: 10.3390/cancers13092036] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 04/15/2021] [Accepted: 04/21/2021] [Indexed: 01/06/2023] Open
Abstract
Natural compounds such as essential oils and tea have been used successfully in naturopathy and folk medicine for hundreds of years. Current research is unveiling the molecular role of their antibacterial, anti-inflammatory, and anticancer properties. Nevertheless, the effect of these compounds on bacteriophages is still poorly understood. The application of bacteriophages against bacteria has gained a particular interest in recent years due to, e.g., the constant rise of antimicrobial resistance to antibiotics, or an increasing awareness of different types of microbiota and their potential contribution to gastrointestinal diseases, including inflammatory and malignant conditions. Thus, a better knowledge of how dietary products can affect bacteriophages and, in turn, the whole gut microbiome can help maintain healthy homeostasis, reducing the risk of developing diseases such as diverse types of gastroenteritis, inflammatory bowel disease, or even cancer. The present review summarizes the effect of dietary compounds on the physiology of bacteriophages. In a majority of works, the substance class of polyphenols showed a particular activity against bacteriophages, and the primary mechanism of action involved structural damage of the capsid, inhibiting bacteriophage activity and infectivity. Some further dietary compounds such as caffeine, salt or oregano have been shown to induce or suppress prophages, whereas others, such as the natural sweeter stevia, promoted species-specific phage responses. A better understanding of how dietary compounds could selectively, and specifically, modulate the activity of individual phages opens the possibility to reorganize the microbial network as an additional strategy to support in the combat, or in prevention, of gastrointestinal diseases, including inflammation and cancer.
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Affiliation(s)
- Luigi Marongiu
- Department of Experimental Surgery—Cancer Metastasis, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Ludolf-Krehl-Str. 13-17, 68167 Mannheim, Germany;
| | - Markus Burkard
- Department of Biochemistry of Nutrition, University of Hohenheim, Garbenstr. 30, 70599 Stuttgart, Germany;
| | - Sascha Venturelli
- Department of Biochemistry of Nutrition, University of Hohenheim, Garbenstr. 30, 70599 Stuttgart, Germany;
- Department of Vegetative and Clinical Physiology, University Hospital of Tuebingen, Otfried-Müllerstr. 27, 72076 Tuebingen, Germany
- Correspondence: (S.V.); (H.A.); Tel.: +49-(0)711-459-24113 (ext. 24195) (S.V.); +49-(0)621-383-71630 (ext. 71635) (H.A.); Fax: +49-(0)-711-459-23822 (S.V.); +49-(0)-621-383-71631 (H.A.)
| | - Heike Allgayer
- Department of Experimental Surgery—Cancer Metastasis, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Ludolf-Krehl-Str. 13-17, 68167 Mannheim, Germany;
- Correspondence: (S.V.); (H.A.); Tel.: +49-(0)711-459-24113 (ext. 24195) (S.V.); +49-(0)621-383-71630 (ext. 71635) (H.A.); Fax: +49-(0)-711-459-23822 (S.V.); +49-(0)-621-383-71631 (H.A.)
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Tang LB, Ma SX, Chen ZH, Huang QY, Wu LY, Wang Y, Zhao RC, Xiong LX. Exosomal microRNAs: Pleiotropic Impacts on Breast Cancer Metastasis and Their Clinical Perspectives. BIOLOGY 2021; 10:biology10040307. [PMID: 33917233 PMCID: PMC8067993 DOI: 10.3390/biology10040307] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/28/2021] [Accepted: 04/03/2021] [Indexed: 01/07/2023]
Abstract
As a major threat factor for female health, breast cancer (BC) has garnered a lot of attention for its malignancy and diverse molecules participating in its carcinogenesis process. Among these complex carcinogenesis processes, cell proliferation, epithelial-to-mesenchymal transition (EMT), mesenchymal-to-epithelial transition (MET), and angiogenesis are the major causes for the occurrence of metastasis and chemoresistance which account for cancer malignancy. MicroRNAs packaged and secreted in exosomes are termed "exosomal microRNAs (miRNAs)". Nowadays, more researches have uncovered the roles of exosomal miRNAs played in BC metastasis. In this review, we recapitulated the dual actions of exosomal miRNAs exerted in the aggressiveness of BC by influencing migration, invasion, and distant metastasis. Next, we presented how exosomal miRNAs modify angiogenesis and stemness maintenance. Clinically, several exosomal miRNAs can govern the transformation between drug sensitivity and chemoresistance. Since the balance of the number and type of exosomal miRNAs is disturbed in pathological conditions, they are able to serve as instructive biomarkers for BC diagnosis and prognosis. More efforts are needed to connect the theoretical studies and clinical traits together. This review provides an outline of the pleiotropic impacts of exosomal miRNAs on BC metastasis and their clinical implications, paving the way for future personalized drugs.
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Affiliation(s)
- Li-Bo Tang
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (L.-B.T.); (Q.-Y.H.); (L.-Y.W.); (Y.W.); (R.-C.Z.)
- Second Clinical Medical College, Nanchang University, Nanchang 330006, China;
| | - Shu-Xin Ma
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang 330006, China;
| | - Zhuo-Hui Chen
- Second Clinical Medical College, Nanchang University, Nanchang 330006, China;
| | - Qi-Yuan Huang
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (L.-B.T.); (Q.-Y.H.); (L.-Y.W.); (Y.W.); (R.-C.Z.)
- Second Clinical Medical College, Nanchang University, Nanchang 330006, China;
| | - Long-Yuan Wu
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (L.-B.T.); (Q.-Y.H.); (L.-Y.W.); (Y.W.); (R.-C.Z.)
- First Clinical Medical College, Nanchang University, Nanchang 330006, China
| | - Yi Wang
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (L.-B.T.); (Q.-Y.H.); (L.-Y.W.); (Y.W.); (R.-C.Z.)
| | - Rui-Chen Zhao
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (L.-B.T.); (Q.-Y.H.); (L.-Y.W.); (Y.W.); (R.-C.Z.)
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang 330006, China;
| | - Li-Xia Xiong
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (L.-B.T.); (Q.-Y.H.); (L.-Y.W.); (Y.W.); (R.-C.Z.)
- Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Nanchang 330006, China
- Correspondence: ; Tel.: +86-791-8636-0556
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10
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Leupold JH, Patil N, Allgayer H. The Chicken Egg Chorioallantoic Membrane (CAM) Model as an In Vivo Method for the Investigation of the Invasion and Metastasis Cascade of Malignant Tumor Cells. Methods Mol Biol 2021; 2294:17-26. [PMID: 33742391 DOI: 10.1007/978-1-0716-1350-4_2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The CAM model enables an in vivo analysis of the individual sub-steps of the metastatic cascade like local invasion, intravasation, or the establishment of metastasis in particular organs. Incubated fertilized chicken eggs are inoculated with human tumor cells and further processed for up to 9-10 days. The invasion and metastasis of these cells is then detected quantitatively with high specificity and sensitivity by means of a PCR for human ALU sequences, using the genomic DNA isolated from distant portions of the CAM, as well as from diverse internal organs of the developing embryo.
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Affiliation(s)
- Jörg H Leupold
- Department of Experimental Surgery - Cancer Metastasis, Medical Faculty Mannheim, Ruprecht Karls University of Heidelberg, Mannheim, Germany.,Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Ruprecht Karls University of Heidelberg, Mannheim, Germany
| | - Nitin Patil
- Department of Experimental Surgery - Cancer Metastasis, Medical Faculty Mannheim, Ruprecht Karls University of Heidelberg, Mannheim, Germany.,Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Ruprecht Karls University of Heidelberg, Mannheim, Germany
| | - Heike Allgayer
- Department of Experimental Surgery - Cancer Metastasis, Medical Faculty Mannheim, Ruprecht Karls University of Heidelberg, Mannheim, Germany. .,Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Ruprecht Karls University of Heidelberg, Mannheim, Germany.
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11
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Lu K, Chen Q, Li M, He L, Riaz F, Zhang T, Li D. Programmed cell death factor 4 (PDCD4), a novel therapy target for metabolic diseases besides cancer. Free Radic Biol Med 2020; 159:150-163. [PMID: 32745771 DOI: 10.1016/j.freeradbiomed.2020.06.016] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 06/05/2020] [Accepted: 06/06/2020] [Indexed: 02/06/2023]
Abstract
Programmed cell death factor 4 (PDCD4) is originally described as a tumor suppressor gene that exerts antineoplastic effects by promoting apoptosis and inhibiting tumor cell proliferation, invasion, and metastasis. Several investigations have probed the aberrant expression of PDCD4 with the progression of metabolic diseases, such as polycystic ovary syndrome (PCOS), obesity, diabetes, and atherosclerosis. It has been ascertained that PDCD4 causes glucose and lipid metabolism disorders, insulin resistance, oxidative stress, chronic inflammatory response, and gut flora disorders to regulate the progression of metabolic diseases. This review aims to summarize the latest researches to uncover the structure, expression regulation, and biological functions of PDCD4 and to elucidate the regulatory mechanism of the development of tumors and metabolic diseases. This review has emphasized the understanding of the PDCD4 role and to provide new ideas for the research, diagnosis, and treatment of tumors and metabolic diseases.
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Affiliation(s)
- Kaikai Lu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, PR China
| | - Qian Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, PR China
| | - Mengda Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, PR China
| | - Lei He
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, PR China
| | - Farooq Riaz
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, PR China
| | - Tianyun Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, PR China
| | - Dongmin Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, PR China.
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12
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Mechanisms of the Epithelial-Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer. Cells 2020; 9:cells9041055. [PMID: 32340207 PMCID: PMC7225971 DOI: 10.3390/cells9041055] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 04/16/2020] [Accepted: 04/17/2020] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori (H. pylori) is one of the most common human pathogens, affecting half of the world’s population. Approximately 20% of the infected patients develop gastric ulcers or neoplastic changes in the gastric stroma. An infection also leads to the progression of epithelial–mesenchymal transition within gastric tissue, increasing the probability of gastric cancer development. This paper aims to review the role of H. pylori and its virulence factors in epithelial–mesenchymal transition associated with malignant transformation within the gastric stroma. The reviewed factors included: CagA (cytotoxin-associated gene A) along with induction of cancer stem-cell properties and interaction with YAP (Yes-associated protein pathway), tumor necrosis factor α-inducing protein, Lpp20 lipoprotein, Afadin protein, penicillin-binding protein 1A, microRNA-29a-3p, programmed cell death protein 4, lysosomal-associated protein transmembrane 4β, cancer-associated fibroblasts, heparin-binding epidermal growth factor (HB-EGF), matrix metalloproteinase-7 (MMP-7), and cancer stem cells (CSCs). The review summarizes the most recent findings, providing insight into potential molecular targets and new treatment strategies for gastric cancer.
