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Chen L, Tang J, Chang Y, Hang D, Ji J, Chen G. SMURF1 leads to the β-catenin signaling-mediated progression of esophageal squamous carcinoma by losing PATZ1-induced CCNG2 transcription. Biochem Pharmacol 2025; 232:116688. [PMID: 39617210 DOI: 10.1016/j.bcp.2024.116688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 11/10/2024] [Accepted: 11/28/2024] [Indexed: 12/16/2024]
Abstract
Cyclin G2 (CCNG2), a known inhibitor of cell cycle progression, has been identified as a suppressor for the canonical β-catenin pathway. This study explores the impact of CCNG2 on β-catenin activity and malignant characteristics of esophageal squamous cell carcinoma (ESCC) cells, and the mechanism behind CCNG2 dysregulation. In ESCC tissues and cells, CCNG2 was under-expressed and associated with poor clinical outcomes, whereas β-catenin showed an opposite trend. Inducing CCNG2 overexpression in ESCC cells led to a reduction in β-catenin levels, which in turn suppressed proliferation, cell cycle progression, migration, invasion, stemness, and tumorigenesis. Additionally, it enhanced the cytotoxicity and proliferation of T cells in co-culture systems. However, these beneficial effects were negated by the Wnt signaling agonist BML-284. Furthermore, PATZ1 was found as a transcription factor promoting CCNG2 transcription. However, the PATZ1 protein in ESCC cells was degraded by SMURF1. Silencing of SMURF1 restored CCNG2 expression and inhibited β-catenin, thereby suppressing the malignant phenotype of ESCC cells and reducing T cell exhaustion. Yet, these effects were blocked by further silencing of PATZ1. In summary, this research demonstrates that SMURF1 activates β-catenin signaling by suppressing the PATZ1/CCNG2 axis, thereby promoting the progression of ESCC.
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Affiliation(s)
- Lingling Chen
- Department of Gastroenterology, Pudong New Area People's Hospital, Shanghai 201299, PR China
| | - Jie Tang
- Department of Gastroenterology, Jiangwan Hospital, Hongkou District, Shanghai 200434, PR China
| | - Yunli Chang
- Department of Gastroenterology, Pudong New Area People's Hospital, Shanghai 201299, PR China
| | - Dongyun Hang
- Department of Gastroenterology, Pudong New Area People's Hospital, Shanghai 201299, PR China
| | - Jieru Ji
- Department of Gastroenterology, Pudong New Area People's Hospital, Shanghai 201299, PR China.
| | - Guoyu Chen
- Department of Gastroenterology, Pudong New Area People's Hospital, Shanghai 201299, PR China.
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Dong F, Zhou J, Wu Y, Gao Z, Li W, Song Z. MicroRNAs in pancreatic cancer drug resistance: mechanisms and therapeutic potential. Front Cell Dev Biol 2025; 12:1499111. [PMID: 39882259 PMCID: PMC11774998 DOI: 10.3389/fcell.2024.1499111] [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: 09/20/2024] [Accepted: 12/30/2024] [Indexed: 01/31/2025] Open
Abstract
Pancreatic cancer (PC) remains one of the most lethal malignancies, primarily due to its intrinsic resistance to conventional therapies. MicroRNAs (miRNAs), key regulators of gene expression, have been identified as crucial modulators of drug resistance mechanisms in this cancer type. This review synthesizes recent advancements in our understanding of how miRNAs influence treatment efficacy in PC. We have thoroughly summarized and discussed the complex role of miRNA in mediating drug resistance in PC treatment. By highlighting specific miRNAs that are implicated in drug resistance pathways, we provide insights into their functional mechanisms and interactions with key molecular targets. We also explore the potential of miRNA-based strategies as novel therapeutic approaches and diagnostic tools to overcome resistance and improve patient outcomes. Despite promising developments, challenges such as specificity, stability, and effective delivery of miRNA-based therapeutics remain. This review aims to offer a critical perspective on current research and propose future directions for leveraging miRNA-based interventions in the fight against PC.
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Affiliation(s)
- Fangying Dong
- Emergency Department, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Jing Zhou
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Yijie Wu
- Department of general practice, Taozhuang Branch of the First People’s Hospital of Jiashan, Jiaxing, Zhejiang, China
| | - Zhaofeng Gao
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Weiwei Li
- Emergency Department, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Zhengwei Song
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
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3
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Ueda H, Takahashi H, Sakaniwa R, Kitamura T, Kobayashi S, Tomimaru Y, Kubo M, Sasaki K, Iwagami Y, Yamada D, Asaoka T, Noda T, Shimizu J, Doki Y, Eguchi H. Preoperative treatment response prediction for pancreatic cancer by multiple microRNAs in plasma exosomes: Optimization using machine learning and network analysis. Pancreatology 2024; 24:1097-1106. [PMID: 39278808 DOI: 10.1016/j.pan.2024.09.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 08/28/2024] [Accepted: 09/10/2024] [Indexed: 09/18/2024]
Abstract
BACKGROUND/OBJECTIVES MicroRNAs (miRNAs) are involved in chemosensitivity through their biological activities in various malignancies, including pancreatic cancer (PC). However, single-miRNA models offer limited predictability of treatment response. We investigated whether a multiple-miRNA prediction model optimized via machine learning could improve treatment response prediction. METHODS A total of 20 and 66 patients who underwent curative resection for PC after gemcitabine-based preoperative treatment were included in the discovery and validation cohorts, respectively. Patients were classified according to their response to preoperative treatment. In the discovery cohort, miRNA microarray and machine learning were used to identify candidate miRNAs (in peripheral plasma exosomes obtained before treatment) associated with treatment response. In the validation cohort, miRNA expression was analyzed using quantitative reverse transcription polymerase chain reaction to validate its ability to predict treatment response. RESULTS In the discovery cohort, six and three miRNAs were associated with good and poor responders, respectively. The combination of these miRNAs significantly improved predictive accuracy compared with using each single miRNA, with area under the curve (AUC) values increasing from 0.485 to 0.672 to 0.909 for good responders and from 0.475 to 0.606 to 0.788 for poor responders. In the validation cohort, improved predictive performance of the miRNA combination over single-miRNA prediction models was confirmed, with AUC values increasing from 0.461 to 0.669 to 0.777 for good responders and from 0.501 to 0.556 to 0.685 for poor responders. CONCLUSIONS Peripheral blood miRNA profiles using an optimized combination of miRNAs may provide a more advanced prediction model for preoperative treatment response in PC.
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Affiliation(s)
- Hiroki Ueda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Hidenori Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
| | - Ryoto Sakaniwa
- Public Health, Department of Social Medicine, Osaka University Graduate School of Medicine, Osaka, Suita, Osaka, Japan
| | - Tetsuhisa Kitamura
- Environment Medicine, Department of Social Medicine, Division of Environment Medicine and Population Sciences, Osaka University Graduate School of Medicine, Osaka, Suita, Osaka, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yoshito Tomimaru
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Masahiko Kubo
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan
| | - Kazuki Sasaki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yoshifumi Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Tadafumi Asaoka
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Takehiro Noda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Junzo Shimizu
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
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Takeda Y, Yamada D, Kobayashi S, Sasaki K, Iwagami Y, Tomimaru Y, Noda T, Takahashi H, Asaoka T, Shimizu J, Doki Y, Eguchi H. MicroRNA-26a-5p is a reliable biomarker in the adjuvant setting for pancreatic ductal adenocarcinoma. PLoS One 2024; 19:e0310328. [PMID: 39288140 PMCID: PMC11407630 DOI: 10.1371/journal.pone.0310328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 08/28/2024] [Indexed: 09/19/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a high recurrence rate even after radical resection because of subclinical tumors. To manage them, a reliable biomarker that can indicate the presence of subclinical tumors and predict their chemosensitivity is required. This study aimed to identify a miRNA as a biomarker that can be used to individualize postoperative adjuvant chemotherapy using postoperative peripheral blood samples. Integrating miRNA microarray data from the blood of 18 patients with PDAC and the in vitro results regarding the phenotypes of chemoresistant PDAC cells, a candidate miRNA was identified. The relationships between candidate miRNA expression and chemosensitivity were examined in vitro and in clinical samples from other cohorts of 33 patients with recurrence. Comprehensive analyses of blood samples detected 5 candidate miRNAs. Of these, miR-26a-5p was considered a candidate biomarker of chemosensitive phenotypes. In validation experiments, chemosensitivity was inversely correlated with miR-26a-5p expression in vitro. Moreover, the ability of miR-26a-5p to predict chemosensitivity was clinically evaluated using blood samples. Patients with high miR-26a-5p expression in the blood after radical resection exhibited a significantly longer survival time after recurrence. Thus, we concluded that miR-26a-5p is a potentially useful biomarker for managing patients with PDAC, especially those undergoing adjuvant chemotherapy.
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Affiliation(s)
- Yu Takeda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Kazuki Sasaki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yoshifumi Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yoshito Tomimaru
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Takehiro Noda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Hidenori Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Tadafumi Asaoka
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- Department of Surgery, Osaka Police Hospital, Osaka, Japan
| | - Junzo Shimizu
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- Department of Surgery, Toyonaka Municipal Hospital, Toyonaka, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
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Kingreen T, Kewitz-Hempel S, Rohde C, Hause G, Sunderkötter C, Gerloff D. Extracellular vesicles from highly invasive melanoma subpopulations increase the invasive capacity of less invasive melanoma cells through mir-1246-mediated inhibition of CCNG2. Cell Commun Signal 2024; 22:442. [PMID: 39285403 PMCID: PMC11403849 DOI: 10.1186/s12964-024-01820-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 09/05/2024] [Indexed: 09/20/2024] Open
Abstract
Invasive growth is a critical process in tumor progression, requiring the activation of various molecular processes in tumor cells at the invasive front. Intercellular communication between heterogeneous tumor cells enhances cellular activation and adaptation to specific microenvironments. One mechanism of intercellular communication is the delivery of miRNAs through tumor cell-derived extracellular vesicles (EVs). In this context we have observed that conditioned media from a highly invasive cell subpopulation (BLM-HI) enhances the invasive capacity of the parental cell line (BLM). Therefore, we hypothesized that this complex change of cellular behavior is influenced by EV-transported miRNAs. The treatment of BLM cells with EVs derived from BLM-HI cells resulted in a significantly enhanced invasive capacity, as observed in Matrigel-embedded spheroids and in 2D Boyden chamber assays, with a dose-dependent effect. Conversely, the invasive capacity of BLM cells was reduced when secretion of EVs was inhibited by a sphingomyelinase inhibitor. To investigate the molecular mechanisms behind this effect, we performed next-generation sequencing and identified an enrichment of miR-1246 in these EVs. In functional analyses we demonstrated that both the EV mediated delivery of miR-1246 as well as overexpression contributes to the enhanced invasiveness of BLM cells. We identified a binding site of miR-1246 in the 3'UTR of cyclin G2 (CCNG2) and demonstrated direct binding by a luciferase reporter assay.Increased expression of CCNG2 has been associated with cancer metastasis and poor patient outcomes in other malignancies. Our study demonstrates that intercellular communication contributes to the transfer of properties, such as increased invasive capacity, between heterogeneous melanoma cells via EV-transported miRNAs.
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Affiliation(s)
- Tim Kingreen
- Department of Dermatology and Venereology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Stefanie Kewitz-Hempel
- Department of Dermatology and Venereology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Christian Rohde
- Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
| | - Gerd Hause
- Biocenter, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Cord Sunderkötter
- Department of Dermatology and Venereology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Dennis Gerloff
- Department of Dermatology and Venereology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
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6
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Aalami AH, Shahriari A, Mazaheri M, Aalami F, Sahebkar A. Advancing gastrointestinal cancer diagnostics: a systematic review and meta-analysis of circulating microRNA-1246 as a non-invasive biomarker. Biomarkers 2024; 29:233-243. [PMID: 38696280 DOI: 10.1080/1354750x.2024.2350714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Accepted: 04/19/2024] [Indexed: 05/04/2024]
Abstract
BACKGROUND Despite numerous reports on the alterations of microRNA-1246 (miR-1246) expression level in digestive system cancers, its role in gastrointestinal cancers (GICs) remains unclear. This meta-analysis aimed to assess the diagnostic potential of circulating miR-1246 in GICs. METHODS Meta-disc version 1.4 and Comprehensive Meta-Analysis (CMA) version 3.7 software were used to calculate pooled sensitivity, specificity, likelihood ratios, diagnostic odds ratio (DOR), area under the curve (AUC), Q*index and summary receiver-operating characteristic (SROC). Subgroup analyses were conducted for cancer type, sample type and geographical region. Publication bias was assessed using Begg's and Egger's tests. RESULTS A total of 14 articles involving 18 studies and 1526 participants (972 cases and 554 controls) were included. The diagnostic accuracy of miRNA-1246 in GICs was as follows: pooled sensitivity: 0.81 (95% CI: 0.79 - 0.83), specificity: 0.74 (95% CI: 0.71 - 0.77), PLR: 3.315 (95% CI: 2.33 - 4.72), NLR: 0.221 (95% CI: 0.153 - 0.319), DOR: 16.87 (95% CI: 9.45 - 30.09), AUC: 0.891, and Q*-index: 0.807. No publication bias was found based on Begg's (p = 0.172) and Egger's (p = 0.113) tests. CONCLUSION Circulating miR-1246 shows promise as a non-invasive biomarker for early detection of GICs.
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Affiliation(s)
- Amir Hossein Aalami
- Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, UT, USA
- Division of Nephrology and Hypertension, Department of Internal Medicine, School of Medicine, University of Utah, Salt Lake City, UT, USA
| | - Ali Shahriari
- Department of Internal Medicine, Mashhad Medical Sciences Branch, Islamic Azad University, Mashhad, Iran
| | - Mohammad Mazaheri
- Department of Molecular, Cell and Systems Biology, College of Natural and Agricultural Sciences, University of California Riverside, Riverside, CA, USA
| | - Farnoosh Aalami
- Student Research Committee, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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7
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Della Bella E, Menzel U, Naros A, Kubosch EJ, Alini M, Stoddart MJ. Identification of circulating miRNAs as fracture-related biomarkers. PLoS One 2024; 19:e0303035. [PMID: 38820355 PMCID: PMC11142570 DOI: 10.1371/journal.pone.0303035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 04/16/2024] [Indexed: 06/02/2024] Open
Abstract
Fracture non-unions affect many patients worldwide, however, known risk factors alone do not predict individual risk. The identification of novel biomarkers is crucial for early diagnosis and timely patient treatment. This study focused on the identification of microRNA (miRNA) related to the process of fracture healing. Serum of fracture patients and healthy volunteers was screened by RNA sequencing to identify differentially expressed miRNA at various times after injury. The results were correlated to miRNA in the conditioned medium of human bone marrow mesenchymal stromal cells (BMSCs) during in vitro osteogenic differentiation. hsa-miR-1246, hsa-miR-335-5p, and miR-193a-5p were identified both in vitro and in fracture patients and their functional role in direct BMSC osteogenic differentiation was assessed. The results showed no influence of the downregulation of the three miRNAs during in vitro osteogenesis. However, miR-1246 may be involved in cell proliferation and recruitment of progenitor cells. Further studies should be performed to assess the role of these miRNA in other processes relevant to fracture healing.
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Affiliation(s)
| | - Ursula Menzel
- AO Research Institute Davos, Davos Platz, Switzerland
| | - Andreas Naros
- AO Research Institute Davos, Davos Platz, Switzerland
- Department of Oral and Maxillofacial Surgery, Tübingen University Hospital, Tübingen, Germany
| | - Eva Johanna Kubosch
- Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center-Albert-Ludwigs-University of Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
| | - Mauro Alini
- AO Research Institute Davos, Davos Platz, Switzerland
| | - Martin J. Stoddart
- AO Research Institute Davos, Davos Platz, Switzerland
- Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center-Albert-Ludwigs-University of Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
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8
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Ramadan F, Saab R, Ghamloush F, Khoueiry R, Herceg Z, Gomez L, Badran B, Clezardin P, Hussein N, Cohen PA, Ghayad SE. Exosome-Mediated Paracrine Signaling Unveils miR-1246 as a Driver of Aggressiveness in Fusion-Negative Rhabdomyosarcoma. Cancers (Basel) 2024; 16:1652. [PMID: 38730605 PMCID: PMC11083369 DOI: 10.3390/cancers16091652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 04/19/2024] [Accepted: 04/19/2024] [Indexed: 05/13/2024] Open
Abstract
Rhabdomyosarcoma is a pediatric cancer associated with aggressiveness and a tendency to develop metastases. Fusion-negative rhabdomyosarcoma (FN-RMS) is the most commonly occurring subtype of RMS, where metastatic disease can hinder treatment success and decrease survival rates. RMS-derived exosomes were previously demonstrated to be enriched with miRNAs, including miR-1246, possibly contributing to disease aggressiveness. We aimed to decipher the functional impact of exosomal miR-1246 on recipient cells and its role in promoting aggressiveness. Treatment of normal fibroblasts with FN-RMS-derived exosomes resulted in a significant uptake of miR-1246 paired with an increase in cell proliferation, migration, and invasion. In turn, delivery of miR-1246-mimic lipoplexes promoted fibroblast proliferation, migration, and invasion in a similar manner. Conversely, when silencing miR-1246 in FN-RMS cells, the resulting derived exosomes demonstrated reversed effects on recipient cells' phenotype. Delivery of exosomal miR-1246 targets GSK3β and promotes β-catenin nuclear accumulation, suggesting a deregulation of the Wnt pathway, known to be important in tumor progression. Finally, a pilot clinical study highlighted, for the first time, the presence of high exosomal miR-1246 levels in RMS patients' sera. Altogether, our results demonstrate that exosomal miR-1246 has the potential to alter the tumor microenvironment of FN-RMS cells, suggesting its potential role in promoting oncogenesis.
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Affiliation(s)
- Farah Ramadan
- Université Lyon 1, Lyon, France; (F.R.); (P.C.)
- INSERM, Research Unit UMR_S1033, LyOS, Faculty of Medicine Lyon-Est, 69372 Lyon, France
- Department of Biology, Faculty of Science II, Lebanese University, Beirut 6573, Lebanon
- Laboratory of Cancer Biology and Molecular Immunology, Department of Chemistry and Biochemistry, Faculty of Science I, Lebanese University, Hadath 1103, Lebanon; (B.B.); (N.H.)
| | - Raya Saab
- Department of Pediatrics & Adolescent Medicine, American University of Beirut Medical Center, Beirut 1107, Lebanon; (R.S.); (F.G.)
- Department of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon
- Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Farah Ghamloush
- Department of Pediatrics & Adolescent Medicine, American University of Beirut Medical Center, Beirut 1107, Lebanon; (R.S.); (F.G.)
| | - Rita Khoueiry
- Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, World Health Organization, 69366 Cedex 07 Lyon, France; (R.K.); (Z.H.)
| | - Zdenko Herceg
- Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, World Health Organization, 69366 Cedex 07 Lyon, France; (R.K.); (Z.H.)
| | - Ludovic Gomez
- Laboratoire CarMeN—IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon, 69500 Bron, France;
| | - Bassam Badran
- Laboratory of Cancer Biology and Molecular Immunology, Department of Chemistry and Biochemistry, Faculty of Science I, Lebanese University, Hadath 1103, Lebanon; (B.B.); (N.H.)
| | - Philippe Clezardin
- Université Lyon 1, Lyon, France; (F.R.); (P.C.)
- INSERM, Research Unit UMR_S1033, LyOS, Faculty of Medicine Lyon-Est, 69372 Lyon, France
| | - Nader Hussein
- Laboratory of Cancer Biology and Molecular Immunology, Department of Chemistry and Biochemistry, Faculty of Science I, Lebanese University, Hadath 1103, Lebanon; (B.B.); (N.H.)
- Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université Lyon 1, 69008 Lyon, France
| | - Pascale A. Cohen
- Université Lyon 1, Lyon, France; (F.R.); (P.C.)
- INSERM, Research Unit UMR_S1033, LyOS, Faculty of Medicine Lyon-Est, 69372 Lyon, France
| | - Sandra E. Ghayad
- Department of Biology, Faculty of Science II, Lebanese University, Beirut 6573, Lebanon
- C2VN, INSERM 1263, INRAE 1260, Aix-Marseille University, 13005 Marseille, France
- Department of Pharmaceutical Biology, Faculty of Pharmacy, Aix-Marseille University, 27 Boulevard Jean Moulin, 13005 Marseille, France
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9
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He B, Stoffel L, He CJ, Cho K, Li AM, Jiang H, Flowers BM, Nguyen KT, Wang KW, Zhao AY, Zhou MN, Ferreira S, Attardi LD, Ye J. Epigenetic priming targets tumor heterogeneity to shift transcriptomic phenotype of pancreatic ductal adenocarcinoma towards a Vitamin D susceptible state. Cell Death Dis 2024; 15:89. [PMID: 38272889 PMCID: PMC10810848 DOI: 10.1038/s41419-024-06460-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 12/18/2023] [Accepted: 01/09/2024] [Indexed: 01/27/2024]
Abstract
As a highly heterogeneous tumor, pancreatic ductal adenocarcinoma (PDAC) exhibits non-uniform responses to therapies across subtypes. Overcoming therapeutic resistance stemming from this heterogeneity remains a significant challenge. Here, we report that Vitamin D-resistant PDAC cells hijacked Vitamin D signaling to promote tumor progression, whereas epigenetic priming with glyceryl triacetate (GTA) and 5-Aza-2'-deoxycytidine (5-Aza) overcame Vitamin D resistance and shifted the transcriptomic phenotype of PDAC toward a Vitamin D-susceptible state. Increasing overall H3K27 acetylation with GTA and reducing overall DNA methylation with 5-Aza not only elevated the Vitamin D receptor (VDR) expression but also reprogrammed the Vitamin D-responsive genes. Consequently, Vitamin D inhibited cell viability and migration in the epigenetically primed PDAC cells by activating genes involved in apoptosis as well as genes involved in negative regulation of cell proliferation and migration, while the opposite effect of Vitamin D was observed in unprimed cells. Studies in genetically engineered mouse PDAC cells further validated the effects of epigenetic priming for enhancing the anti-tumor activity of Vitamin D. Using gain- and loss-of-function experiments, we further demonstrated that VDR expression was necessary but not sufficient for activating the favorable transcriptomic phenotype in respond to Vitamin D treatment in PDAC, highlighting that both the VDR and Vitamin D-responsive genes were prerequisites for Vitamin D response. These data reveal a previously undefined mechanism in which epigenetic state orchestrates the expression of both VDR and Vitamin D-responsive genes and determines the therapeutic response to Vitamin D in PDAC.
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Affiliation(s)
- Bo He
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Lauren Stoffel
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Clifford Jiajun He
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Kumsun Cho
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Albert M Li
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 94305, USA
- Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Haowen Jiang
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Brittany M Flowers
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Kha The Nguyen
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Kelly Wen Wang
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Audrey Yixin Zhao
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Meng-Ning Zhou
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Sofia Ferreira
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Laura D Attardi
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 94305, USA
- Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, 94305, USA
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Jiangbin Ye
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
- Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, 94305, USA.
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA.