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13
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PDCD4 controls the G1/S-phase transition in a telomerase-immortalized epithelial cell line and affects the expression level and translation of multiple mRNAs. Sci Rep 2020; 10:2758. [PMID: 32066800 PMCID: PMC7026441 DOI: 10.1038/s41598-020-59678-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 12/27/2019] [Indexed: 12/11/2022] Open
Abstract
PDCD4, the protein encoded by the tumor suppressor gene PDCD4 (programmed cell death 4) has been implicated in the control of cellular transcription and translation by modulating the activity of specific transcription factors and suppressing the translation of mRNAs with structured 5′-UTRs. Most studies of human PDCD4 have employed tumor cell lines, possibly resulting in a biased picture of its role in normal cells. Here, we have studied the function of PDCD4 in a telomerase-immortalized human epithelial cell line. We show for the first time that PDCD4 is required for the G1/S-transition, demonstrating its crucial role in the cell cycle. Inhibition of p53-dependent activation of p21WAF1/CIP1 overrides the requirement for PDCD4 for the G1/S-transition, suggesting that PDCD4 counteracts basal p53 activity to prevent activation of the G1/S checkpoint by p53. Transcriptome and ribosome profiling data show that silencing of PDCD4 changes the expression levels and translation of many mRNAs, providing an unbiased view of the cellular processes that are affected by PDCD4 in an epithelial cell line. Our data identify PDCD4 as a key regulator of cell cycle- and DNA-related functions that are inhibited when it is silenced, suggesting that decreased expression of PDCD4 might contribute to tumor development by compromising genomic integrity.
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14
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Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy. Cells 2020; 9:cells9010218. [PMID: 31952347 PMCID: PMC7016974 DOI: 10.3390/cells9010218] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Revised: 01/10/2020] [Accepted: 01/11/2020] [Indexed: 02/07/2023] Open
Abstract
PDCD4 (programmed cell death 4) is a tumor suppressor that plays a crucial role in multiple cellular functions, such as the control of protein synthesis and transcriptional control of some genes, the inhibition of cancer invasion and metastasis. The expression of this protein is controlled by synthesis, such as via transcription and translation, and degradation by the ubiquitin-proteasome system. The mitogens, known as tumor promotors, EGF (epidermal growth factor) and TPA (12-O-tetradecanoylphorbol-13-acetate) stimulate the degradation of PDCD4 protein. However, the whole picture of PDCD4 degradation mechanisms is still unclear, we therefore investigated the relationship between PDCD4 and autophagy. The proteasome inhibitor MG132 and the autophagy inhibitor bafilomycin A1 were found to upregulate the PDCD4 levels. PDCD4 protein levels increased synergistically in the presence of both inhibitors. Knockdown of p62/SQSTM1 (sequestosome-1), a polyubiquitin binding partner, also upregulated the PDCD4 levels. P62 and LC3 (microtubule-associated protein 1A/1B-light chain 3)-II were co-immunoprecipitated by an anti-PDCD4 antibody. Colocalization particles of PDCD4, p62 and the autophagosome marker LC3 were observed and the colocalization areas increased in the presence of autophagy and/or proteasome inhibitor(s) in Huh7 cells. In ATG (autophagy related) 5-deficient Huh7 cells in which autophagy was impaired, the PDCD4 levels were increased at the basal levels and upregulated in the presence of autophagy inhibitors. Based on the above findings, we concluded that after phosphorylation in the degron and ubiquitination, PDCD4 is degraded by both the proteasome and autophagy systems.
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15
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Li Y, Wang X, Wang X, Wan L, Liu Y, Shi Y, Zhang L, Fang Z, Wei Z. PDCD4 suppresses proliferation, migration, and invasion of endometrial cells by inhibiting autophagy and NF-κB/MMP2/MMP9 signal pathway. Biol Reprod 2019; 99:360-372. [PMID: 29912279 DOI: 10.1093/biolre/ioy052] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Accepted: 06/14/2018] [Indexed: 11/12/2022] Open
Abstract
Endometriosis (EM) is a kind of estrogen-dependent disease in reproductive-age women. Ovarian EM is the most common type. Although EM is a benign disease, it shares many similar features with cancers. Programmed cell death 4 (PDCD4), a newly identified tumor suppressor, plays an important role in inhibiting tumorigenesis and tumor progression at the transcriptional and translational levels. To explore the roles of PDCD4 in EM, we detected the expression of PDCD4 in control endometrium and eutopic/ectopic endometrium of ovarian EM patients, and analyzed the effects of PDCD4 on the biological behaviors of endometrial cell lines and primary endometrial cells. The results demonstrated that PDCD4 was downregulated in eutopic and ectopic endometrium of EM patients compared with control endometrium. PDCD4 effectively inhibited the proliferation and colony-forming ability of endometrial cells maybe by inhibiting cell autophagy. In addition, PDCD4 also suppressed the migration and invasion ability of endometrial cells, the mechanism may be related to NF-κB/MMP2/MMP9 signal pathway. Taken together, these results suggest that PDCD4 could be involved in the pathogenesis of EM, and provide a novel approach to target the aberrant PDCD4 expression in EM.
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Affiliation(s)
- Yue Li
- Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, P. R. China
| | - Xiaoyan Wang
- Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, P. R. China
| | - Xishuang Wang
- Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, P. R. China
| | - Lu Wan
- Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, P. R. China
| | - Yanping Liu
- Department of Gynecology and Obstetrics, Jinan Central Hospital affiliated to Shandong University, Jinan, Shandong, P. R. China
| | - Yongyu Shi
- Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, P. R. China
| | - Lining Zhang
- Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, P. R. China
| | - Zhenghui Fang
- Department of Gynecology and Obstetrics, Jinan Central Hospital affiliated to Shandong University, Jinan, Shandong, P. R. China
| | - Zengtao Wei
- Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, P. R. China.,Department of Gynecology and Obstetrics, Jinan Central Hospital affiliated to Shandong University, Jinan, Shandong, P. R. China.,Department of Gynecology and Obstetrics, Clinical Medical School, Shandong University, Jinan, Shandong, P. R. China
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16
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Allgayer H, Leupold JH, Patil N. Defining the "Metastasome": Perspectives from the genome and molecular landscape in colorectal cancer for metastasis evolution and clinical consequences. Semin Cancer Biol 2019; 60:1-13. [PMID: 31362074 DOI: 10.1016/j.semcancer.2019.07.018] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 07/22/2019] [Accepted: 07/23/2019] [Indexed: 02/07/2023]
Abstract
Metastasis still poses the highest challenge for personalized therapy in cancer, partly due to a still incomplete understanding of its molecular evolution. We recently presented the most comprehensive whole-genome study of colorectal metastasis vs. matched primary tumors and suggested novel components of disease progression and metastasis evolution, some of them potentially relevant for targeted therapy. In this review, we try to put these findings into perspective with latest discoveries of colleagues and recent literature, and propose a systematic international team effort to collectively define the "metastasome", a term we introduce to summarize all genomic, epigenomic, transcriptomic, further -omic, molecular and functional characteristics rendering metastases different from primary tumors. Based on recent discoveries, we propose a revised metastasis model for colorectal cancer which is based on a common ancestor clone, early dissemination but flexible early or late stage clonal separation paralleling stromal interactions. Furthermore, we discuss hypotheses on site-specific metastasis, colorectal cancer progression, metastasis-targeted diagnosis and therapy, and metastasis prevention based on latest metastasome data.
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Affiliation(s)
- Heike Allgayer
- Department of Experimental Surgery - Cancer Metastasis, Medical Faculty Mannheim, Theodor Kutzer Ufer 1-3, 68135, Mannheim, Ruprecht Karls University of Heidelberg, Germany; Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Ludolf-Krehl-Str. 6, 68135, Mannheim, Ruprecht Karls University of Heidelberg, Germany.
| | - Jörg H Leupold
- Department of Experimental Surgery - Cancer Metastasis, Medical Faculty Mannheim, Theodor Kutzer Ufer 1-3, 68135, Mannheim, Ruprecht Karls University of Heidelberg, Germany; Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Ludolf-Krehl-Str. 6, 68135, Mannheim, Ruprecht Karls University of Heidelberg, Germany
| | - Nitin Patil
- Department of Experimental Surgery - Cancer Metastasis, Medical Faculty Mannheim, Theodor Kutzer Ufer 1-3, 68135, Mannheim, Ruprecht Karls University of Heidelberg, Germany; Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Ludolf-Krehl-Str. 6, 68135, Mannheim, Ruprecht Karls University of Heidelberg, Germany
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17
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Mei M, Zhang M. Non-coding RNAs in Natural Killer/T-Cell Lymphoma. Front Oncol 2019; 9:515. [PMID: 31263681 PMCID: PMC6584837 DOI: 10.3389/fonc.2019.00515] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Accepted: 05/29/2019] [Indexed: 12/19/2022] Open
Abstract
Natural killer/T-cell lymphoma (NKTCL) is a rare and aggressive subtype of non-Hodgkin's lymphoma that is associated with a poor outcome. Non-coding RNAs (ncRNAs), which account for 98% of human RNAs, lack the function of encoding proteins but instead have the important function of regulating gene expression, including transcription, translation, RNA splicing, editing, and turnover. However, the roles and mechanisms of aberrantly expressed ncRNAs in NKTCL are not fully clear. Aberrant expressions of microRNA (miRNAs) affect the PI3K/AKT signaling pathways (miRNA-21, miRNA-155, miRNA-150, miRNA-142, miRNA-494), NF-κB (miRNA-146a, miRNA-155) and cell cycle signaling pathways to regulate cell function. Moreover, Epstein-Barr virus (EBV) encoded miRNAs and EBV oncoprotein LMP-1 regulated the expression of cellular genes that induce invasion, metastasis, cell cycle progression and cellular transformation. In addition, NKTCL-associated Long non-coding RNA (lncRNA) ZFAS1 regulated certain pathways and lncRNA MALAT1 acted as a predictive marker. This review article provides an overview of ncRNAs associated with NKTCL, summarizes the function of significantly differentially expressed hotspot non-coding RNAs that contribute to the pathogenesis, diagnoses, treatment and prognosis of NKTCL and discusses the relevance of these ncRNAs to clinical practice.
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Affiliation(s)
- Mei Mei
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,The Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Mingzhi Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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18
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Matsuhashi S, Manirujjaman M, Hamajima H, Ozaki I. Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions. Int J Mol Sci 2019; 20:ijms20092304. [PMID: 31075975 PMCID: PMC6539695 DOI: 10.3390/ijms20092304] [Citation(s) in RCA: 105] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 05/05/2019] [Accepted: 05/07/2019] [Indexed: 02/06/2023] Open
Abstract
PDCD4 is a novel tumor suppressor to show multi-functions inhibiting cell growth, tumor invasion, metastasis, and inducing apoptosis. PDCD4 protein binds to the translation initiation factor eIF4A, some transcription factors, and many other factors and modulates the function of the binding partners. PDCD4 downregulation stimulates and PDCD4 upregulation inhibits the TPA-induced transformation of cells. However, PDCD4 gene mutations have not been found in tumor cells but gene expression was post transcriptionally downregulated by micro environmental factors such as growth factors and interleukins. In this review, we focus on the suppression mechanisms of PDCD4 protein that is induced by the tumor promotors EGF and TPA, and in the inflammatory conditions. PDCD4-protein is phosphorylated at 2 serines in the SCFβTRCP ubiquitin ligase binding sequences via EGF and/or TPA induced signaling pathway, ubiquitinated, by the ubiquitin ligase and degraded in the proteasome system. The PDCD4 protein synthesis is inhibited by microRNAs including miR21.
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Affiliation(s)
- Sachiko Matsuhashi
- Department of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan.
| | - M Manirujjaman
- Department of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan.
| | - Hiroshi Hamajima
- Saga Food & Cosmetics Laboratory, Division of Food Manufacturing Industry Promotion, SAGA Regional Industry Support Center, 114 Yaemizo, Nabesima-Machi, Saga 849-0932, Japan.
| | - Iwata Ozaki
- Health Administration Center, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan.
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19
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Lin J, Ma L, Zhang D, Gao J, Jin Y, Han Z, Lin D. Tumour biomarkers-Tracing the molecular function and clinical implication. Cell Prolif 2019; 52:e12589. [PMID: 30873683 PMCID: PMC6536410 DOI: 10.1111/cpr.12589] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Revised: 12/19/2018] [Accepted: 01/10/2019] [Indexed: 12/19/2022] Open
Abstract
In recent years, with the increase in cancer mortality caused by metastasis, and with the development of individualized and precise medical treatment, early diagnosis with precision becomes the key to decrease the death rate. Since detecting tumour biomarkers in body fluids is the most non‐invasive way to identify the status of tumour development, it has been widely investigated for the usage in clinic. These biomarkers include different expression or mutation in microRNAs (miRNAs), circulating tumour DNAs (ctDNAs), proteins, exosomes and circulating tumour cells (CTCs). In the present article, we summarized and discussed some updated research on these biomarkers. We overviewed their biological functions and evaluated their multiple roles in human and small animal clinical treatment, including diagnosis of cancers, classification of cancers, prognostic and predictive values for therapy response, monitors for therapy efficacy, and anti‐cancer therapeutics. Biomarkers including different expression or mutation in miRNAs, ctDNAs, proteins, exosomes and CTCs provide more choice for early diagnosis of tumour detection at early stage before metastasis. Combination detection of these tumour biomarkers may provide higher accuracy at the lowest molecule combination number for tumour early detection. Moreover, tumour biomarkers can provide valuable suggestions for clinical anti‐cancer treatment and execute monitoring of treatment efficiency.
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Affiliation(s)
- Jiahao Lin
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Lie Ma
- Department of Respiratory Disease, The Navy General Hospital of PLA, Beijing, China
| | - Di Zhang
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Jiafeng Gao
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Yipeng Jin
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Zhihai Han
- Department of Respiratory Disease, The Navy General Hospital of PLA, Beijing, China
| | - Degui Lin
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China
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20
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Kamińska K, Nalejska E, Kubiak M, Wojtysiak J, Żołna Ł, Kowalewski J, Lewandowska MA. Prognostic and Predictive Epigenetic Biomarkers in Oncology. Mol Diagn Ther 2019; 23:83-95. [PMID: 30523565 PMCID: PMC6394434 DOI: 10.1007/s40291-018-0371-7] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Epigenetic patterns, such as DNA methylation, histone modifications, and non-coding RNAs, can be both driver factors and characteristic features of certain malignancies. Aberrant DNA methylation can lead to silencing of crucial tumor suppressor genes or upregulation of oncogene expression. Histone modifications and chromatin spatial organization, which affect transcription, regulation of gene expression, DNA repair, and replication, have been associated with multiple tumors. Certain microRNAs (miRNAs), mainly those that silence tumor suppressor genes and occur in a greater number of copies, have also been shown to promote oncogenesis. Multiple patterns of these epigenetic factors occur specifically in certain malignancies, which allows their potential use as biomarkers. This review presents examples of tests for each group of epigenetic factors that are currently available or in development for use in early cancer detection, prediction, prognosis, and response to treatment. The availability of blood-based biomarkers is noted, as they allow sampling invasiveness to be reduced and the sampling procedure to be simplified. The article stresses the role of epigenetics as a crucial element of future cancer diagnostics and therapy.
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Affiliation(s)
- Katarzyna Kamińska
- Molecular Oncology and Genetics Department, Innovative Medical Forum, The F. Lukaszczyk Oncology Center, Bydgoszcz, Poland
- Department of Thoracic Surgery and Tumors, L. Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Ewelina Nalejska
- Molecular Oncology and Genetics Department, Innovative Medical Forum, The F. Lukaszczyk Oncology Center, Bydgoszcz, Poland
- Department of Thoracic Surgery and Tumors, L. Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Marta Kubiak
- Molecular Oncology and Genetics Department, Innovative Medical Forum, The F. Lukaszczyk Oncology Center, Bydgoszcz, Poland
- Department of Thoracic Surgery and Tumors, L. Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Joanna Wojtysiak
- Molecular Oncology and Genetics Department, Innovative Medical Forum, The F. Lukaszczyk Oncology Center, Bydgoszcz, Poland
- Department of Thoracic Surgery and Tumors, L. Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Łukasz Żołna
- Department of Thoracic Surgery and Tumors, L. Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Janusz Kowalewski
- Department of Thoracic Surgery and Tumors, L. Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Marzena Anna Lewandowska
- Molecular Oncology and Genetics Department, Innovative Medical Forum, The F. Lukaszczyk Oncology Center, Bydgoszcz, Poland.
- Department of Thoracic Surgery and Tumors, L. Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
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Guo J, Ozaki I, Xia J, Kuwashiro T, Kojima M, Takahashi H, Ashida K, Anzai K, Matsuhashi S. PDCD4 Knockdown Induces Senescence in Hepatoma Cells by Up-Regulating the p21 Expression. Front Oncol 2019; 8:661. [PMID: 30687637 PMCID: PMC6334536 DOI: 10.3389/fonc.2018.00661] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Accepted: 12/13/2018] [Indexed: 12/26/2022] Open
Abstract
While the over-expression of tumor suppressor programmed cell death 4 (PDCD4) induces apoptosis, it was recently shown that PDCD4 knockdown also induced apoptosis. In this study, we examined the cell cycle regulators whose activation is affected by PDCD4 knockdown to investigate the contribution of PDCD4 to cell cycle regulation in three types of hepatoma cells: HepG2, Huh7 (mutant p53 and p16-deficient), and Hep3B (p53- and Rb-deficient). PDCD4 knockdown suppressed cell growth in all three cell lines by inhibiting Rb phosphorylation via down-regulating the expression of Rb itself and CDKs, which phosphorylate Rb, and up-regulating the expression of the CDK inhibitor p21 through a p53-independent pathway. We also found that apoptosis was induced in a p53-dependent manner in PDCD4 knockdown HepG2 cells (p53+), although the mechanism of cell death in PDCD4 knockdown Hep3B cells (p53-) was different. Furthermore, PDCD4 knockdown induced cellular senescence characterized by β-galactosidase staining, and p21 knockdown rescued the senescence and cell death as well as the inhibition of Rb phosphorylation induced by PDCD4 knockdown. Thus, PDCD4 is an important cell cycle regulator of hepatoma cells and may be a promising therapeutic target for the treatment of hepatocellular carcinoma.
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Affiliation(s)
- Jing Guo
- Division of Hepatology, Diabetology and Endocrinology, Department of Internal Medicine, Saga Medical School, Saga University, Saga, Japan
| | - Iwata Ozaki
- Division of Hepatology, Diabetology and Endocrinology, Department of Internal Medicine, Saga Medical School, Saga University, Saga, Japan.,Health Administration Centre, Saga Medical School, Saga University, Saga, Japan
| | - Jinghe Xia
- Division of Hepatology, Diabetology and Endocrinology, Department of Internal Medicine, Saga Medical School, Saga University, Saga, Japan
| | - Takuya Kuwashiro
- Division of Hepatology, Diabetology and Endocrinology, Department of Internal Medicine, Saga Medical School, Saga University, Saga, Japan
| | - Motoyasu Kojima
- Division of Hepatology, Diabetology and Endocrinology, Department of Internal Medicine, Saga Medical School, Saga University, Saga, Japan
| | - Hirokazu Takahashi
- Division of Hepatology, Diabetology and Endocrinology, Department of Internal Medicine, Saga Medical School, Saga University, Saga, Japan
| | - Kenji Ashida
- Division of Hepatology, Diabetology and Endocrinology, Department of Internal Medicine, Saga Medical School, Saga University, Saga, Japan
| | - Keizo Anzai
- Division of Hepatology, Diabetology and Endocrinology, Department of Internal Medicine, Saga Medical School, Saga University, Saga, Japan
| | - Sachiko Matsuhashi
- Division of Hepatology, Diabetology and Endocrinology, Department of Internal Medicine, Saga Medical School, Saga University, Saga, Japan
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22
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Maust JD, Frankowski-McGregor CL, Bankhead A, Simeone DM, Sebolt-Leopold JS. Cyclooxygenase-2 Influences Response to Cotargeting of MEK and CDK4/6 in a Subpopulation of Pancreatic Cancers. Mol Cancer Ther 2018; 17:2495-2506. [PMID: 30254182 PMCID: PMC6279520 DOI: 10.1158/1535-7163.mct-18-0082] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 07/18/2018] [Accepted: 09/21/2018] [Indexed: 12/11/2022]
Abstract
The ineffectiveness of chemotherapy in patients with pancreatic cancer highlights a critical unmet need in pancreatic cancer therapy. Two commonly mutated genes in pancreatic cancer, KRAS and CDKN2A, have an incidence exceeding 90%, supporting investigation of dual targeting of MEK and CDK4/6 as a potential therapeutic strategy for this patient population. An in vitro proliferation synergy screen was conducted to evaluate response of a panel of high passage and patient-derived pancreatic cancer models to the combination of trametinib and palbociclib to inhibit MEK and CDK4/6, respectively. Two adenosquamous carcinoma models, L3.6pl and UM59, stood out for their high synergy response. In vivo studies confirmed that this combination treatment approach was highly effective in subcutaneously implanted L3.6pl and UM59 tumor-bearing animals. Both models were refractory to single-agent treatment. Reverse-phase protein array analysis of L3.6pl tumors excised from treated animals revealed strong downregulation of COX-2 expression in response to combination treatment. Expression of COX-2 under a CMV-driven promoter and shRNA knockdown of COX-2 both led to resistance to combination treatment. Our findings suggest that COX-2 may be involved in the improved therapeutic outcome seen in some pancreatic tumors that fail to respond to MEK or CDK4/6 inhibitors alone but respond favorably to their combination.
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Affiliation(s)
- Joel D Maust
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan
| | | | - Armand Bankhead
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan
| | - Diane M Simeone
- Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan
| | - Judith S Sebolt-Leopold
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan.
- Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan
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23
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Long J, Yin Y, Guo H, Li S, Sun Y, Zeng C, Zhu W. The mechanisms and clinical significance of PDCD4 in colorectal cancer. Gene 2018; 680:59-64. [PMID: 30243936 DOI: 10.1016/j.gene.2018.09.034] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Revised: 09/17/2018] [Accepted: 09/19/2018] [Indexed: 12/14/2022]
Abstract
In recent years, the incidence and mortality of colorectal cancer (CRC) have been on a global upward trend. There is an urgent need for effective tools to prevent and treat CRC and reduce morbidity and mortality of CRC patients. Recent evidence suggests that programmed cell death 4 (PDCD4), a novel tumor suppressor gene, inhibits tumor progression at transcriptional and translational levels and regulates multiple signal transduction pathways. However, little is known about the precise mechanisms regulating PDCD4 expression in CRC. In addition, several studies have demonstrated that the expression of in CRC is down-regulated or even absent. PDCD4 is therefore considered to be an independent prognostic factor in CRC and may be a potential support diagnostic tool for distinguishing in normal colon tissue, benign adenoma and CRC. This review will focus on the expression of PDCD4 in CRC and the relevant molecular mechanisms.
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Affiliation(s)
- Jiali Long
- Department of Pathology, School of Basic Medicine, Guangdong Medical University, Dongguan 523808, Guangdong Province, China
| | - Yuting Yin
- Department of Pathology, School of Basic Medicine, Guangdong Medical University, Dongguan 523808, Guangdong Province, China
| | - Haina Guo
- Department of Pathology, Dongguan Maternal and Child Health Hospital, Dongguan 523013, Guangdong Province, China
| | - Shuling Li
- Department of Pathology, Dongguan Hospital of Southern Medical University, Dongguan 523059, Guangdong Province, China
| | - Yanqin Sun
- Department of Pathology, School of Basic Medicine, Guangdong Medical University, Dongguan 523808, Guangdong Province, China
| | - Chao Zeng
- Department of Pathology, School of Basic Medicine, Guangdong Medical University, Dongguan 523808, Guangdong Province, China.
| | - Wei Zhu
- Department of Pathology, School of Basic Medicine, Guangdong Medical University, Dongguan 523808, Guangdong Province, China.
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24
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Liu Y, Sun H, Mao H, Gao M, Tan X, Li Y, Li Y, Muloye GM, Zhang L, Wang X, Wei Z. Expression of tumor suppressor programmed cell death 4 in endometrioid endometrial carcinomas and clinicopathological significance. Oncol Lett 2018; 15:9369-9376. [PMID: 29805661 DOI: 10.3892/ol.2018.8517] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 03/30/2017] [Indexed: 02/06/2023] Open
Abstract
Programmed cell death 4 (PDCD4), as a novel tumor suppressor, serves important roles in the pathogenesis of tumors. The expression of PDCD4 is downregulated or lost in various human tumors. However, the expression of PDCD4 in endometrial cancer and the clinicopathological significance remain unclear. The aim of the present study was to investigate the expression of PDCD4 in endometrioid endometrial carcinoma (EEC) and the association with clinicopathological parameters. The expression of PDCD4 in EEC tissues and control endometrium was detected by reverse transcription-quantitative polymerase chain reaction, western blotting and immunohistochemistry. PDCD4 expression was also investigated in control endometrial glandular epithelial cells and the endometrial cancer KLE cell line by immunocytochemistry, and the association between PDCD4 expression and clinicopathological parameters of patients with EEC was analyzed. The results demonstrated that PDCD4-positive staining was mainly located in the cytoplasm of endometrial glandular epithelial cells and EEC cells. The staining index of PDCD4 in the proliferative phase was significantly increased compared with that in the secretory phase of control endometrium (P<0.001). There was significantly decreased PDCD4 expression in grade (G) 2/3 EEC tissues compared with the proliferative phase of control endometrium (P<0.001). PDCD4 expression was significantly associated with tumor grade. The PDCD4 levels in G1 EEC tissues were higher compared with the G2/3 EEC group (P<0.01). The results indicated that PDCD4 is associated with the histological grade of EEC, and that PDCD4 may be a valuable indicator of the degree of tumor malignancy in patients with EEC.
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Affiliation(s)
- Yanping Liu
- Department of Gynecology and Obstetrics, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China
| | - Han Sun
- Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.,Department of Clinical Laboratory Services, Linyi People's Hospital, Linyi, Shandong 276000, P.R. China
| | - Hongju Mao
- Department of Infection, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
| | - Meng Gao
- Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China
| | - Xiao Tan
- Department of Pathology, The People's Hospital of Linyi City, Linyi, Shandong 276000, P.R. China
| | - Yue Li
- Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China
| | - Yan Li
- Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China
| | - Guy Mutangala Muloye
- Department of Gynecology and Obstetrics, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China
| | - Lining Zhang
- Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China
| | - Xiaoyan Wang
- Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China
| | - Zengtao Wei
- Department of Gynecology and Obstetrics, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.,Department of Gynecology and Obstetrics, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
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25
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Wang Q, Yang HS. The role of Pdcd4 in tumour suppression and protein translation. Biol Cell 2018; 110:10.1111/boc.201800014. [PMID: 29806708 PMCID: PMC6261700 DOI: 10.1111/boc.201800014] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 05/03/2018] [Accepted: 05/13/2018] [Indexed: 01/07/2023]
Abstract
Programmed cell death 4 (Pdcd4), a tumour suppressor, is frequently down-regulated in various types of cancer. Pdcd4 has been demonstrated to efficiently suppress tumour promotion, progression and proliferation. The biochemical function of Pdcd4 is a protein translation inhibitor. Although the fact that Pdcd4 inhibits protein translation has been known for more than a decade, the mechanism by which Pdcd4 controls tumorigenesis through translational regulation of its target genes is still not fully understood. Recent studies show that Pdcd4 inhibits translation of stress-activated-protein kinase interacting protein 1 to suppress tumour invasion, depicting a picture of how Pdcd4 inhibits tumorigenesis through translational inhibition. Thus, understanding the mechanism of how Pdcd4 attenuates tumorigenesis by translational control should provide a new strategy for combating cancer.
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Affiliation(s)
- Qing Wang
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky
| | - Hsin-Sheng Yang
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky
- Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, Kentucky
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26
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Hao Y, Huang J, Ma Y, Chen W, Fan Q, Sun X, Shao M, Cai H. Asiatic acid inhibits proliferation, migration and induces apoptosis by regulating Pdcd4 via the PI3K/Akt/mTOR/p70S6K signaling pathway in human colon carcinoma cells. Oncol Lett 2018; 15:8223-8230. [PMID: 29805556 PMCID: PMC5950025 DOI: 10.3892/ol.2018.8417] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 05/25/2017] [Indexed: 12/15/2022] Open
Abstract
Previous studies have demonstrated that asiatic acid (AA), the major component of Centella asiatica, is able to meditate cytotoxic and anticancer effects on various types of carcinoma cells. In order to investigate the molecular mechanism that underlies the antitumor effect of AA, the present study investigated the effects of AA on proliferation, migration and apoptosis of SW480 and HCT116 colon cancer cells. Viability and changes in cell morphology in the cells were assessed by MTT assay and transmission electron microscopy, respectively. Colony formation analysis was used to observe proliferation of the single cell, and migratory ability of the cells was assessed by performing Transwell migration assay. Hoechst 33342 nuclear staining and flow cytometry were used to assess apoptosis in colon carcinoma cells. The expression of proteins associated with the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/p70S6K signaling pathway and epithelial-mesenchymal transition (EMT) marker were analyzed by western blotting. The present study revealed that proliferation and migration of colon carcinoma cells were inhibited by AA in a dose-dependent and time-dependent manner. Numerous apoptotic bodies were observed, and G2/M and S phase progression were delayed in colon cancer cells treated with AA, but not in the control group. A number of phosphorylated proteins, including PI3K, Akt (Ser473), mTOR, ribosomal protein S6 kinase (p70S6K) downregulated, while the expression of Pdcd4 was upregulated following treatment with AA. Additionally, AA affects expression of EMT markers in a dose-dependent manner. On the basis of these results, it was concluded that AA inhibited proliferation, migration and induced apoptosis of colon cancer cells by regulating Pdcd4 via the PI3K/Akt/mTOR/p70S6K signaling pathway. These observations suggest that AA may be a potential therapeutic agent for the treatment of colon carcinoma.
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Affiliation(s)
- Yajuan Hao
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Jiawei Huang
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Yun Ma
- Department of Pharmacy, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Wancheng Chen
- Cancer Research Institute, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Qin Fan
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Xuegang Sun
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Meng Shao
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Hongbing Cai
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
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27
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Strubberg AM, Madison BB. MicroRNAs in the etiology of colorectal cancer: pathways and clinical implications. Dis Model Mech 2017; 10:197-214. [PMID: 28250048 PMCID: PMC5374322 DOI: 10.1242/dmm.027441] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) are small single-stranded RNAs that repress mRNA translation
and trigger mRNA degradation. Of the ∼1900 miRNA-encoding genes present
in the human genome, ∼250 miRNAs are reported to have changes in
abundance or altered functions in colorectal cancer. Thousands of studies have
documented aberrant miRNA levels in colorectal cancer, with some miRNAs reported
to actively regulate tumorigenesis. A recurrent phenomenon with miRNAs is their
frequent participation in feedback loops, which probably serve to reinforce or
magnify biological outcomes to manifest a particular cellular phenotype. Here,
we review the roles of oncogenic miRNAs (oncomiRs), tumor suppressive miRNAs
(anti-oncomiRs) and miRNA regulators in colorectal cancer. Given their stability
in patient-derived samples and ease of detection with standard and novel
techniques, we also discuss the potential use of miRNAs as biomarkers in the
diagnosis of colorectal cancer and as prognostic indicators of this disease.
MiRNAs also represent attractive candidates for targeted therapies because their
function can be manipulated through the use of synthetic antagonists and miRNA
mimics. Summary: This Review provides an overview of some important
microRNAs and their roles in colorectal cancer.