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10
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Pal A, Ojha A, Ju J. Functional and Potential Therapeutic Implication of MicroRNAs in Pancreatic Cancer. Int J Mol Sci 2023; 24:17523. [PMID: 38139352 PMCID: PMC10744132 DOI: 10.3390/ijms242417523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 12/01/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
The alarmingly low five-year survival rate for pancreatic cancer presents a global health challenge, contributing to about 7% of all cancer-related deaths. Late-stage diagnosis and high heterogeneity are the biggest hurdles in treating pancreatic cancer. Thus, there is a pressing need to discover novel biomarkers that could help in early detection as well as improve therapeutic strategies. MicroRNAs (miRNAs), a class of short non-coding RNA, have emerged as promising candidates with regard to both diagnostics and therapeutics. Dysregulated miRNAs play pivotal roles in accelerating tumor growth and metastasis, orchestrating tumor microenvironment, and conferring chemoresistance in pancreatic cancer. The differential expression profiles of miRNAs in pancreatic cancer could be utilized to explore novel therapeutic strategies. In this review, we also covered studies on recent advancements in various miRNA-based therapeutics such as restoring miRNAs with a tumor-suppressive function, suppressing miRNA with an oncogenic function, and combination with chemotherapeutic drugs. Despite several challenges in terms of specificity and targeted delivery, miRNA-based therapies hold the potential to revolutionize the treatment of pancreatic cancer by simultaneously targeting multiple signaling pathways.
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Affiliation(s)
- Amartya Pal
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; (A.P.); (A.O.)
- Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11794, USA
| | - Anushka Ojha
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; (A.P.); (A.O.)
- Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11794, USA
| | - Jingfang Ju
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; (A.P.); (A.O.)
- The Northport Veteran’s Administration Medical Center, Northport, NY 11768, USA
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11
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Wei L, Sun J, Wang X, Huang Y, Huang L, Han L, Zheng Y, Xu Y, Zhang N, Yang M. Noncoding RNAs: an emerging modulator of drug resistance in pancreatic cancer. Front Cell Dev Biol 2023; 11:1226639. [PMID: 37560164 PMCID: PMC10407809 DOI: 10.3389/fcell.2023.1226639] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 07/17/2023] [Indexed: 08/11/2023] Open
Abstract
Pancreatic cancer is the eighth leading cause of cancer-related deaths worldwide. Chemotherapy including gemcitabine, 5-fluorouracil, adriamycin and cisplatin, immunotherapy with immune checkpoint inhibitors and targeted therapy have been demonstrated to significantly improve prognosis of pancreatic cancer patients with advanced diseases. However, most patients developed drug resistance to these therapeutic agents, which leading to shortened patient survival. The detailed molecular mechanisms contributing to pancreatic cancer drug resistance remain largely unclear. The growing evidences have shown that noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), are involved in pancreatic cancer pathogenesis and development of drug resistance. In the present review, we systematically summarized the new insight on of various miRNAs, lncRNAs and circRNAs on drug resistance of pancreatic cancer. These results demonstrated that targeting the tumor-specific ncRNA may provide novel options for pancreatic cancer treatments.
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Affiliation(s)
- Ling Wei
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Jujie Sun
- Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Xingwu Wang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yizhou Huang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Linying Huang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Linyu Han
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yanxiu Zheng
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yuan Xu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Nasha Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
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12
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Zhao Y, Qin C, Zhao B, Wang Y, Li Z, Li T, Yang X, Wang W. Pancreatic cancer stemness: dynamic status in malignant progression. J Exp Clin Cancer Res 2023; 42:122. [PMID: 37173787 PMCID: PMC10182699 DOI: 10.1186/s13046-023-02693-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 04/30/2023] [Indexed: 05/15/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most aggressive malignancies worldwide. Increasing evidence suggests that the capacity for self-renewal, proliferation, and differentiation of pancreatic cancer stem cells (PCSCs) contribute to major challenges with current PC therapies, causing metastasis and therapeutic resistance, leading to recurrence and death in patients. The concept that PCSCs are characterized by their high plasticity and self-renewal capacities is central to this review. We focused specifically on the regulation of PCSCs, such as stemness-related signaling pathways, stimuli in tumor cells and the tumor microenvironment (TME), as well as the development of innovative stemness-targeted therapies. Understanding the biological behavior of PCSCs with plasticity and the molecular mechanisms regulating PC stemness will help to identify new treatment strategies to treat this horrible disease.
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Affiliation(s)
- Yutong Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Cheng Qin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Bangbo Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Yuanyang Wang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Zeru Li
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Tianyu Li
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Xiaoying Yang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Weibin Wang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China.
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China.
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China.
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13
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microRNAs Associated with Gemcitabine Resistance via EMT, TME, and Drug Metabolism in Pancreatic Cancer. Cancers (Basel) 2023; 15:cancers15041230. [PMID: 36831572 PMCID: PMC9953943 DOI: 10.3390/cancers15041230] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/13/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
Despite extensive research, pancreatic cancer remains a lethal disease with an extremely poor prognosis. The difficulty in early detection and chemoresistance to therapeutic agents are major clinical concerns. To improve prognosis, novel biomarkers, and therapeutic strategies for chemoresistance are urgently needed. microRNAs (miRNAs) play important roles in the development, progression, and metastasis of several cancers. During the last few decades, the association between pancreatic cancer and miRNAs has been extensively elucidated, with several miRNAs found to be correlated with patient prognosis. Moreover, recent evidence has revealed that miRNAs are intimately involved in gemcitabine sensitivity and resistance through epithelial-to-mesenchymal transition, the tumor microenvironment, and drug metabolism. Gemcitabine is the gold standard drug for pancreatic cancer treatment, but gemcitabine resistance develops easily after chemotherapy initiation. Therefore, in this review, we summarize the gemcitabine resistance mechanisms associated with aberrantly expressed miRNAs in pancreatic cancer, especially focusing on the mechanisms associated with epithelial-to-mesenchymal transition, the tumor microenvironment, and metabolism. This novel evidence of gemcitabine resistance will drive further research to elucidate the mechanisms of chemoresistance and improve patient outcomes.
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14
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Rezaee M, Mohammadi F, Keshavarzmotamed A, Yahyazadeh S, Vakili O, Milasi YE, Veisi V, Dehmordi RM, Asadi S, Ghorbanhosseini SS, Rostami M, Alimohammadi M, Azadi A, Moussavi N, Asemi Z, Aminianfar A, Mirzaei H, Mafi A. The landscape of exosomal non-coding RNAs in breast cancer drug resistance, focusing on underlying molecular mechanisms. Front Pharmacol 2023; 14:1152672. [PMID: 37153758 PMCID: PMC10154547 DOI: 10.3389/fphar.2023.1152672] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Accepted: 03/29/2023] [Indexed: 05/10/2023] Open
Abstract
Breast cancer (BC) is the most common malignancy among women worldwide. Like many other cancers, BC therapy is challenging and sometimes frustrating. In spite of the various therapeutic modalities applied to treat the cancer, drug resistance, also known as, chemoresistance, is very common in almost all BCs. Undesirably, a breast tumor might be resistant to different curative approaches (e.g., chemo- and immunotherapy) at the same period of time. Exosomes, as double membrane-bound extracellular vesicles 1) secreted from different cell species, can considerably transfer cell products and components through the bloodstream. In this context, non-coding RNAs (ncRNAs), including miRNAs, long ncRNAs (lncRNAs), and circular RNAs (circRNAs), are a chief group of exosomal constituents with amazing abilities to regulate the underlying pathogenic mechanisms of BC, such as cell proliferation, angiogenesis, invasion, metastasis, migration, and particularly drug resistance. Thereby, exosomal ncRNAs can be considered potential mediators of BC progression and drug resistance. Moreover, as the corresponding exosomal ncRNAs circulate in the bloodstream and are found in different body fluids, they can serve as foremost prognostic/diagnostic biomarkers. The current study aims to comprehensively review the most recent findings on BC-related molecular mechanisms and signaling pathways affected by exosomal miRNAs, lncRNAs, and circRNAs, with a focus on drug resistance. Also, the potential of the same exosomal ncRNAs in the diagnosis and prognosis of BC will be discussed in detail.
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Affiliation(s)
- Malihe Rezaee
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Mohammadi
- Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | | | - Sheida Yahyazadeh
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Omid Vakili
- Autophagy Research Center, Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Yaser Eshaghi Milasi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Vida Veisi
- School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Rohollah Mousavi Dehmordi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
- Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Sepideh Asadi
- Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran
| | - Seyedeh Sara Ghorbanhosseini
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mehdi Rostami
- Department of Clinical Biochemistry, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mina Alimohammadi
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- *Correspondence: Mina Alimohammadi, ; Abbas Azadi, ; Hamed Mirzaei, ; Alireza Mafi,
| | - Abbas Azadi
- Department of Internal Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
- *Correspondence: Mina Alimohammadi, ; Abbas Azadi, ; Hamed Mirzaei, ; Alireza Mafi,
| | - Nushin Moussavi
- Department of Surgery, Kashan University of Medical Sciences, Kashan, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Azadeh Aminianfar
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
- *Correspondence: Mina Alimohammadi, ; Abbas Azadi, ; Hamed Mirzaei, ; Alireza Mafi,
| | - Alireza Mafi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
- *Correspondence: Mina Alimohammadi, ; Abbas Azadi, ; Hamed Mirzaei, ; Alireza Mafi,
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15
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Kalemaj Z, Marino MM, Santini AC, Tomaselli G, Auti A, Cagetti MG, Borsello T, Costantino A, Inchingolo F, Boccellino M, Di Domenico M, Tartaglia GM. Salivary microRNA profiling dysregulation in autism spectrum disorder: A pilot study. Front Neurosci 2022; 16:945278. [PMID: 36340774 PMCID: PMC9629840 DOI: 10.3389/fnins.2022.945278] [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: 05/16/2022] [Accepted: 09/23/2022] [Indexed: 01/10/2024] Open
Abstract
INTRODUCTION Autism spectrum disorders (ASD) are the most prevalent neurobiological disorders in children. The etiology comprises genetic, epigenetic, and environmental factors such as dysfunction of the immune system. Epigenetic mechanisms are mainly represented by DNA methylation, histone modifications, and microRNAs (miRNA). The major explored epigenetic mechanism is mediated by miRNAs which target genes known to be involved in ASD pathogenesis. Salivary poly-omic RNA measurements have been associated with ASD and are helpful to differentiate ASD endophenotypes. This study aims to comprehensively examine miRNA expression in children with ASD and to reveal potential biomarkers and possible disease mechanisms so that they can be used to improve faction between individuals by promoting more personalized therapeutic approaches. MATERIALS AND METHODS Saliva samples were collected from 10 subjects: 5 samples of children with ASD and 5 from healthy controls. miRNAs were analyzed using an Illumina Next-Generation-Sequencing (NGS) system. RESULTS Preliminary data highlighted the presence of 365 differentially expressed miRNAs. Pathway analysis, molecular function, biological processes, and target genes of 41 dysregulated miRNAs were assessed, of which 20 were upregulated, and 21 were downregulated in children with ASD compared to healthy controls. CONCLUSION The results of this study represent preliminary but promising data, as the identified miRNA pathways could represent useful biomarkers for the early non-invasive diagnosis of ASD.
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Affiliation(s)
- Zamira Kalemaj
- UOC Maxillo-Facial Surgery and Dentistry, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Maria Michela Marino
- Department of Precision Medicine, Università della Campania “Luigi Vanvitelli”, Naples, Italy
| | | | - Giovanni Tomaselli
- Pharmacological Research Institute Mario Negri-IRCCS, Milan, Italy
- Department of Pharmacological and Biomolecular Sciences, Università di Milano, Milan, Italy
| | - Amogh Auti
- Department of Precision Medicine, Università della Campania “Luigi Vanvitelli”, Naples, Italy
| | - Maria Grazia Cagetti
- Department of Biomedical, Surgical and Dental Science, Università di Milano, Milan, Italy
| | - Tiziana Borsello
- Pharmacological Research Institute Mario Negri-IRCCS, Milan, Italy
- Department of Pharmacological and Biomolecular Sciences, Università di Milano, Milan, Italy
| | - Antonella Costantino
- Child and Adolescent Neuropsychiatric Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Francesco Inchingolo
- Section of Dental Medicine, Department of Interdisciplinary Medicine, Università di Bari “Aldo Moro”, Bari, Italy
| | - Mariarosaria Boccellino
- Department of Precision Medicine, Università della Campania “Luigi Vanvitelli”, Naples, Italy
| | - Marina Di Domenico
- Department of Precision Medicine, Università della Campania “Luigi Vanvitelli”, Naples, Italy
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, United States
| | - Gianluca Martino Tartaglia
- UOC Maxillo-Facial Surgery and Dentistry, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy
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16
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Parayath NN, Gandham SK, Amiji MM. Tumor-targeted miRNA nanomedicine for overcoming challenges in immunity and therapeutic resistance. Nanomedicine (Lond) 2022; 17:1355-1373. [PMID: 36255330 PMCID: PMC9706370 DOI: 10.2217/nnm-2022-0130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
miRNA are critical messengers in the tumor microenvironment (TME) that influence various processes leading to immune suppression, tumor progression, metastasis and resistance. Strategies to modulate miRNAs in the TME have important implications in overcoming these challenges. However, miR delivery to specific cells in the TME has been challenging. This review discusses nanomedicine strategies to achieve cell-specific delivery of miRNAs. The key goal of delivery is to activate the tumor immune landscape as well as to prevent chemotherapy resistance. Specifically, the use of hyaluronic acid-based nanoparticle miRNA delivery to the TME is discussed. The discussion is focused on miRNA-125b for reprogramming tumor-associated macrophages to overcome immunosuppression and miRNA-let-7b to overcome resistance to anticancer chemotherapeutics because both these miRNAs have been extensively evaluated for delivery with hyaluronic acid-based delivery systems.
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Affiliation(s)
- Neha N Parayath
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA
| | - Srujan K Gandham
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA
| | - Mansoor M Amiji
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA,Department of Chemical Engineering, College of Engineering, Northeastern University, Boston, MA 02115, USA,Author for correspondence: Tel.: +1 617 373 3137;
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17
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Rahnama N, Jahangir M, Alesaeid S, Kahrizi MS, Adili A, Mohammed RN, Aslaminabad R, Akbari M, Özgönül AM. Association between microRNAs and chemoresistance in pancreatic cancer: Current knowledge, new insights, and forthcoming perspectives. Pathol Res Pract 2022; 236:153982. [PMID: 35779293 DOI: 10.1016/j.prp.2022.153982] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 05/27/2022] [Accepted: 06/11/2022] [Indexed: 11/25/2022]
Abstract
Pancreatic duct adenocarcinoma, commonly known as pancreatic cancer (PC), is a cancer-related cause of death due to delayed diagnosis, metastasis, and drug resistance. Patients with PC suffer from incorrect responses to chemotherapy due to inherent and acquired chemical resistance. Numerous studies have shown the mechanism of the effect of chemoresistance on PC, such as genetic and epigenetic changes or the elucidation of signaling pathways. In this regard, microRNAs (miRNAs) have been identified as essential modulators of gene expression in various cellular functions, including chemoresistance. Thus, identifying the underlying link between microRNAs and PC chemoresistance helps determine the exact pathogenesis of PC. This study aims to classify miRNAs and signaling pathways related to PC chemoresistance, suggesting new therapeutic approaches to overcome PC chemoresistance.
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Affiliation(s)
- Negin Rahnama
- Department of Internal Medicine and Health Services, Semnan University of Medical Sciences, Semnan, Iran
| | | | - Samira Alesaeid
- Department of Internal Medicine and Rheumatology, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Ali Adili
- Senior Adult Oncology Department, Moffitt Cancer Center, University of South Florida, FL, USA; Department of Oncology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rebar N Mohammed
- Medical Laboratory Analysis Department, College of Health Sciences, Cihan University of Sulaimaniya, Kurdistan Region, Iraq; College of Veterinary Medicine, University of Sulaimani, Sulaimaniyah, Iraq
| | - Ramin Aslaminabad
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Ali Mert Özgönül
- Department of Biochemistry, Faculty of Medicine, Ege University, Bornova, Izmir, Turkey.
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18
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Levati L, Bassi C, Mastroeni S, Lupini L, Antonini Cappellini GC, Bonmassar L, Alvino E, Caporali S, Lacal PM, Narducci MG, Molineris I, De Galitiis F, Negrini M, Russo G, D’Atri S. Circulating miR-1246 and miR-485-3p as Promising Biomarkers of Clinical Response and Outcome in Melanoma Patients Treated with Targeted Therapy. Cancers (Basel) 2022; 14:cancers14153706. [PMID: 35954369 PMCID: PMC9367338 DOI: 10.3390/cancers14153706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 07/16/2022] [Accepted: 07/24/2022] [Indexed: 01/27/2023] Open
Abstract
Despite the significant improvements in advanced melanoma therapy, there is still a pressing need for biomarkers that can predict patient response and prognosis, and therefore support rational treatment decisions. Here, we investigated whether circulating miRNAs could be biomarkers of clinical outcomes in patients treated with targeted therapy. Using next-generation sequencing, we profiled plasma miRNAs at baseline and at progression in patients treated with BRAF inhibitors (BRAFi) or BRAFi + MEKi. Selected miRNAs associated with response to therapy were subjected to validation by real-time quantitative RT-PCR . Receiver Operating Characteristics (ROC), Kaplan–Meier and univariate and multivariate Cox regression analyses were performed on the validated miR-1246 and miR-485-3p baseline levels. The median baseline levels of miR-1246 and miR-485-3p were significantly higher and lower, respectively, in the group of patients not responding to therapy (NRs) as compared with the group of responding patients (Rs). In Rs, a trend toward an increase in miR-1246 and a decrease in miR-485-3p was observed at progression. Baseline miR-1246 level and the miR-1246/miR-485-3p ratio showed a good ability to discriminate between Rs and NRs. Poorer PFS and OS were observed in patients with unfavorable levels of at least one miRNA. In multivariate analysis, a low level of miR-485-3p and a high miR-1246/miR-485-3p ratio remained independent negative prognostic factors for PFS, while a high miR-1246/miR-485-3p ratio was associated with an increased risk of mortality, although statistical significance was not reached. Evaluation of miR-1246 and miR-485-3p baseline plasma levels might help clinicians to identify melanoma patients most likely to be unresponsive to targeted therapy or at higher risk for short-term PFS and mortality, thus improving their management.
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Affiliation(s)
- Lauretta Levati
- Laboratory of Molecular Oncology, IDI-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy; (L.L.); (L.B.); (S.C.); (P.M.L.); (M.G.N.); (G.R.)
| | - Cristian Bassi
- Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 70, 44121 Ferrara, Italy; (C.B.); (L.L.); (M.N.)
- LTTA Center, University of Ferrara, Via Fossato di Mortara 70, 44121 Ferrara, Italy
| | - Simona Mastroeni
- Clinical Epidemiology Unit, IDI-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy;
| | - Laura Lupini
- Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 70, 44121 Ferrara, Italy; (C.B.); (L.L.); (M.N.)
| | - Gian Carlo Antonini Cappellini
- Department of Oncology and Dermatological Oncology, IDI-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy; (G.C.A.C.); (F.D.G.)
| | - Laura Bonmassar
- Laboratory of Molecular Oncology, IDI-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy; (L.L.); (L.B.); (S.C.); (P.M.L.); (M.G.N.); (G.R.)
| | - Ester Alvino
- Institute of Translational Pharmacology, National Council of Research, Via Fosso del Cavaliere 100, 00133 Rome, Italy;
| | - Simona Caporali
- Laboratory of Molecular Oncology, IDI-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy; (L.L.); (L.B.); (S.C.); (P.M.L.); (M.G.N.); (G.R.)
| | - Pedro Miguel Lacal
- Laboratory of Molecular Oncology, IDI-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy; (L.L.); (L.B.); (S.C.); (P.M.L.); (M.G.N.); (G.R.)
| | - Maria Grazia Narducci
- Laboratory of Molecular Oncology, IDI-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy; (L.L.); (L.B.); (S.C.); (P.M.L.); (M.G.N.); (G.R.)
| | - Ivan Molineris
- Department of Life Science and System Biology, University of Turin, Via Accademia Albertina 13, 10123 Turin, Italy;
| | - Federica De Galitiis
- Department of Oncology and Dermatological Oncology, IDI-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy; (G.C.A.C.); (F.D.G.)
| | - Massimo Negrini
- Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 70, 44121 Ferrara, Italy; (C.B.); (L.L.); (M.N.)
- LTTA Center, University of Ferrara, Via Fossato di Mortara 70, 44121 Ferrara, Italy
| | - Giandomenico Russo
- Laboratory of Molecular Oncology, IDI-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy; (L.L.); (L.B.); (S.C.); (P.M.L.); (M.G.N.); (G.R.)
| | - Stefania D’Atri
- Laboratory of Molecular Oncology, IDI-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy; (L.L.); (L.B.); (S.C.); (P.M.L.); (M.G.N.); (G.R.)
- Correspondence:
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Bakhsh T, Alhazmi S, Alburae NA, Farsi A, Alzahrani F, Choudhry H, Bahieldin A. Exosomal miRNAs as a Promising Source of Biomarkers in Colorectal Cancer Progression. Int J Mol Sci 2022; 23:ijms23094855. [PMID: 35563246 PMCID: PMC9103063 DOI: 10.3390/ijms23094855] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/24/2022] [Accepted: 04/26/2022] [Indexed: 01/27/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common type of cancer worldwide amongst males and females. CRC treatment is multidisciplinary, often including surgery, chemotherapy, and radiotherapy. Early diagnosis of CRC can lead to treatment initiation at an earlier stage. Blood biomarkers are currently used to detect CRC, but because of their low sensitivity and specificity, they are considered inadequate diagnostic tools and are used mainly for following up patients for recurrence. It is necessary to detect novel, noninvasive, specific, and sensitive biomarkers for the screening and diagnosis of CRC at earlier stages. The tumor microenvironment (TME) has an essential role in tumorigenesis; for example, extracellular vesicles (EVs) such as exosomes can play a crucial role in communication between cancer cells and different components of TME, thereby inducing tumor progression. The importance of miRNAs that are sorted into exosomes has recently attracted scientists’ attention. Some unique sequences of miRNAs are favorably packaged into exosomes, and it has been illustrated that particular miRNAs can be directed into exosomes by special mechanisms that occur inside the cells. This review illustrates and discusses the sorted and transported exosomal miRNAs in the CRC microenvironment and their impact on CRC progression as well as their potential use as biomarkers.
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Affiliation(s)
- Tahani Bakhsh
- Department of Biology, Faculty of Science, Jeddah University, Jeddah 21589, Saudi Arabia
- Correspondence:
| | - Safiah Alhazmi
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (S.A.); (N.A.A.); (A.B.)
| | - Najla Ali Alburae
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (S.A.); (N.A.A.); (A.B.)
| | - Ali Farsi
- Department of Surgry, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Faisal Alzahrani
- King Fahd Medical Research Center, Embryonic Stem Cells Unit, Department of Biochemistry, Faculty of Science, King AbdulAziz University, Jeddah 21589, Saudi Arabia;
- Centre of Artificial Intelligence in Precision Medicines, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Hani Choudhry
- Centre of Artificial Intelligence in Precision Medicines, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
- Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Ahmed Bahieldin
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (S.A.); (N.A.A.); (A.B.)
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microRNA-21 Regulates Stemness in Pancreatic Ductal Adenocarcinoma Cells. Int J Mol Sci 2022; 23:ijms23031275. [PMID: 35163198 PMCID: PMC8835847 DOI: 10.3390/ijms23031275] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/13/2022] [Accepted: 01/21/2022] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer (PCa) with a low survival rate. microRNAs (miRs) are endogenous, non-coding RNAs that moderate numerous biological processes. miRs have been associated with the chemoresistance and metastasis of PDAC and the presence of a subpopulation of highly plastic "stem"-like cells within the tumor, known as cancer stem cells (CSCs). In this study, we investigated the role of miR-21, which is highly expressed in Panc-1 and MiaPaCa-2 PDAC cells in association with CSCs. Following miR-21 knockouts (KO) from both MiaPaCa-2 and Panc-1 cell lines, reversed expressions of epithelial-mesenchymal transition (EMT) and CSCs markers were observed. The expression patterns of key CSC markers, including CD44, CD133, CX-C chemokine receptor type 4 (CXCR4), and aldehyde dehydrogenase-1 (ALDH1), were changed depending on miR-21 status. miR-21 (KO) suppressed cellular invasion of Panc-1 and MiaPaCa-2 cells, as well as the cellular proliferation of MiaPaCa-2 cells. Our data suggest that miR-21 is involved in the stemness of PDAC cells, may play roles in mesenchymal transition, and that miR-21 poses as a novel, functional biomarker for PDAC aggressiveness.