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Affiliation(s)
- Ashlee M Strubberg
- Division of Gastroenterology, Washington University School of Medicine, Washington University, Saint Louis, MO 63110, USA
| | - Blair B Madison
- Division of Gastroenterology, Washington University School of Medicine, Washington University, Saint Louis, MO 63110, USA
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28
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Abdulhussain MM, Hasan NA, Hussain AG. Interrelation of the Circulating and Tissue MicroRNA-21 with Tissue PDCD4 Expression and the Invasiveness of Iraqi Female Breast Tumors. Indian J Clin Biochem 2017; 34:26-38. [PMID: 30728670 DOI: 10.1007/s12291-017-0710-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 11/06/2017] [Indexed: 12/18/2022]
Abstract
The changes in the translational repression and variation in mRNA degradation induced by micro RNA are important aspects of tumorigenesis. The association of microRNA-21 with clinicopathologic features and expression of programed cell death 4 (PDCD4) in Iraqi female's with breast tumors has not been studied. MicroRNAs were extracted from a set of 60 breast tumor tissues and blood samples of females with breast cancer and benign breast lesions obtained after breast-reductive surgery, and only blood samples from 30 normal volunteers. These extracts were evaluated for miR-21 expression by quantitative RT-PCR. Analysis of PDCD4 protein expression was carried out as miR-21 target gene by immunohistochemical tests and correlating the results with patients' clinicopathological features. Significant overexpression of miRNA-21 was found in breast cancer group. The fold increase in the miR-21 gene expression was significantly higher in circulating exosomes and breast tissues of breast cancer patients as compared to other groups (P < 0.001). Overexpression of miR-21 was also significantly associated with the advanced tumor stage and histological grade. In breast cancer patients, PDCD4 protein expression was decreased to about 70% of the level in the control group. The delta Ct of exosomal and breast tissue miRNA-21 was negatively associated with PDCD4 expression. In conclusion, the translational repression of the PDCD4 induced by the high expression of miR-21 promotes breast cell transformation and development of breast tumor, and circulating miR-21 level could be applied to the screening panels for early detection of women breast cancer.
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Affiliation(s)
- Meena M Abdulhussain
- 1Department of Chemistry and Biochemistry, College of Medicine, Alnahrain University, Baghdad, Iraq
| | - Najat A Hasan
- 1Department of Chemistry and Biochemistry, College of Medicine, Alnahrain University, Baghdad, Iraq
| | - Alaa G Hussain
- 2Department of Clinical Pathology, College of Medicine, Alnahrain University, Baghdad, Iraq
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29
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Evaluation of miRNA-196a2 and apoptosis-related target genes: ANXA1, DFFA and PDCD4 expression in gastrointestinal cancer patients: A pilot study. PLoS One 2017; 12:e0187310. [PMID: 29091952 PMCID: PMC5665540 DOI: 10.1371/journal.pone.0187310] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 10/17/2017] [Indexed: 12/26/2022] Open
Abstract
Previous reports have suggested the significant association of miRNAs aberrant expression with tumor initiation, progression and metastasis in cancer, including gastrointestinal (GI) cancers. The current preliminary study aimed to evaluate the relative expression levels of miR-196a2 and three of its selected apoptosis-related targets; ANXA1, DFFA and PDCD4 in a sample of GI cancer patients. Quantitative real-time PCR for miR-196a2 and its selected mRNA targets, as well as immunohistochemical assay for annexin A1 protein expression were detected in 58 tissues with different GI cancer samples. In addition, correlation with the clinicopathological features and in silico network analysis of the selected molecular markers were analyzed. Stratified analyses by cancer site revealed elevated levels of miR-196a2 and low expression of the selected target genes. Annexin protein expression was positively correlated with its gene expression profile. In colorectal cancer, miR-196a over-expression was negatively correlated with annexin A1 protein expression (r = -0.738, p < 0.001), and both were indicators of unfavorable prognosis in terms of poor differentiation, larger tumor size, and advanced clinical stage. Taken together, aberrant expression of miR-196a2 and the selected apoptosis-related biomarkers might be involved in GI cancer development and progression and could have potential diagnostic and prognostic roles in these types of cancer; particularly colorectal cancer, provided the results experimentally validated and confirmed in larger multi-center studies.
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30
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Liu F, Song D, Wu Y, Liu X, Zhu J, Tang Y. MiR-155 inhibits proliferation and invasion by directly targeting PDCD4 in non-small cell lung cancer. Thorac Cancer 2017; 8:613-619. [PMID: 28842954 PMCID: PMC5668490 DOI: 10.1111/1759-7714.12492] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 07/18/2017] [Accepted: 07/19/2017] [Indexed: 12/16/2022] Open
Abstract
Background MicroRNAs are often abnormally expressed in human non‐small cell lung cancer (NSCLC) and are thought to play a critical role in the emergence or maintenance of NSCLC by binding to its target messenger RNA. We assessed the effects of miR‐155 on cell proliferation and invasion to elucidate the role played by miR‐155/PDCD4 in NSCLC. Methods Quantitative reverse transcription‐PCR, Western blotting, and cell counting kit‐8, luciferase, and transwell invasion assays were conducted on a normal human bronchial epithelial cell line (BEAS‐2B) and three NSCLC cell lines (SPC‐A‐1, A549, and H2170). Results We confirmed that miR‐155 was upregulated, while PDCD4 messenger RNA and protein levels were downregulated in NSCLC cell lines. miR‐155 negatively regulated PDCD4 at both transcriptional and post‐transcriptional levels. Moreover, PDCD4 was forecast as an assumed target of miR‐155 using bioinformatic methods and we demonstrated that PDCD4 was a direct target of miR‐155 using luciferase reporter assays. Furthermore, PDCD4 overexpression could restrain NSCLC proliferation and invasion induced by miR‐155. Conclusion Our results collectively demonstrate that miR‐155 exerts an oncogenic role in NSCLC by directly targeting PDCD4.
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Affiliation(s)
- Feng Liu
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Cardiothoracic Surgery, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, China.,Department of Cardiothoracic Surgery, Suzhou Science and Technology Town Hospital, Suzhou, China
| | - Dalong Song
- Department of Urology, GuiZhou Provincial People's Hospital, Guiyang, China.,Medical College, Guizhou University, Guiyang, China.,CAS Key Laboratory of Bio-Medical Diagnostic, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Yanhu Wu
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiang Liu
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jinfu Zhu
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yihu Tang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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31
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Kumar S, Marriott CE, Alhasawi NF, Bone AJ, Macfarlane WM. The role of tumour suppressor PDCD4 in beta cell death in hypoxia. PLoS One 2017; 12:e0181235. [PMID: 28750063 PMCID: PMC5531437 DOI: 10.1371/journal.pone.0181235] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 06/28/2017] [Indexed: 12/31/2022] Open
Abstract
Objective Hypoxia is known to induce pancreatic beta cell dysfunction and apoptosis. Changes in Programmed Cell Death Gene 4 (PDCD4) expression have previously been linked with beta cell neogenesis and function. Our aim was to investigate the effects of hypoxia on cell viability, PDCD4 expression and subcellular localisation. Methods MIN6 beta cells and ARIP ductal cells were exposed to 1% (hypoxia) or 21% O2 (normoxia) for 12 or 24 hours. MTT assay, HPI staining, scanning electron microscopy, western blotting and immunocytochemistry analyses were performed to determine the effect of hypoxia on cell viability, morphology and PDCD4 expression. Results 24 hour exposure to hypoxia resulted in ~70% loss of beta cell viability (P<0.001) compared to normoxia. Both HPI staining and SEM analysis demonstrated beta cell apoptosis and necrosis after 12 hours exposure to hypoxia. ARIP cells also displayed hypoxia-induced apoptosis and altered surface morphology after 24 hours, but no significant growth difference (p>0.05) was observed between hypoxic and normoxic conditions. Significantly higher expression of PDCD4 was observed in both beta cells (P<0.001) and ductal (P<0.01) cells under hypoxic conditions compared to controls. PDCD4 expression was localised to the cytoplasm of both beta cells and ductal cells, with no observed effects of hypoxia, normoxia or serum free conditions on intracellular shuttling of PDCD4. Conclusion These findings indicate that hypoxia-induced expression of PDCD4 is associated with increased beta cell death and suggests that PDCD4 may be an important factor in regulating beta cell survival during hypoxic stress.
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Affiliation(s)
- Sandeep Kumar
- Diabetes Research Group, School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, United Kingdom
| | - Claire E. Marriott
- Diabetes Research Group, School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, United Kingdom
| | - Nouf F. Alhasawi
- Diabetes Research Group, School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, United Kingdom
| | - Adrian J. Bone
- Diabetes Research Group, School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, United Kingdom
| | - Wendy M. Macfarlane
- Diabetes Research Group, School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, United Kingdom
- * E-mail:
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32
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Laudato S, Patil N, Abba ML, Leupold JH, Benner A, Gaiser T, Marx A, Allgayer H. P53-induced miR-30e-5p inhibits colorectal cancer invasion and metastasis by targeting ITGA6 and ITGB1. Int J Cancer 2017; 141:1879-1890. [DOI: 10.1002/ijc.30854] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Revised: 06/01/2017] [Accepted: 06/12/2017] [Indexed: 01/26/2023]
Affiliation(s)
- Sara Laudato
- Department of Experimental Surgery-Cancer Metastasis; Medical Faculty Mannheim, University of Heidelberg; Germany
- Centre for Biomedicine and Medical Technology, Medical Faculty Mannheim, University of Heidelberg; Germany
| | - Nitin Patil
- Department of Experimental Surgery-Cancer Metastasis; Medical Faculty Mannheim, University of Heidelberg; Germany
- Centre for Biomedicine and Medical Technology, Medical Faculty Mannheim, University of Heidelberg; Germany
| | - Mohammed L. Abba
- Department of Experimental Surgery-Cancer Metastasis; Medical Faculty Mannheim, University of Heidelberg; Germany
- Centre for Biomedicine and Medical Technology, Medical Faculty Mannheim, University of Heidelberg; Germany
| | - Joerg H. Leupold
- Department of Experimental Surgery-Cancer Metastasis; Medical Faculty Mannheim, University of Heidelberg; Germany
- Centre for Biomedicine and Medical Technology, Medical Faculty Mannheim, University of Heidelberg; Germany
| | - Axel Benner
- Department of Biostatistics; German Cancer Research Center (DKFZ); Heidelberg Germany
| | - Timo Gaiser
- Institute of Pathology, University Hospital Mannheim (UMM); Mannheim Germany
| | - Alexander Marx
- Institute of Pathology, University Hospital Mannheim (UMM); Mannheim Germany
| | - Heike Allgayer
- Department of Experimental Surgery-Cancer Metastasis; Medical Faculty Mannheim, University of Heidelberg; Germany
- Centre for Biomedicine and Medical Technology, Medical Faculty Mannheim, University of Heidelberg; Germany
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Non-coding RNAs Enabling Prognostic Stratification and Prediction of Therapeutic Response in Colorectal Cancer Patients. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 937:183-204. [PMID: 27573901 DOI: 10.1007/978-3-319-42059-2_10] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Colorectal cancer (CRC) is a heterogeneous disease and current treatment options for patients are associated with a wide range of outcomes and tumor responses. Although the traditional TNM staging system continues to serve as a crucial tool for estimating CRC prognosis and for stratification of treatment choices and long-term survival, it remains limited as it relies on macroscopic features and cases of surgical resection, fails to incorporate new molecular data and information, and cannot perfectly predict the variety of outcomes and responses to treatment associated with tumors of the same stage. Although additional histopathologic features have recently been applied in order to better classify individual tumors, the future might incorporate the use of novel molecular and genetic markers in order to maximize therapeutic outcome and to provide accurate prognosis. Such novel biomarkers, in addition to individual patient tumor phenotyping and other validated genetic markers, could facilitate the prediction of risk of progression in CRC patients and help assess overall survival. Recent findings point to the emerging role of non-protein-coding regions of the genome in their contribution to the progression of cancer and tumor formation. Two major subclasses of non-coding RNAs (ncRNAs), microRNAs and long non-coding RNAs, are often dysregulated in CRC and have demonstrated their diagnostic and prognostic potential as biomarkers. These ncRNAs are promising molecular classifiers and could assist in the stratification of patients into appropriate risk groups to guide therapeutic decisions and their expression patterns could help determine prognosis and predict therapeutic options in CRC.