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21
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Ghafouri-Fard S, Khoshbakht T, Hussen BM, Taheri M, Samadian M. A Review on the Role of miR-1246 in the Pathoetiology of Different Cancers. Front Mol Biosci 2022; 8:771835. [PMID: 35047553 PMCID: PMC8762223 DOI: 10.3389/fmolb.2021.771835] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 11/22/2021] [Indexed: 01/22/2023] Open
Abstract
miR-1246 is a microRNA firstly recognized through application of a high throughput sequencing technique in human embryonic stem cells. Subsequent studies have shown the role of this microRNA in the carcinogenesis. miR-1246 has been found to exert oncogenic roles in colorectal, breast, renal, oral, laryngeal, pancreatic and ovarian cancers as well as melanoma and glioma. In lung, cervical and liver cancers, studies have reported contradictory results regarding the role of miR-1246. miR-1246 has been reported to regulate activity of RAF/MEK/ERK, GSK3β, Wnt/β-catenin, JAK/STAT, PI3K/AKT, THBS2/MMP and NOTCH2 pathways. In addition to affecting cell cycle progression and proliferation, miR-1246 can influence stemness and resistance of cancer cells to therapeutics. In the current review, we describe the summary of in vitro and in vivo studies about the influence of miR-1246 in carcinogenesis in addition to studies that measured expression levels of miR-1246 in clinical samples.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tayyebeh Khoshbakht
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq.,Center of Research and Strategic Studies, Lebanese French University, Erbil, Iraq
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
| | - Mohammad Samadian
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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22
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Wu L, Zuo N, Pan S, Wang Y, Wang Q, Ma J. miR-1246 promotes laryngeal squamous cell carcinoma progression by interacting with THBS1. J Environ Pathol Toxicol Oncol 2022; 41:65-75. [DOI: 10.1615/jenvironpatholtoxicoloncol.2022040516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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23
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Xia T, Chen XY, Zhang YN. MicroRNAs as biomarkers and perspectives in the therapy of pancreatic cancer. Mol Cell Biochem 2021; 476:4191-4203. [PMID: 34324119 DOI: 10.1007/s11010-021-04233-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 07/20/2021] [Indexed: 12/12/2022]
Abstract
Pancreatic cancer is considered as one of the most aggressive tumor types, representing over 45,750 mortality cases annually in the USA solely. The aggressive nature and late identification of pancreatic cancer, combined with the restrictions of existing chemotherapeutics, present the mandatory need for the advancement of novel treatment systems. Ongoing reports have shown an important role of microRNAs (miRNAs) in the initiation, migration, and metastasis of malignancies. Besides, abnormal transcriptional levels of miRNAs have regularly been related with etiopathogenesis of pancreatic malignancy, underlining the conceivable utilization of miRNAs in the management of pancreatic disease patients. In this review article, we give a concise outline of molecular pathways involved in etiopathogenesis of pancreatic cancer patients as well as miRNA implications in pancreatic cancer patients. Ensuing sections describe the involvement of miRNAs in the diagnosis, prognosis, and therapy of pancreatic cancer patients. The involvement of miRNAs in the chemoresistance of pancreatic cancers was also discussed. End area portrays the substance of survey with future headings.
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Affiliation(s)
- Tao Xia
- Department of Gastrointestinal-Pancreatic Surgery, General Surgery, Zhejiang Provincial People's Hospital, Affiliated Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang Province, People's Republic of China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang Province, People's Republic of China
| | - Xiao-Yi Chen
- Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated Hospital of Hangzhou Medical College, No. 158 Shangtang Road, Hangzhou, 310014, Zhejiang Province, People's Republic of China.
| | - You-Ni Zhang
- Department of Laboratory Medicine, Tiantai People's Hospital of Zhejiang Province (Tiantai Branch of Zhejiang People's Hospital), Kangning Middle Road, Shifeng Street, Tiantai County, Taizhou, 317200, Zhejiang Province, People's Republic of China.
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24
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Wei W, Wang L, Xu L, Liang J, Teng L. MiR-199 Reverses the Resistance to Gemcitabine in Pancreatic Cancer by Suppressing Stemness through Regulating the Epithelial-Mesenchymal Transition. ACS OMEGA 2021; 6:31435-31446. [PMID: 34869970 PMCID: PMC8637594 DOI: 10.1021/acsomega.1c02945] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 08/04/2021] [Indexed: 06/13/2023]
Abstract
PURPOSE the present study aims to investigate the function of miR-199 on gemcitabine (GEM)-resistance in pancreatic cancer, as well as the underlying mechanism. METHODS the GEM-resistant SW1990 cell line (SW1990/SZ) was established. The CCK-8 assay was used to detect the cell viability. The self-renewal of SW1990/SZ cells was evaluated by sphere formation and the colony formation assay. The apoptosis was detected by flow cytometry and the migration ability was measured by the transwell assay. The dual-luciferase gene reporter assay was utilized to confirm the binding between miR-199 and Snail. The expression level of CD44, ALDH1, Nanog, E-cadherin, Vimentin, β-catenin, and Snail was determined by the Western blotting assay. RESULTS the cell sphere formation rate, number of spheres, and expression level of CD44, ALDH1, and Nanog in GEM-treated SW1990/SZ cells were significantly suppressed by miR-199, accompanied by declined proliferation ability, an increased apoptotic rate, inhibited migration ability, and suppressed EMT progression. The binding site between miR-199 and 3'-UTR of Snail was predicted and confirmed. The inhibitory effect of miR-199 on self-renewal of SW1990/GZ cells and the faciliating property of miR-199 on the inhibitory effect of GEM against the proliferation ability, migration ability, and EMT progression were abolished by overexpressing Snail. CONCLUSION MiR-199 reversed the resistance to GEM in pancreatic cancer by suppressing stemness through regulating the EMT.
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Affiliation(s)
- Weitian Wei
- Department
of Surgical Oncology, Zhejiang University
School of Medicine First Affiliated Hospital, No. 79 Qingchun Road, Shangcheng District, Hangzhou 310009, China
- Department
of Surgical Oncology, Zhejiang Cancer Hospital, No. 1, East Banshan Road, Gongshu District, Hangzhou 310022, China
| | - Liang Wang
- Department
of Surgical Oncology, Zhejiang Cancer Hospital, No. 1, East Banshan Road, Gongshu District, Hangzhou 310022, China
| | - Liwei Xu
- Department
of Surgical Oncology, Zhejiang Cancer Hospital, No. 1, East Banshan Road, Gongshu District, Hangzhou 310022, China
| | - Jinxiao Liang
- Department
of Surgical Oncology, Zhejiang Cancer Hospital, No. 1, East Banshan Road, Gongshu District, Hangzhou 310022, China
| | - Lisong Teng
- Department
of Surgical Oncology, Zhejiang University
School of Medicine First Affiliated Hospital, No. 79 Qingchun Road, Shangcheng District, Hangzhou 310009, China
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25
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Gastrointestinal cancer drug resistance: the role of exosomal miRNAs. Mol Biol Rep 2021; 49:2421-2432. [PMID: 34850336 DOI: 10.1007/s11033-021-07007-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 11/23/2021] [Indexed: 12/19/2022]
Abstract
Resistance of gastrointestinal (GI) cancer cells to therapeutic agents are one of the major problems in treating this type of cancer. Although the exact mechanism of drug resistance has not yet been fully elucidated, various factors have been identified as contributing factors involved in this process. Several studies have revealed the role of exosomes, especially exosomal microRNAs (miRNAs), in GI tumorigenesis, invasion, angiogenesis, and drug resistance. Exosomes, a type of small extracellular vesicles (EVs), are originated from endosomes and are released into the extracellular environment and body fluids by different cell types. Exosomes mediate cell-cell communication by transferring different cargos, including miRNAs, between parent and recipient cells. Therefore, identifying these exosomal miRNAs and their functions in GI cancers might provide new clues to further explore the secret of this process and thus help in drug-resistance management. This review article will discuss the roles of exosomal miRNAs and their mechanisms of action in drug resistance of different types of GI cancer cells (e.g., stomach, esophagus, liver, pancreas, and colon) to therapeutic agents.
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26
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Bi X, Lv X, Liu D, Guo H, Yao G, Wang L, Liang X, Yang Y. METTL3 promotes the initiation and metastasis of ovarian cancer by inhibiting CCNG2 expression via promoting the maturation of pri-microRNA-1246. Cell Death Discov 2021; 7:237. [PMID: 34497267 PMCID: PMC8426370 DOI: 10.1038/s41420-021-00600-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 06/22/2021] [Accepted: 07/06/2021] [Indexed: 12/13/2022] Open
Abstract
Ovarian cancer is a common gynecological malignant tumor with a high mortality rate and poor prognosis. There is inadequate knowledge of the molecular mechanisms underlying ovarian cancer. We examined the expression of methyltransferase-like 3 (METTL3) in tumor specimens using RT-qPCR, immunohistochemistry, and Western blot analysis, and tested the methylation of METTL3 by MSP. Levels of METTL3, miR-1246, pri-miR-1246 and CCNG2 were then analyzed and their effects on cell biological processes were also investigated, using in vivo assay to validate the in vitro findings. METTL3 showed hypomethylation and high expression in ovarian cancer tissues and cells. Hypomethylation of METTL3 was pronounced in ovarian cancer samples, which was negatively associated with patient survival. Decreased METTL3 inhibited the proliferation and migration of ovarian cancer cells and promoted apoptosis, while METTL3 overexpression exerted opposite effects. Mechanistically, METTL3 aggravated ovarian cancer by targeting miR-1246, while miR-1246 targeted and inhibited CCNG2 expression. High expression of METTL3 downregulated CCNG2, promoted the metabolism and growth of transplanted tumors in nude mice, and inhibited apoptosis. The current study highlights the promoting role of METTL3 in the development of ovarian cancer, and presents new targets for its treatment.
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Affiliation(s)
- Xuehan Bi
- Department of Obstetrics and Gynecology, The First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China
- Department of Obstetrics and Gynecology, The First Hospital of Lanzhou University, Key Laboratory of Gynecologic Oncology Gansu Province, Lanzhou, 730000, People's Republic of China
| | - Xiao Lv
- Department of Obstetrics and Gynecology, The First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China
- Department of Obstetrics and Gynecology, The First Hospital of Lanzhou University, Key Laboratory of Gynecologic Oncology Gansu Province, Lanzhou, 730000, People's Republic of China
| | - Dajiang Liu
- Department of Obstetrics and Gynecology, The First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China
- Department of Obstetrics and Gynecology, The First Hospital of Lanzhou University, Key Laboratory of Gynecologic Oncology Gansu Province, Lanzhou, 730000, People's Republic of China
| | - Hongtao Guo
- Department of Obstetrics and Gynecology, The First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China
- Department of Obstetrics and Gynecology, The First Hospital of Lanzhou University, Key Laboratory of Gynecologic Oncology Gansu Province, Lanzhou, 730000, People's Republic of China
| | - Guang Yao
- Department of Obstetrics and Gynecology, The First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China
- Department of Obstetrics and Gynecology, The First Hospital of Lanzhou University, Key Laboratory of Gynecologic Oncology Gansu Province, Lanzhou, 730000, People's Republic of China
| | - Lijuan Wang
- Department of Obstetrics and Gynecology, The First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China
- Department of Obstetrics and Gynecology, The First Hospital of Lanzhou University, Key Laboratory of Gynecologic Oncology Gansu Province, Lanzhou, 730000, People's Republic of China
| | - Xiaolei Liang
- Department of Obstetrics and Gynecology, The First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China
- Department of Obstetrics and Gynecology, The First Hospital of Lanzhou University, Key Laboratory of Gynecologic Oncology Gansu Province, Lanzhou, 730000, People's Republic of China
| | - Yongxiu Yang
- Department of Obstetrics and Gynecology, The First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China.
- Department of Obstetrics and Gynecology, The First Hospital of Lanzhou University, Key Laboratory of Gynecologic Oncology Gansu Province, Lanzhou, 730000, People's Republic of China.
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27
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Patil K, Khan FB, Akhtar S, Ahmad A, Uddin S. The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance. Cancer Metastasis Rev 2021; 40:691-720. [PMID: 34453639 PMCID: PMC8556195 DOI: 10.1007/s10555-021-09979-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 07/12/2021] [Indexed: 02/07/2023]
Abstract
The ever-growing perception of cancer stem cells (CSCs) as a plastic state rather than a hardwired defined entity has evolved our understanding of the functional and biological plasticity of these elusive components in malignancies. Pancreatic cancer (PC), based on its biological features and clinical evolution, is a prototypical example of a CSC-driven disease. Since the discovery of pancreatic CSCs (PCSCs) in 2007, evidence has unraveled their control over many facets of the natural history of PC, including primary tumor growth, metastatic progression, disease recurrence, and acquired drug resistance. Consequently, the current near-ubiquitous treatment regimens for PC using aggressive cytotoxic agents, aimed at ‘‘tumor debulking’’ rather than eradication of CSCs, have proven ineffective in providing clinically convincing improvements in patients with this dreadful disease. Herein, we review the key hallmarks as well as the intrinsic and extrinsic resistance mechanisms of CSCs that mediate treatment failure in PC and enlist the potential CSC-targeting ‘natural agents’ that are gaining popularity in recent years. A better understanding of the molecular and functional landscape of PCSC-intrinsic evasion of chemotherapeutic drugs offers a facile opportunity for treating PC, an intractable cancer with a grim prognosis and in dire need of effective therapeutic advances.
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Affiliation(s)
- Kalyani Patil
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Farheen B Khan
- Department of Biology, College of Science, The United Arab Emirates University, PO Box 15551, Al Ain, United Arab Emirates
| | - Sabah Akhtar
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Aamir Ahmad
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.,Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar. .,Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar. .,Laboratory Animal Research Center, Qatar University, Doha, Qatar.
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Pedroza DA, Ramirez M, Rajamanickam V, Subramani R, Margolis V, Gurbuz T, Estrada A, Lakshmanaswamy R. miRNome and Functional Network Analysis of PGRMC1 Regulated miRNA Target Genes Identify Pathways and Biological Functions Associated With Triple Negative Breast Cancer. Front Oncol 2021; 11:710337. [PMID: 34350123 PMCID: PMC8327780 DOI: 10.3389/fonc.2021.710337] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 06/24/2021] [Indexed: 12/14/2022] Open
Abstract
Background Increased expression of the progesterone receptor membrane component 1, a heme and progesterone binding protein, is frequently found in triple negative breast cancer tissue. The basis for the expression of PGRMC1 and its regulation on cellular signaling mechanisms remain largely unknown. Therefore, we aim to study microRNAs that target selective genes and mechanisms that are regulated by PGRMC1 in TNBCs. Methods To identify altered miRNAs, whole human miRNome profiling was performed following AG-205 treatment and PGRMC1 silencing. Network analysis identified miRNA target genes while KEGG, REACTOME and Gene ontology were used to explore altered signaling pathways, biological processes, and molecular functions. Results KEGG term pathway analysis revealed that upregulated miRNAs target specific genes that are involved in signaling pathways that play a major role in carcinogenesis. While multiple downregulated miRNAs are known oncogenes and have been previously demonstrated to be overexpressed in a variety of cancers. Overlapping miRNA target genes associated with KEGG term pathways were identified and overexpression/amplification of these genes was observed in invasive breast carcinoma tissue from TCGA. Further, the top two genes (CCND1 and YWHAZ) which are highly genetically altered are also associated with poorer overall survival. Conclusions Thus, our data demonstrates that therapeutic targeting of PGRMC1 in aggressive breast cancers leads to the activation of miRNAs that target overexpressed genes and deactivation of miRNAs that have oncogenic potential.
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Affiliation(s)
- Diego A Pedroza
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Matthew Ramirez
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Venkatesh Rajamanickam
- Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, United States
| | - Ramadevi Subramani
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States.,Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Victoria Margolis
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Tugba Gurbuz
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Adriana Estrada
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Rajkumar Lakshmanaswamy
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States.,Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
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29
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Torii C, Maishi N, Kawamoto T, Morimoto M, Akiyama K, Yoshioka Y, Minami T, Tsumita T, Alam MT, Ochiya T, Hida Y, Hida K. miRNA-1246 in extracellular vesicles secreted from metastatic tumor induces drug resistance in tumor endothelial cells. Sci Rep 2021; 11:13502. [PMID: 34226586 PMCID: PMC8257582 DOI: 10.1038/s41598-021-92879-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
Tumor endothelial cells (TECs) reportedly exhibit altered phenotypes. We have demonstrated that TECs acquire drug resistance with the upregulation of P-glycoprotein (P-gp, ABCB1), contrary to traditional assumptions. Furthermore, P-gp expression was higher in TECs of highly metastatic tumors than in those of low metastatic tumors. However, the detailed mechanism of differential P-gp expression in TECs remains unclear. miRNA was identified in highly metastatic tumor extracellular vesicles (EVs) and the roles of miRNA in endothelial cell resistance were analyzed in vitro and in vivo. In the present study, we found that treatment of highly metastatic tumor-conditioned medium induced resistance to 5-fluorouracil (5-FU) with interleukin-6 (IL-6) upregulation in endothelial cells (ECs). Among the soluble factors secreted from highly metastatic tumors, we focused on EVs and determined that miR-1246 was contained at a higher level in highly metastatic tumor EVs than in low metastatic tumor EVs. Furthermore, miR-1246 was transported via the EVs into ECs and induced IL-6 expression. Upregulated IL-6 induced resistance to 5-FU with STAT3 and Akt activation in ECs in an autocrine manner. These results suggested that highly metastatic tumors induce drug resistance in ECs by transporting miR-1246 through EVs.
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Affiliation(s)
- Chisaho Torii
- Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
- Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan
- Department of Oral and Maxillofacial Surgery, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
| | - Nako Maishi
- Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
- Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan
- Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
| | - Taisuke Kawamoto
- Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
| | - Masahiro Morimoto
- Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan
- Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
- Department of Oral Diagnosis and Medicine, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
| | - Kosuke Akiyama
- Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
| | - Yusuke Yoshioka
- Institute of Medical Science, Tokyo Medical University, Tokyo, 160-0023, Japan
| | - Takashi Minami
- Division of Molecular and Vascular Biology, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, 860-0811, Japan
| | - Takuya Tsumita
- Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
| | - Mohammad Towfik Alam
- Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
- Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan
- Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
| | - Takahiro Ochiya
- Institute of Medical Science, Tokyo Medical University, Tokyo, 160-0023, Japan
| | - Yasuhiro Hida
- Department of Cardiovascular and Thoracic Surgery, Hokkaido University Faculty of Medicine, Sapporo, 060-8638, Japan
| | - Kyoko Hida
- Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan.
- Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan.
- Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan.
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Mortoglou M, Tabin ZK, Arisan ED, Kocher HM, Uysal-Onganer P. Non-coding RNAs in pancreatic ductal adenocarcinoma: New approaches for better diagnosis and therapy. Transl Oncol 2021; 14:101090. [PMID: 33831655 PMCID: PMC8042452 DOI: 10.1016/j.tranon.2021.101090] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 03/14/2021] [Accepted: 03/26/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with a 5-year survival rate less than 8%, which has remained unchanged over the last 50 years. Early detection is particularly difficult due to the lack of disease-specific symptoms and a reliable biomarker. Multimodality treatment including chemotherapy, radiotherapy (used sparingly) and surgery has become the standard of care for patients with PDAC. Carbohydrate antigen 19-9 (CA 19-9) is the most common diagnostic biomarker; however, it is not specific enough especially for asymptomatic patients. Non-coding RNAs are often deregulated in human malignancies and shown to be involved in cancer-related mechanisms such as cell growth, differentiation, and cell death. Several micro, long non-coding and circular RNAs have been reported to date which are involved in PDAC. Aim of this review is to discuss the roles and functions of non-coding RNAs in diagnosis and treatments of PDAC.
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Affiliation(s)
- Maria Mortoglou
- Cancer Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK.
| | - Zoey Kathleen Tabin
- Cancer Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK.
| | - E Damla Arisan
- Institution of Biotechnology, Gebze Technical University, Gebze, Turkey.
| | - Hemant M Kocher
- Centre for Tumour Biology, Barts Cancer Institute-a CRUK Centre of Excellence, Queen Mary University London, London EC1M 6BQ, UK.
| | - Pinar Uysal-Onganer
- Cancer Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK.
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31
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Ueta E, Tsutsumi K, Kato H, Matsushita H, Shiraha H, Fujii M, Matsumoto K, Horiguchi S, Okada H. Extracellular vesicle-shuttled miRNAs as a diagnostic and prognostic biomarker and their potential roles in gallbladder cancer patients. Sci Rep 2021; 11:12298. [PMID: 34112884 PMCID: PMC8192895 DOI: 10.1038/s41598-021-91804-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 05/25/2021] [Indexed: 02/07/2023] Open
Abstract
Circulating microRNAs (miRNAs) in serum extracellular vesicles (EVs) are a promising biomarker in cancer. We aimed to elucidate the serum EVs miRNA biomarkers to identify patients with gallbladder cancer (GBC) and to clarify their potential roles. One hundred nineteen serum EVs from GBC and non-GBC individuals were isolated by pure-EVs-yieldable size-exclusion chromatography, and then were analyzed using a comprehensive miRNAs array and RT-qPCR-based validation. The functional roles of the identified miRNAs were also investigated using GBC cell lines. Serum EVs miR-1246 and miR-451a were significantly upregulated and downregulated, respectively in GBC patients (P = 0.005 and P = 0.001), in line with their expression levels in cancer tissue according to an in silico analysis. The combination of CEA and CA19-9 with miR-1246 showed the highest diagnostic power (AUC, 0.816; Sensitivity, 72.0%; Specificity, 90.8%), and miR-1246 was an independent prognostic marker of GBC (Hazard ratio, 3.05; P = 0.017) according to a Cox proportional hazards model. In vitro, miR-1246 promoted cell proliferation and invasion, while miR-451a inhibited cell proliferation and induced apoptosis with the targeting of MIF, PSMB8 and CDKN2D. Taken together, miR-1246 in serum EVs has potential application as a diagnostic and prognostic marker and miR-451a may be a novel therapeutic target in GBC.