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Tumor suppressor Pdcd4 attenuates Sin1 translation to inhibit invasion in colon carcinoma. Oncogene 2017; 36:6225-6234. [PMID: 28692058 PMCID: PMC5680133 DOI: 10.1038/onc.2017.228] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 05/22/2017] [Accepted: 06/01/2017] [Indexed: 12/16/2022]
Abstract
Programmed cell death 4 (Pdcd4), a tumor invasion suppressor, is frequently down-regulated in colorectal cancer and other cancers. In this study, we find that loss of Pdcd4 increases the activity of mammalian target of rapamycin complex 2 (mTORC2) and thereby upregulates Snail expression. Examining the components of mTORC2 showed that Pdcd4 knockdown increased the protein but not mRNA level of stress-activated-protein kinase interacting protein 1 (Sin1), which resulted from enhanced Sin1 translation. To understand how Pdcd4 regulates Sin1 translation, the SIN1 5’ untranslated region (5’UTR) was fused with luciferase reporter and named as 5’Sin1-Luc. Pdcd4 knockdown/knockout significantly increased the translation of 5’Sin1-Luc but not the control luciferase without the SIN1 5’UTR, suggesting that Sin1 5’UTR is necessary for Pdcd4 to inhibit Sin1 translation. Ectopic expression of wild type Pdcd4 and Pdcd4(157–469), a deletion mutant that binds to translation initiation factor 4A (eIF4A), sufficiently inhibited Sin1 translation, and thus suppressed mTORC2 kinase activity and invasion in colon tumor cells. By contrast, Pdcd4(157–469)(D253A,D418A), a mutant that does not bind to eIF4A, failed to inhibit Sin1 translation, and consequently failed to repress mTORC2 activity and invasion. In addition, directly inhibiting eIF4A with silvestrol significantly suppressed Sin1 translation and attenuated invasion. These results indicate that Pdcd4-inhibited Sin1 translation is through suppressing eIF4A, and functionally important for suppression of mTORC2 activity and invasion. Moreover, in colorectal cancer tissues, the Sin1 protein but not mRNA was significantly up-regulated while Pdcd4 protein was down-regulated, suggesting that loss of Pdcd4 might correlate with Sin1 protein level but not mRNA level in colorectal cancer patients. Taken together, our work reveals a novel mechanism by which Pdcd4 inhibits Sin1 translation to attenuatemTORC2 activity and thereby suppresses invasion.
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Grisard E, Nicoloso MS. Following MicroRNAs Through the Cancer Metastatic Cascade. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2017; 333:173-228. [PMID: 28729025 DOI: 10.1016/bs.ircmb.2017.04.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Approximately a decade ago the first MicroRNAs (MiRNAs) participating in cancer metastasis were identified and metastmiRs were initially only a handful. Since those first reports, MiRNA research has explosively thrived, mainly due to their revolutionary mechanism of action and the hope of having at hand a novel tool to control cancer aggressiveness. This has ultimately led to delineate an almost impenetrable regulatory network: hundreds of MiRNAs transversally dominating every aspect of normal and cancer biology, each MiRNA having hundreds of targets and context-dependent activity. Providing a comprehensive description of MiRNA roles in cancer metastasis is a daunting task; nevertheless, we still believe that grasping the big picture of MiRNAs in cancer metastasis can give a different perspective on the potential insights and approaches that MiRNAs can offer to understand cancer complexity (e.g., as predictive and prognostic markers) and to tackle cancer metastasis (e.g., as therapeutic targets or tools). This chapter presents a schematic overview of the role of MiRNAs in governing cancer metastasis, describing step by step the cellular and molecular processes whereby cancer cells conquer distant organs and can grow as secondary tumors at different distant sites, and for each step, we will introduce how MiRNAs impinge on each one of them. We deeply apologize with our colleagues for any of their research work that, for clarity, for our effort to streamline and due to space limitations, we did not cite.
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Circulating MiRNA-21 and programed cell death (PDCD) 4 gene expression in hepatocellular carcinoma (HCC) in Egyptian patients. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2017. [DOI: 10.1016/j.ejmhg.2016.04.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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Chen B, Huang SG, Ju L, Li M, Nie FF, Zhang Y, Zhang YH, Chen X, Gao F. Effect of microRNA-21 on the proliferation of human degenerated nucleus pulposus by targeting programmed cell death 4. ACTA ACUST UNITED AC 2017; 49:S0100-879X2016000600602. [PMID: 27240294 PMCID: PMC4897996 DOI: 10.1590/1414-431x20155020] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 11/16/2015] [Indexed: 12/28/2022]
Abstract
This study aims to explore the effect of microRNA-21 (miR-21) on the proliferation of
human degenerated nucleus pulposus (NP) by targeting programmed cell death 4 (PDCD4)
tumor suppressor. NP tissues were collected from 20 intervertebral disc degeneration
(IDD) patients, and from 5 patients with traumatic spine fracture. MiR-21 expressions
were tested. NP cells from IDD patients were collected and divided into blank control
group, negative control group (transfected with miR-21 negative sequences), miR-21
inhibitor group (transfected with miR-21 inhibitors), miR-21 mimics group
(transfected with miR-21 mimics) and PDCD4 siRNA group (transfected with PDCD4
siRNAs). Cell growth was estimated by Cell Counting Kit-8; PDCD4, MMP-2,MMP-9 mRNA
expressions were evaluated by qRT-PCR; PDCD4, c-Jun and p-c-Jun expressions were
tested using western blot. In IDD patients, the expressions of miR-21 and PDCD4 mRNA
were respectively elevated and decreased (both P<0.05). The miR-21 expressions
were positively correlated with Pfirrmann grades, but negatively correlated with
PDCD4 mRNA (both P<0.001). In miR-21 inhibitor group, cell growth, MMP-2 and MMP-9
mRNA expressions, and p-c-Jun protein expressions were significantly lower, while
PDCD4 mRNA and protein expressions were higher than the other groups (all P<0.05).
These expressions in the PDCD4 siRNA and miR-21 mimics groups was inverted compared
to that in the miR-21 inhibitor group (all P<0.05). MiR-21 could promote the
proliferation of human degenerated NP cells by targeting PDCD4, increasing
phosphorylation of c-Jun protein, and activating AP-1-dependent transcription of
MMPs, indicating that miR-21 may be a crucial biomarker in the pathogenesis of
IDD.
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Affiliation(s)
- B Chen
- Department of Orthopedics, Linyi Second People's Hospital, Linyi, China
| | - S G Huang
- Department of Orthopedics, Linyi Second People's Hospital, Linyi, China
| | - L Ju
- Department of Orthopedics, Linyi Second People's Hospital, Linyi, China
| | - M Li
- Department of Orthopedics, Linyi Second People's Hospital, Linyi, China
| | - F F Nie
- Department of Orthopedics, Linyi Second People's Hospital, Linyi, China
| | - Y Zhang
- Department of General Surgery, Affiliated Hospital of Taishan Medical University, Taian, China
| | - Y H Zhang
- Department of Orthopedics, Linyi Second People's Hospital, Linyi, China
| | - X Chen
- Department of Orthopedics, Linyi Second People's Hospital, Linyi, China
| | - F Gao
- Department of Orthopedics, Linyi Second People's Hospital, Linyi, China
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Li JZH, Gao W, Ho WK, Lei WB, Wei WI, Chan JYW, Wong TS. The clinical association of programmed cell death protein 4 (PDCD4) with solid tumors and its prognostic significance: a meta-analysis. CHINESE JOURNAL OF CANCER 2016; 35:95. [PMID: 27852288 PMCID: PMC5112731 DOI: 10.1186/s40880-016-0158-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 04/15/2016] [Indexed: 12/26/2022]
Abstract
Background Programmed cell death protein 4 (PDCD4) is a novel tumor suppressor protein involved in programmed cell death. Its association with cancer progression has been observed in multiple tumor models, but evidence supporting its association with solid tumors in humans remains controversial. This study aimed to determine the clinical significance and prognostic value of PDCD4 in solid tumors. Methods A systematic literature review was performed to retrieve publications with available clinical information and survival data. The eligibility of the selected articles was based on the criteria of the Dutch Cochrane Centre proposed by the Meta-analysis Of Observational Studies in Epidemiology group. Pooled odds ratios (ORs), hazard ratios (HRs), and 95% confidence intervals (CIs) for survival analysis were calculated. Publication bias was examined by Begg’s and Egger’s tests. Results Clinical data of 2227 cancer patients with solid tumors from 23 studies were evaluated. PDCD4 expression was significantly associated with the differentiation status of head and neck cancer (OR 4.25, 95% CI 1.87–9.66) and digestive system cancer (OR 2.87, 95% CI 1.84–4.48). Down-regulation of PDCD4 was significantly associated with short overall survival of patients with head and neck (HR: 3.44, 95% CI 2.38–4.98), breast (HR: 1.86, 95% CI 1.36–2.54), digestive system (HR: 2.12, 95% CI 1.75–2.56), and urinary system cancers (HR: 3.16, 95% CI 1.06–9.41). Conclusions The current evidence suggests that PDCD4 down-regulation is involved in the progression of several types of solid tumor and is a potential marker for solid tumor prognoses. Its clinical usefulness should be confirmed by large-scale prospective studies.
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Affiliation(s)
- John Zeng Hong Li
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong, SAR, P. R. China
| | - Wei Gao
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong, SAR, P. R. China
| | - Wai-Kuen Ho
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong, SAR, P. R. China
| | - Wen Bin Lei
- Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, P. R. China
| | - William Ignace Wei
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong, SAR, P. R. China
| | - Jimmy Yu-Wai Chan
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong, SAR, P. R. China
| | - Thian-Sze Wong
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong, SAR, P. R. China.
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Chen Y, Bian Y, Zhao S, Kong F, Li X. Suppression of PDCD4 mediated by the long non-coding RNA HOTAIR inhibits the proliferation and invasion of glioma cells. Oncol Lett 2016; 12:5170-5176. [PMID: 28105224 DOI: 10.3892/ol.2016.5323] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Accepted: 05/26/2016] [Indexed: 11/06/2022] Open
Abstract
Programmed cell death protein 4 (PDCD4) has recently been demonstrated to be implicated in translation and transcription, and the regulation of cell growth. However, the mechanisms underlying PDCD4 function in glioma cells remain to be elucidated. The current study investigated the function and regulation of PDCD4 and the results demonstrated that the expression of PDCD4 was significantly reduced in glioma cells compared with normal cells. When PDCD4 was overexpressed in glioma cells, the proliferation rate and invasive capability of the cells greatly decreased, suggesting that PDCD4 functions as a tumor suppressor in this cell type. In addition, the histone modification status of the PDCD4 gene was analyzed, and chromatin immunoprecipitation assay identified a high density of histone 3 lysine 27 trimethylation on the promoter of PDCD4, which was associated with the long non-coding RNA, homeobox transcript antisense RNA (HOTAIR). The expression of HOTAIR was significantly increased in glioma cells compared with normal cells, and it exerted its function in a polycomb repressive complex 2-dependent manner. These results may provide novel approaches to therapeutically target PDCD4 and HOTAIR in patients with gliomas.
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Affiliation(s)
- Yong'An Chen
- Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China; Emergency Centre, Yantai Yuhuangding Hospital Affiliated to Qingdao University Medical College, Yantai, Shandong 264000, P.R. China
| | - Yusong Bian
- Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China; Emergency Centre, Yantai Yuhuangding Hospital Affiliated to Qingdao University Medical College, Yantai, Shandong 264000, P.R. China
| | - Shanpeng Zhao
- Emergency Centre, Yantai Yuhuangding Hospital Affiliated to Qingdao University Medical College, Yantai, Shandong 264000, P.R. China
| | - Fanqiang Kong
- Emergency Centre, Yantai Yuhuangding Hospital Affiliated to Qingdao University Medical College, Yantai, Shandong 264000, P.R. China
| | - Xin'Gang Li
- Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
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Zhang X, Liu R, Huang B, Zhang X, Yu W, Bao C, Li J, Sun C. Programmed cell death 4 and BCR-ABL fusion gene expression are negatively correlated in chronic myeloid leukemia. Oncol Lett 2016; 12:2976-2981. [PMID: 27698886 DOI: 10.3892/ol.2016.4942] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 07/20/2016] [Indexed: 02/07/2023] Open
Abstract
Programmed cell death 4 (PDCD4) is a tumor suppressor that inhibits carcinogenesis, tumor progression and invasion by preventing gene transcription and translation. Downregulation of PDCD4 expression has been identified in multiple types of human cancer, however, to date, the function of PDCD4 in leukemia has not been investigated. In the present study, PDCD4 mRNA and protein expression was investigated in 50 patients exhibiting various phases of chronic myeloid leukemia (CML) and 20 healthy individuals by reverse transcription-quantitative polymerase chain reaction and western blot analysis. PDCD4 expression and cell proliferation was also investigated following treatment with the tyrosine kinase inhibitor, imatinib, in K562 cells. The results demonstrated that PDCD4 mRNA and protein expression was decreased in all CML samples when compared with healthy controls, who expressed high levels of PDCD4 mRNA and protein. No significant differences in PDCD4 expression were identified between chronic phase, accelerated phase and blast phase CML patients. In addition, PDCD4 expression was negatively correlated with BCR-ABL gene expression (r=-0.6716; P<0.001). Furthermore, K562 cells treated with imatinib exhibited significantly enhanced PDCD4 expression. These results indicate that downregulation of PDCD4 expression may exhibit a critical function in the progression and malignant proliferation of human CML.
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Affiliation(s)
- Xia Zhang
- Department of Laboratory Medicine, Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Riming Liu
- Department of Laboratory Medicine, Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Baohua Huang
- Department of Laboratory Medicine, Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Xiaolu Zhang
- Department of Laboratory Medicine, Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Weijuan Yu
- Department of Laboratory Medicine, Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Cuixia Bao
- Department of Laboratory Medicine, Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Jie Li
- Department of Laboratory Medicine, Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Chengming Sun
- Department of Laboratory Medicine, Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
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Goswami MT, Chen G, Chakravarthi BVSK, Pathi SS, Anand SK, Carskadon SL, Giordano TJ, Chinnaiyan AM, Thomas DG, Palanisamy N, Beer DG, Varambally S. Role and regulation of coordinately expressed de novo purine biosynthetic enzymes PPAT and PAICS in lung cancer. Oncotarget 2016; 6:23445-61. [PMID: 26140362 PMCID: PMC4695129 DOI: 10.18632/oncotarget.4352] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 06/12/2015] [Indexed: 12/13/2022] Open
Abstract
Cancer cells exhibit altered metabolism including aerobic glycolysis that channels several glycolytic intermediates into de novo purine biosynthetic pathway. We discovered increased expression of phosphoribosyl amidotransferase (PPAT) and phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) enzymes of de novo purine biosynthetic pathway in lung adenocarcinomas. Transcript analyses from next-generation RNA sequencing and gene expression profiling studies suggested that PPAT and PAICS can serve as prognostic biomarkers for aggressive lung adenocarcinoma. Immunohistochemical analysis of PAICS performed on tissue microarrays showed increased expression with disease progression and was significantly associated with poor prognosis. Through gene knockdown and over-expression studies we demonstrate that altering PPAT and PAICS expression modulates pyruvate kinase activity, cell proliferation and invasion. Furthermore we identified genomic amplification and aneuploidy of the divergently transcribed PPAT-PAICS genomic region in a subset of lung cancers. We also present evidence for regulation of both PPAT and PAICS and pyruvate kinase activity by L-glutamine, a co-substrate for PPAT. A glutamine antagonist, 6-Diazo-5-oxo-L-norleucine (DON) blocked glutamine mediated induction of PPAT and PAICS as well as reduced pyruvate kinase activity. In summary, this study reveals the regulatory mechanisms by which purine biosynthetic pathway enzymes PPAT and PAICS, and pyruvate kinase activity is increased and exposes an existing metabolic vulnerability in lung cancer cells that can be explored for pharmacological intervention.
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Affiliation(s)
- Moloy T Goswami
- Michigan Center for Translational Pathology, Ann Arbor, MI 48109, USA.,Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Guoan Chen
- Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Balabhadrapatruni V S K Chakravarthi
- Michigan Center for Translational Pathology, Ann Arbor, MI 48109, USA.,Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.,Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Satya S Pathi
- Michigan Center for Translational Pathology, Ann Arbor, MI 48109, USA.,Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.,Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Sharath K Anand
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Shannon L Carskadon
- Michigan Center for Translational Pathology, Ann Arbor, MI 48109, USA.,Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Thomas J Giordano
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.,Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Arul M Chinnaiyan
- Michigan Center for Translational Pathology, Ann Arbor, MI 48109, USA.,Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.,Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA.,Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.,Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Dafydd G Thomas
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.,Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Nallasivam Palanisamy
- Michigan Center for Translational Pathology, Ann Arbor, MI 48109, USA.,Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.,Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.,Department of Urology, Henry Ford Health System, Detroit, MI 48202, USA
| | - David G Beer
- Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.,Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Sooryanarayana Varambally
- Michigan Center for Translational Pathology, Ann Arbor, MI 48109, USA.,Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.,Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.,Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA
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Liu Y, Tan X, Wang Z, Li Y, Gao M, Li Y, Fang Z, Sun Y, Zhang L, Wang X, Wei Z. Down-regulation of tumor suppressor PDCD4 expression in endometrium of adenomyosis patients. Curr Res Transl Med 2016; 64:123-128. [PMID: 27765271 DOI: 10.1016/j.retram.2016.04.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 04/22/2016] [Indexed: 10/21/2022]
Abstract
OBJECTIVE Adenomyosis is a common benign gynecological disease which has some malignant behaviors. Programmed cell death 4 (PDCD4) is a newly identified tumor suppressor gene which lowly expresses in various cancers. However, the expression status of PDCD4 in endometrium of adenomyosis patients has not been investigated. The aim of this study is to assess the expression levels of PDCD4 in endometrium of normal controls and adenomyosis patients. METHODS The expression of PDCD4 in endometrium of normal controls and eutopic or ectopic endometrium of patients with adenomyosis was evaluated with quantitative real-time PCR, western blot and immunohistochemistry. In addition, the levels of serum estradiol and progesterone in normal controls and adenomyosis patients were detected using electrochemiluminescence immunoassay. RESULTS The results showed that PDCD4 mainly expressed in the cytoplasma of glandular epithelium of control endometrium and varied during the cycle changes of endometrium, which may be regulated by changing concentrations of progesterone in the menstrual cycle. Compared with the proliferative phase of control endometrium, PDCD4 expression was down-regulated in proliferative phase of eutopic endometrium or ectopic endometrium, and there was no cyclic variation of PDCD4 expression in eutopic endometrium of adenomyosis patients due to progesterone resistance. CONCLUSION These results suggest that PDCD4 may be involved in the pathogenesis of adenomyosis, which will provide a novel strategy for the early diagnosis and new therapeutic target of adenomyosis.
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Affiliation(s)
- Y Liu
- Department of gynecology and obstetrics, Shandong university school of medicine, 44#, Wenhua Xi Road, 250012 Jinan, Shandong, P.R. China
| | - X Tan
- Department of immunology, Shandong university school of medicine, 44#, Wenhua Xi Road, 250012 Jinan, Shandong, P.R. China; Department of pathology, Linyi People's hospital, Linyi, Shandong, P.R. China
| | - Z Wang
- Department of gynecology and obstetrics, Jinan central hospital affiliated to Shandong university, 105#, Jiefang Road, 250013 Jinan, Shandong, P.R. China
| | - Y Li
- Department of immunology, Shandong university school of medicine, 44#, Wenhua Xi Road, 250012 Jinan, Shandong, P.R. China
| | - M Gao
- Department of immunology, Shandong university school of medicine, 44#, Wenhua Xi Road, 250012 Jinan, Shandong, P.R. China
| | - Y Li
- Department of immunology, Shandong university school of medicine, 44#, Wenhua Xi Road, 250012 Jinan, Shandong, P.R. China
| | - Z Fang
- Department of gynecology and obstetrics, Jinan central hospital affiliated to Shandong university, 105#, Jiefang Road, 250013 Jinan, Shandong, P.R. China
| | - Y Sun
- Department of gynecology and obstetrics, Shandong university school of medicine, 44#, Wenhua Xi Road, 250012 Jinan, Shandong, P.R. China
| | - L Zhang
- Department of immunology, Shandong university school of medicine, 44#, Wenhua Xi Road, 250012 Jinan, Shandong, P.R. China
| | - X Wang
- Department of immunology, Shandong university school of medicine, 44#, Wenhua Xi Road, 250012 Jinan, Shandong, P.R. China.
| | - Z Wei
- Department of gynecology and obstetrics, Shandong university school of medicine, 44#, Wenhua Xi Road, 250012 Jinan, Shandong, P.R. China; Department of gynecology and obstetrics, Jinan central hospital affiliated to Shandong university, 105#, Jiefang Road, 250013 Jinan, Shandong, P.R. China.