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Affiliation(s)
- Eijiro Ueta
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
| | - Koichiro Tsutsumi
- Department of Gastroenterology, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama-city, Okayama, 700-8558, Japan.
| | - Hironari Kato
- Department of Gastroenterology, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama-city, Okayama, 700-8558, Japan
| | - Hiroshi Matsushita
- Department of Gastroenterology, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama-city, Okayama, 700-8558, Japan
| | - Hidenori Shiraha
- Department of Gastroenterology, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama-city, Okayama, 700-8558, Japan
| | - Masakuni Fujii
- Department of Internal Medicine, Okayama Saiseikai General Hospital, Okayama, Japan
| | - Kazuyuki Matsumoto
- Department of Gastroenterology, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama-city, Okayama, 700-8558, Japan
| | - Shigeru Horiguchi
- Department of Gastroenterology, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama-city, Okayama, 700-8558, Japan
| | - Hiroyuki Okada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan.,Department of Gastroenterology, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama-city, Okayama, 700-8558, Japan
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Romano R, Picca A, Eusebi LHU, Marzetti E, Calvani R, Moro L, Bucci C, Guerra F. Extracellular Vesicles and Pancreatic Cancer: Insights on the Roles of miRNA, lncRNA, and Protein Cargos in Cancer Progression. Cells 2021; 10:1361. [PMID: 34205944 PMCID: PMC8226820 DOI: 10.3390/cells10061361] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 05/28/2021] [Accepted: 05/29/2021] [Indexed: 01/18/2023] Open
Abstract
Pancreatic cancer (PC) is among the most devastating digestive tract cancers worldwide. This cancer is characterized by poor diagnostic detection, lack of therapy, and difficulty in predicting tumorigenesis progression. Although mutations of key oncogenes and oncosuppressor involved in tumor growth and in immunosurveillance escape are known, the underlying mechanisms that orchestrate PC initiation and progression are poorly understood or still under debate. In recent years, the attention of many researchers has been concentrated on the role of extracellular vesicles and of a particular subset of extracellular vesicles, known as exosomes. Literature data report that these nanovesicles are able to deliver their cargos to recipient cells playing key roles in the pathogenesis and progression of many pancreatic precancerous conditions. In this review, we have summarized and discussed principal cargos of extracellular vesicles characterized in PC, such as miRNAs, lncRNAs, and several proteins, to offer a systematic overview of their function in PC progression. The study of extracellular vesicles is allowing to understand that investigation of their secretion and analysis of their content might represent a new and potential diagnostic and prognostic tools for PC.
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Affiliation(s)
- Roberta Romano
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy;
| | - Anna Picca
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy; (A.P.); (E.M.); (R.C.)
- Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institute and Stockholm University, 171 77 Stockholm, Sweden
| | - Leonardo Henry Umberto Eusebi
- Gastroenterology and Endoscopy Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Gastroenterology and Endoscopy Unit, Sant’Orsola University Hospital, 40138 Bologna, Italy
| | - Emanuele Marzetti
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy; (A.P.); (E.M.); (R.C.)
- Institute of Internal Medicine and Geriatrics, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Riccardo Calvani
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy; (A.P.); (E.M.); (R.C.)
- Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institute and Stockholm University, 171 77 Stockholm, Sweden
| | - Loredana Moro
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA; or
- Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, 70126 Bari, Italy
| | - Cecilia Bucci
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy;
| | - Flora Guerra
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy;
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Ghatnatti V, Vastrad B, Patil S, Vastrad C, Kotturshetti I. Identification of potential and novel target genes in pituitary prolactinoma by bioinformatics analysis. AIMS Neurosci 2021; 8:254-283. [PMID: 33709028 PMCID: PMC7940115 DOI: 10.3934/neuroscience.2021014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 01/29/2021] [Indexed: 02/05/2023] Open
Abstract
Pituitary prolactinoma is one of the most complicated and fatally pathogenic pituitary adenomas. Therefore, there is an urgent need to improve our understanding of the underlying molecular mechanism that drives the initiation, progression, and metastasis of pituitary prolactinoma. The aim of the present study was to identify the key genes and signaling pathways associated with pituitary prolactinoma using bioinformatics analysis. Transcriptome microarray dataset GSE119063 was downloaded from Gene Expression Omnibus (GEO) database. Limma package in R software was used to screen DEGs. Pathway and Gene ontology (GO) enrichment analysis were conducted to identify the biological role of DEGs. A protein-protein interaction (PPI) network was constructed and analyzed by using HIPPIE database and Cytoscape software. Module analyses was performed. In addition, a target gene-miRNA regulatory network and target gene-TF regulatory network were constructed by using NetworkAnalyst and Cytoscape software. Finally, validation of hub genes by receiver operating characteristic (ROC) curve analysis. A total of 989 DEGs were identified, including 461 up regulated genes and 528 down regulated genes. Pathway enrichment analysis showed that the DEGs were significantly enriched in the retinoate biosynthesis II, signaling pathways regulating pluripotency of stem cells, ALK2 signaling events, vitamin D3 biosynthesis, cell cycle and aurora B signaling. Gene Ontology (GO) enrichment analysis showed that the DEGs were significantly enriched in the sensory organ morphogenesis, extracellular matrix, hormone activity, nuclear division, condensed chromosome and microtubule binding. In the PPI network and modules, SOX2, PRSS45, CLTC, PLK1, B4GALT6, RUNX1 and GTSE1 were considered as hub genes. In the target gene-miRNA regulatory network and target gene-TF regulatory network, LINC00598, SOX4, IRX1 and UNC13A were considered as hub genes. Using integrated bioinformatics analysis, we identified candidate genes in pituitary prolactinoma, which might improve our understanding of the molecular mechanisms of pituitary prolactinoma.
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Affiliation(s)
- Vikrant Ghatnatti
- Department of Endocrinology, J N Medical College, Belagavi and KLE Academy of Higher Education & Research 590010, Karnataka, India
| | - Basavaraj Vastrad
- Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India
| | - Swetha Patil
- Department of Obstetrics and Gynaecology, J N Medical College, Belagavi and KLE Academy of Higher Education & Research 590010, Karnataka, India
| | - Chanabasayya Vastrad
- Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India
| | - Iranna Kotturshetti
- Department of Ayurveda, Rajiv Gandhi Education Society's Ayurvedic Medical College, Ron 562209, Karanataka, India
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Noncoding RNAs Associated with Therapeutic Resistance in Pancreatic Cancer. Biomedicines 2021; 9:biomedicines9030263. [PMID: 33799952 PMCID: PMC7998345 DOI: 10.3390/biomedicines9030263] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/26/2021] [Accepted: 03/02/2021] [Indexed: 02/06/2023] Open
Abstract
Therapeutic resistance is an inevitable impediment towards effective cancer therapies. Evidence accumulated has shown that the signaling pathways and related factors are fundamentally responsible for therapeutic resistance via regulating diverse cellular events, such as epithelial-to-mesenchymal transition (EMT), stemness, cell survival/apoptosis, autophagy, etcetera. Noncoding RNAs (ncRNAs) have been identified as essential cellular components in gene regulation. The expression of ncRNAs is altered in cancer, and dysregulated ncRNAs participate in gene regulatory networks in pathological contexts. An in-depth understanding of molecular mechanisms underlying the modulation of therapeutic resistance is required to refine therapeutic benefits. This review presents an overview of the recent evidence concerning the role of human ncRNAs in therapeutic resistance, together with the feasibility of ncRNAs as therapeutic targets in pancreatic cancer.
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Integrated Genomics Identifies miR-181/TFAM Pathway as a Critical Driver of Drug Resistance in Melanoma. Int J Mol Sci 2021; 22:ijms22041801. [PMID: 33670365 PMCID: PMC7918089 DOI: 10.3390/ijms22041801] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 02/01/2021] [Accepted: 02/05/2021] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs) are attractive therapeutic targets and promising candidates as molecular biomarkers for various therapy-resistant tumors. However, the association between miRNAs and drug resistance in melanoma remains to be elucidated. We used an integrative genomic analysis to comprehensively study the miRNA expression profiles of drug-resistant melanoma patients and cell lines. MicroRNA-181a and -181b (miR181a/b) were identified as the most significantly down-regulated miRNAs in resistant melanoma patients and cell lines. Re-establishment of miR-181a/b expression reverses the resistance of melanoma cells to the BRAF inhibitor dabrafenib. Introduction of miR-181 mimics markedly decreases the expression of TFAM in A375 melanoma cells resistant to BRAF inhibitors. Furthermore, melanoma growth was inhibited in A375 and M14 resistant melanoma cells transfected with miR-181a/b mimics, while miR-181a/b depletion enhanced resistance in sensitive cell lines. Collectively, our study demonstrated that miR-181a/b could reverse the resistance to BRAF inhibitors in dabrafenib resistant melanoma cell lines. In addition, miR-181a and -181b are strongly down-regulated in tumor samples from patients before and after the development of resistance to targeted therapies. Finally, melanoma tissues with high miR-181a and -181b expression presented favorable outcomes in terms of Progression Free Survival, suggesting that miR-181 is a clinically relevant candidate for therapeutic development or biomarker-based therapy selection.
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Hwang GR, Yuen JG, Ju J. Roles of microRNAs in Gastrointestinal Cancer Stem Cell Resistance and Therapeutic Development. Int J Mol Sci 2021; 22:ijms22041624. [PMID: 33562727 PMCID: PMC7915611 DOI: 10.3390/ijms22041624] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 12/12/2022] Open
Abstract
Resistance to cancer treatment is one of the major challenges currently faced when treating gastrointestinal (GI) cancers. A major contributing factor to this resistance is the presence of cancer stem cells (CSCs) in GI cancers (e.g., colorectal, pancreatic, gastric, liver cancer). Non-coding RNAs, such as microRNAs (miRNAs), have been found to regulate several key targets that are responsible for cancer stemness, and function as oncogenic miRNAs (oncomiRs) or tumor suppressor miRNAs. As a result, several miRNAs have been found to alter, or be altered by, the expression of CSC-defining markers and their related pathways. These miRNAs can be utilized to affect stemness in multiple ways, including directly targeting CSCs and enhancing the efficacy of cancer therapeutics. This review highlights current studies regarding the roles of miRNAs in GI CSCs, and efforts towards the development of cancer therapeutics.
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Stoica AF, Chang CH, Pauklin S. Molecular Therapeutics of Pancreatic Ductal Adenocarcinoma: Targeted Pathways and the Role of Cancer Stem Cells. Trends Pharmacol Sci 2020; 41:977-993. [PMID: 33092892 DOI: 10.1016/j.tips.2020.09.008] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 09/01/2020] [Accepted: 09/23/2020] [Indexed: 12/12/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in humans due to late detection and highly metastatic characteristics. PDAC cells vary in their tumorigenic capabilities with the presence of a subset of PDAC cells known as pancreatic cancer stem cells (CSCs), which are more resistant to currently used therapeutics. Here, we describe the role of CSCs and tumour stroma in developing therapeutic strategies for PDAC and suggest that developmental plasticity could be considered a hallmark of cancers. We provide an overview of the molecular targets in PDAC treatments, including targeted therapies of cellular processes such as proliferation, evasion of growth suppressors, activating metastasis, and metabolic effects. Since PDAC is an inflammation-driven cancer, we also revisit therapeutic strategies targeting inflammation and immunotherapy. Lastly, we suggest that targeting epigenetic mechanisms opens therapeutic routes for heterogeneous cancer cell populations, including CSCs.
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Affiliation(s)
- Andrei-Florian Stoica
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Old Road, University of Oxford, Oxford OX3 7LD, UK
| | - Chao-Hui Chang
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Old Road, University of Oxford, Oxford OX3 7LD, UK
| | - Siim Pauklin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Old Road, University of Oxford, Oxford OX3 7LD, UK.
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Wang H, Wu B, Wang J, Hu Y, Dai X, Ye L, Cheng H. Methylation associated miR-1246 contributes to poor prognosis in gliomas treated with temozolomide. Clin Neurol Neurosurg 2020; 200:106344. [PMID: 33153768 DOI: 10.1016/j.clineuro.2020.106344] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 10/16/2020] [Accepted: 10/27/2020] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Glioblastoma (GBM) is the most aggressive type of glioma. In this study, we aimed to investigate the biological functions and the possible mechanisms of miR-1246 in glioma. METHODS A miRNA-seq array was conducted in both the tumor tissues and the glioma cell lines treated with 5-Aza to determine the methylation statues of miRNAs. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to verify the miR-1246 expressions. We used overall survival (OS) and the progress-free survival (PFS) to investigate the clinical significance of miR-1246 in the prognosis of glioma patients. Additionally, bioinformatic analysis was used for discovering the potential targets of miR-1246. Cell viability, wound-healing assay and protein expression tests were conducted after the transfection or knockdown of miR-1246 and CCNG2, respectively. RESULTS We found the reduced expression of miR-1246 in IDH1MUT tumor tissues and the increased expression in the glioma cell lines treated with 5-Aza. Therefore, miR-1246 was selected as a candidate for further analysis. Kaplan-Meier analysis showed that the glioma patients with the high level of miR-1246 had the worst survival rate compared to the low level counterparts. Overexpression of miR-1246 promoted cell proliferation, migration and invasion in glioma cells. Moreover, the results showed that the downregulation of miR-1246 decreased chemoresistance by targeting CCNG2. In addition, Gene ontology (GO) analysis revealed that miR-1246 was associated with the regulations of transcription, cell cycle, cell proliferation, cell adhesion and apoptosis. CONCLUSION These results indicated that the miR-1246/CCNG2 axis might be a potential target for improving the drug resistance in glioma.