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Larrea E, Sole C, Manterola L, Goicoechea I, Armesto M, Arestin M, Caffarel MM, Araujo AM, Araiz M, Fernandez-Mercado M, Lawrie CH. New Concepts in Cancer Biomarkers: Circulating miRNAs in Liquid Biopsies. Int J Mol Sci 2016; 17:ijms17050627. [PMID: 27128908 PMCID: PMC4881453 DOI: 10.3390/ijms17050627] [Citation(s) in RCA: 181] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2016] [Revised: 04/18/2016] [Accepted: 04/18/2016] [Indexed: 12/19/2022] Open
Abstract
The effective and efficient management of cancer patients relies upon early diagnosis and/or the monitoring of treatment, something that is often difficult to achieve using standard tissue biopsy techniques. Biological fluids such as blood hold great possibilities as a source of non-invasive cancer biomarkers that can act as surrogate markers to biopsy-based sampling. The non-invasive nature of these “liquid biopsies” ultimately means that cancer detection may be earlier and that the ability to monitor disease progression and/or treatment response represents a paradigm shift in the treatment of cancer patients. Below, we review one of the most promising classes of circulating cancer biomarkers: microRNAs (miRNAs). In particular, we will consider their history, the controversy surrounding their origin and biology, and, most importantly, the hurdles that remain to be overcome if they are really to become part of future clinical practice.
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Affiliation(s)
- Erika Larrea
- Molecular Oncology, Biodonostia Research Institute, 20014 San Sebastián, Spain.
| | - Carla Sole
- Molecular Oncology, Biodonostia Research Institute, 20014 San Sebastián, Spain.
| | - Lorea Manterola
- Molecular Oncology, Biodonostia Research Institute, 20014 San Sebastián, Spain.
| | - Ibai Goicoechea
- Molecular Oncology, Biodonostia Research Institute, 20014 San Sebastián, Spain.
| | - María Armesto
- Molecular Oncology, Biodonostia Research Institute, 20014 San Sebastián, Spain.
| | - María Arestin
- Molecular Oncology, Biodonostia Research Institute, 20014 San Sebastián, Spain.
| | - María M Caffarel
- Molecular Oncology, Biodonostia Research Institute, 20014 San Sebastián, Spain.
- IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain.
| | - Angela M Araujo
- Molecular Oncology, Biodonostia Research Institute, 20014 San Sebastián, Spain.
| | - María Araiz
- Hematology Department, Donostia Hospital, 20014 San Sebastián, Spain.
| | | | - Charles H Lawrie
- Molecular Oncology, Biodonostia Research Institute, 20014 San Sebastián, Spain.
- IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain.
- Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 9DU, UK.
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Abstract
The process of entering the bloodstream, intravasation, is a necessary step in the development of distant metastases. The focus of this review is on the pathways and molecules that have been identified as being important based on current in vitro and in vivo assays for intravasation. Properties of the vasculature which are important for intravasation include microvessel density and also diameter of the vasculature, with increased intravasation correlating with increased vessel diameter in some tumors. TGFB signaling can enhance intravasation at least in part through induction of EMT, and we discuss other TGFB target genes that are important for intravasation. In addition to TGFB signaling, a number of studies have demonstrated that activation of EGF receptor family members stimulates intravasation, with downstream signaling through PI3K, N-WASP, RhoA, and WASP to induce invadopodia. With respect to proteases, there is strong evidence for contributions by uPA/uPAR, while the roles of MMPs in intravasation may be more tumor specific. Other cells including macrophages, fibroblasts, neutrophils, and platelets can also play a role in enhancing tumor cell intravasation. The technology is now available to interrogate the expression patterns of circulating tumor cells, which will provide an important reality check for the model systems being used. With a better understanding of the mechanisms underlying intravasation, the goal is to provide new opportunities for improving prognosis as well as potentially developing new treatments.
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Affiliation(s)
- Serena P H Chiang
- Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York
| | - Ramon M Cabrera
- Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York
| | - Jeffrey E Segall
- Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York
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45
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Perez F, Waldeck AR, Krische MJ. Total Synthesis of Cryptocaryol A by Enantioselective Iridium-Catalyzed Alcohol C-H Allylation. Angew Chem Int Ed Engl 2016; 55:5049-52. [PMID: 27079820 PMCID: PMC4834877 DOI: 10.1002/anie.201600591] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Indexed: 11/06/2022]
Abstract
The polyketide natural product cryptocaryol A is prepared in 8 steps via iridium catalyzed enantioselective diol double C-H allylation, which directly generates an acetate-based triketide stereodiad. In 4 previously reported total syntheses, 17-28 steps were required.
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Affiliation(s)
- Felix Perez
- University of Texas at Austin, Department of Chemistry, 105 E 24th St. (A5300), Austin, TX, 78712-1167, USA
| | - Andrew R Waldeck
- University of Texas at Austin, Department of Chemistry, 105 E 24th St. (A5300), Austin, TX, 78712-1167, USA
| | - Michael J Krische
- University of Texas at Austin, Department of Chemistry, 105 E 24th St. (A5300), Austin, TX, 78712-1167, USA.
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Schmid T, Blees JS, Bajer MM, Wild J, Pescatori L, Cuzzucoli Crucitti G, Scipione L, Costi R, Henrich CJ, Brüne B, Colburn NH, Di Santo R. Diaryl Disulfides as Novel Stabilizers of Tumor Suppressor Pdcd4. PLoS One 2016; 11:e0151643. [PMID: 26982744 PMCID: PMC4794182 DOI: 10.1371/journal.pone.0151643] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 03/02/2016] [Indexed: 01/01/2023] Open
Abstract
The translation inhibitor and tumor suppressor Pdcd4 was reported to be lost in various tumors and put forward as prognostic marker in tumorigenesis. Decreased Pdcd4 protein stability due to PI3K-mTOR-p70S6K1 dependent phosphorylation of Pdcd4 followed by β-TrCP1-mediated ubiquitination, and proteasomal destruction of the protein was characterized as a major mechanism contributing to the loss of Pdcd4 expression in tumors. In an attempt to identify stabilizers of Pdcd4, we used a luciferase-based high-throughput compatible cellular assay to monitor phosphorylation-dependent proteasomal degradation of Pdcd4 in response to mitogen stimulation. Following a screen of approximately 2000 compounds, we identified 1,2-bis(4-chlorophenyl)disulfide as a novel Pdcd4 stabilizer. To determine an initial structure-activity relationship, we used 3 additional compounds, synthesized according to previous reports, and 2 commercially available compounds for further testing, in which either the linker between the aryls was modified (compounds 2-4) or the chlorine residues were replaced by groups with different electronic properties (compounds 5 and 6). We observed that those compounds with alterations in the sulfide linker completely lost the Pdcd4 stabilizing potential. In contrast, modifications in the chlorine residues showed only minor effects on the Pdcd4 stabilizing activity. A reporter with a mutated phospho-degron verified the specificity of the compounds for stabilizing the Pdcd4 reporter. Interestingly, the active diaryl disulfides inhibited proliferation and viability at concentrations where they stabilized Pdcd4, suggesting that Pdcd4 stabilization might contribute to the anti-proliferative properties. Finally, computational modelling indicated that the flexibility of the disulfide linker might be necessary to exert the biological functions of the compounds, as the inactive compound appeared to be energetically more restricted.
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Affiliation(s)
- Tobias Schmid
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590, Frankfurt, Germany
| | - Johanna S. Blees
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590, Frankfurt, Germany
| | - Magdalena M. Bajer
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590, Frankfurt, Germany
| | - Janine Wild
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590, Frankfurt, Germany
| | - Luca Pescatori
- Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur – Fondazione Cenci Bolognetti, “Sapienza” University of Rome, 00185, Rome, Italy
| | - Giuliana Cuzzucoli Crucitti
- Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur – Fondazione Cenci Bolognetti, “Sapienza” University of Rome, 00185, Rome, Italy
| | - Luigi Scipione
- Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur – Fondazione Cenci Bolognetti, “Sapienza” University of Rome, 00185, Rome, Italy
| | - Roberta Costi
- Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur – Fondazione Cenci Bolognetti, “Sapienza” University of Rome, 00185, Rome, Italy
| | - Curtis J. Henrich
- Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD, 21702, United States of America
- Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, United States of America
| | - Bernhard Brüne
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590, Frankfurt, Germany
| | - Nancy H. Colburn
- Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD, 21702, United States of America
| | - Roberto Di Santo
- Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur – Fondazione Cenci Bolognetti, “Sapienza” University of Rome, 00185, Rome, Italy
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47
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Perez F, Waldeck AR, Krische MJ. Total Synthesis of Cryptocaryol A by Enantioselective Iridium-Catalyzed Alcohol C−H Allylation. Angew Chem Int Ed Engl 2016. [DOI: 10.1002/ange.201600591] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Felix Perez
- University of Texas at Austin; Department of Chemistry; 105 E 24th St. (A5300) Austin TX 78712-1167 USA
| | - Andrew R. Waldeck
- University of Texas at Austin; Department of Chemistry; 105 E 24th St. (A5300) Austin TX 78712-1167 USA
| | - Michael J. Krische
- University of Texas at Austin; Department of Chemistry; 105 E 24th St. (A5300) Austin TX 78712-1167 USA
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48
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Brun E, Bellosta V, Cossy J. Total Synthesis of (+)-Cryptocaryol A Using a Prins Cyclization/Reductive Cleavage Sequence. J Org Chem 2015; 80:8668-76. [DOI: 10.1021/acs.joc.5b01323] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Elodie Brun
- Laboratoire de Chimie Organique,
Institute of Chemistry, Biology and Innovation (CBI) - UMR 8231 -
ESPCI ParisTech/CNRS, PSL Research University, 10 rue Vauquelin, 75231 Paris Cedex 05, France
| | - Véronique Bellosta
- Laboratoire de Chimie Organique,
Institute of Chemistry, Biology and Innovation (CBI) - UMR 8231 -
ESPCI ParisTech/CNRS, PSL Research University, 10 rue Vauquelin, 75231 Paris Cedex 05, France
| | - Janine Cossy
- Laboratoire de Chimie Organique,
Institute of Chemistry, Biology and Innovation (CBI) - UMR 8231 -
ESPCI ParisTech/CNRS, PSL Research University, 10 rue Vauquelin, 75231 Paris Cedex 05, France
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49
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Targeting the eIF4A RNA helicase as an anti-neoplastic approach. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2015; 1849:781-91. [DOI: 10.1016/j.bbagrm.2014.09.006] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 09/03/2014] [Indexed: 01/22/2023]
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50
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Programmed cell death 4 protein (Pdcd4) and homeodomain-interacting protein kinase 2 (Hipk2) antagonistically control translation of Hipk2 mRNA. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2015; 1853:1564-73. [DOI: 10.1016/j.bbamcr.2015.03.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Revised: 03/11/2015] [Accepted: 03/14/2015] [Indexed: 12/29/2022]
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