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Affiliation(s)
- Haoyuan Wang
- Department of Neurosurgery, First Affiliated Hospital of Anhui Medical University, Jixi 218, Hefei, 230022, Anhui, China; Chinese Glioma Cooperative Group (CGCG), Beijing, China
| | - Bingshan Wu
- Department of Neurosurgery, First Affiliated Hospital of Anhui Medical University, Jixi 218, Hefei, 230022, Anhui, China
| | - Jingtao Wang
- Department of Neurosurgery, First Affiliated Hospital of Anhui Medical University, Jixi 218, Hefei, 230022, Anhui, China
| | - Yangchun Hu
- Department of Neurosurgery, First Affiliated Hospital of Anhui Medical University, Jixi 218, Hefei, 230022, Anhui, China
| | - Xingliang Dai
- Department of Neurosurgery, First Affiliated Hospital of Anhui Medical University, Jixi 218, Hefei, 230022, Anhui, China
| | - Lei Ye
- Department of Neurosurgery, First Affiliated Hospital of Anhui Medical University, Jixi 218, Hefei, 230022, Anhui, China.
| | - Hongwei Cheng
- Department of Neurosurgery, First Affiliated Hospital of Anhui Medical University, Jixi 218, Hefei, 230022, Anhui, China.
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Lin Z, Lu S, Xie X, Yi X, Huang H. Noncoding RNAs in drug-resistant pancreatic cancer: A review. Biomed Pharmacother 2020; 131:110768. [PMID: 33152930 DOI: 10.1016/j.biopha.2020.110768] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 09/17/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is the fourth-leading cause of cancer-related deaths and is expected to be the second-leading cause of cancer-related deaths in Europe and the United States by 2030. The high fatality rate of pancreatic cancer is ascribed to untimely diagnosis, early metastasis and limited responses to both chemotherapy and radiotherapy. Although gemcitabine, 5-fluorouracil and some other drugs can profoundly improve patient prognosis, most pancreatic cancer patients eventually develop drug resistance, leading to poor clinical outcomes. The underlying mechanisms of pancreatic cancer drug resistance are complicated and inconclusive. Interestingly, accumulating evidence has demonstrated that different noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), play a crucial role in pancreatic cancer resistance to chemotherapy reagents. In this paper, we systematically summarize the molecular mechanism underlying the influence of ncRNAs on the generation and development of drug resistance in pancreatic cancer and discuss the potential role of ncRNAs as prognostic markers and new therapeutic targets for pancreatic cancer.
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Affiliation(s)
- Zhengjun Lin
- Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, China.
| | - Shiyao Lu
- Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, China.
| | - Xubin Xie
- Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, China.
| | - Xuyang Yi
- Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, China.
| | - He Huang
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, China; State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, School of Pre-Clinical Medicine/ Second Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang, 830011, China.
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Johansson P, Dierichs L, Klein-Hitpass L, Bergmann AK, Möllmann M, Menninger S, Habenberger P, Klebl B, Siveke JT, Dührsen U, Choidas A, Dürig J. Anti-leukemic effect of CDK9 inhibition in T-cell prolymphocytic leukemia. Ther Adv Hematol 2020; 11:2040620720933761. [PMID: 33117517 PMCID: PMC7570784 DOI: 10.1177/2040620720933761] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 05/19/2020] [Indexed: 12/22/2022] Open
Abstract
T-cell prolymphocytic leukemia (T-PLL) is an aggressive malignancy characterized by chemotherapy resistance and a median survival of less than 2 years. Here, we investigated the pharmacological effects of the novel highly specific cyclin-dependent kinase 9 (CDK9) inhibitor LDC526 and its clinically used derivate atuveciclib employing primary T-PLL cells in an ex vivo drug sensitivity testing platform. Importantly, all T-PLL samples were sensitive to CDK9 inhibition at submicromolar concentrations, while conventional cytotoxic drugs were found to be largely ineffective. At the cellular level LDC526 inhibited the phosphorylation at serine 2 of the RNA polymerase II C-terminal domain resulting in decreased de novo RNA transcription. LDC526 induced apoptotic leukemic cell death through down-regulating MYC and MCL1 both at the mRNA and protein level. Microarray-based transcriptomic profiling revealed that genes down-modulated in response to CDK9 inhibition were enriched for MYC and JAK-STAT targets. By contrast, CDK9 inhibition increased the expression of the tumor suppressor FBXW7, which may contribute to decreased MYC and MCL1 protein levels. Finally, the combination of atuvecliclib and the BCL2 inhibitor venetoclax exhibited synergistic anti-leukemic activity, providing the rationale for a novel targeted-agent-based treatment of T-PLL.
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Affiliation(s)
| | - Laura Dierichs
- Institute for Developmental Cancer Therapeutics, West German Cancer Center, University Hospital Essen, Essen, Germany
- Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany
| | - Ludger Klein-Hitpass
- Institute of Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Anke K. Bergmann
- Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Michael Möllmann
- Department of Hematology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | | | | | - Bert Klebl
- Lead Discovery Center GmbH, Dortmund, Germany
| | - Jens T. Siveke
- Institute for Developmental Cancer Therapeutics, West German Cancer Center, University Hospital Essen, Essen, Germany
- Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany
| | - Ulrich Dührsen
- Department of Hematology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | | | - Jan Dürig
- Department of Hematology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center (DKFZ), Heidelberg, Germany
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Kyriazi AA, Papiris E, Kitsos Kalyvianakis K, Sakellaris G, Baritaki S. Dual Effects of Non-Coding RNAs (ncRNAs) in Cancer Stem Cell Biology. Int J Mol Sci 2020; 21:ijms21186658. [PMID: 32932969 PMCID: PMC7556003 DOI: 10.3390/ijms21186658] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/04/2020] [Accepted: 09/07/2020] [Indexed: 12/12/2022] Open
Abstract
The identification of cancer stem cells (CSCs) as initiators of carcinogenesis has revolutionized the era of cancer research and our perception for the disease treatment options. Additional CSC features, including self-renewal and migratory and invasive capabilities, have further justified these cells as putative diagnostic, prognostic, and therapeutic targets. Given the CSC plasticity, the identification of CSC-related biomarkers has been a serious burden in CSC characterization and therapeutic targeting. Over the past decades, a compelling amount of evidence has demonstrated critical regulatory functions of non-coding RNAs (ncRNAs) on the exclusive features of CSCs. We now know that ncRNAs may interfere with signaling pathways, vital for CSC phenotype maintenance, such as Notch, Wnt, and Hedgehog. Here, we discuss the multifaceted contribution of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), as representative ncRNA classes, in sustaining the CSC-like traits, as well as the underlying molecular mechanisms of their action in various CSC types. We further discuss the use of CSC-related ncRNAs as putative biomarkers of high diagnostic, prognostic, and therapeutic value.
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Affiliation(s)
- Athina A. Kyriazi
- Laboratory of Experimental Oncology, Division of Surgery, School of Medicine, University of Crete, 71500 Heraklion, Greece; (A.A.K.); (E.P.); (K.K.K.)
| | - Efstathios Papiris
- Laboratory of Experimental Oncology, Division of Surgery, School of Medicine, University of Crete, 71500 Heraklion, Greece; (A.A.K.); (E.P.); (K.K.K.)
| | - Konstantinos Kitsos Kalyvianakis
- Laboratory of Experimental Oncology, Division of Surgery, School of Medicine, University of Crete, 71500 Heraklion, Greece; (A.A.K.); (E.P.); (K.K.K.)
| | - George Sakellaris
- Surgery Unit, University General Hospital, 71500 Heraklion (PAGNH), Greece;
| | - Stavroula Baritaki
- Laboratory of Experimental Oncology, Division of Surgery, School of Medicine, University of Crete, 71500 Heraklion, Greece; (A.A.K.); (E.P.); (K.K.K.)
- Correspondence: ; Tel.: +30-2810394727
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Sun W, Ren Y, Lu Z, Zhao X. The potential roles of exosomes in pancreatic cancer initiation and metastasis. Mol Cancer 2020; 19:135. [PMID: 32878635 PMCID: PMC7466807 DOI: 10.1186/s12943-020-01255-w] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 08/25/2020] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer (PaCa) is an insidious and highly metastatic malignancy, with a 5-year survival rate of less than 5%. So far, the pathogenesis and progression mechanisms of PaCa have been poorly characterized. Exosomes correspond to a class of extracellular nanovesicles, produced by a broad range of human somatic and cancerous cells. These particular nanovesicles are mainly composed by proteins, genetic substances and lipids, which mediate signal transduction and material transport. A large number of studies have indicated that exosomes may play decisive roles in the occurrence and metastatic progression of PaCa. This article summarizes the specific functions of exosomes and their underlying molecular mechanisms in mediating the initiation and metastatic capability of PaCa.
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Affiliation(s)
- Wei Sun
- Department of Radiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Ying Ren
- Department of Radiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Zaiming Lu
- Department of Radiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Xiangxuan Zhao
- Department of Radiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China.
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Takeda Y, Kobayashi S, Kitakaze M, Yamada D, Akita H, Asai A, Konno M, Arai T, Kitagawa T, Ofusa K, Yabumoto M, Hirotsu T, Vecchione A, Taniguchi M, Doki Y, Eguchi H, Ishii H. Immuno-Surgical Management of Pancreatic Cancer with Analysis of Cancer Exosomes. Cells 2020; 9:cells9071645. [PMID: 32659892 PMCID: PMC7408222 DOI: 10.3390/cells9071645] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 07/05/2020] [Accepted: 07/05/2020] [Indexed: 02/07/2023] Open
Abstract
Exosomes (EXs), a type of extracellular vesicles secreted from various cells and especially cancer cells, mesenchymal cells, macrophages and other cells in the tumor microenvironment (TME), are involved in biologically malignant behaviors of cancers. Recent studies have revealed that EXs contain microRNAs on their inside and express proteins and glycolipids on their outsides, every component of which plays a role in the transmission of genetic and/or epigenetic information in cell-to-cell communications. It is also known that miRNAs are involved in the signal transduction. Thus, EXs may be useful for monitoring the TME of tumor tissues and the invasion and metastasis, processes that are associated with patient survival. Because several solid tumors secrete immune checkpoint proteins, including programmed cell death-ligand 1, the EX-mediated mechanisms are suggested to be potent targets for monitoring patients. Therefore, a companion therapeutic approach against cancer metastasis to distant organs is proposed when surgical removal of the primary tumor is performed. However, EXs and immune checkpoint mechanisms in pancreatic cancer are not fully understood, we provide an update on the recent advances in this field and evidence that EXs will be useful for maximizing patient benefit in precision medicine.
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Affiliation(s)
- Yu Takeda
- Center of Medical Innovation and Translational Research (CoMIT), Osaka University Graduate School of Medicine, Suita, Yamadaoka 2-2, Osaka 565-0871, Japan; (Y.T.); (M.K.); (A.A.); (M.K.); (T.A.); (T.K.); (K.O.); (M.Y.); (T.H.); (Y.D.); (H.E.)
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan; (S.K.); (D.Y.); (H.A.)
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan; (S.K.); (D.Y.); (H.A.)
| | - Masatoshi Kitakaze
- Center of Medical Innovation and Translational Research (CoMIT), Osaka University Graduate School of Medicine, Suita, Yamadaoka 2-2, Osaka 565-0871, Japan; (Y.T.); (M.K.); (A.A.); (M.K.); (T.A.); (T.K.); (K.O.); (M.Y.); (T.H.); (Y.D.); (H.E.)
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan; (S.K.); (D.Y.); (H.A.)
| | - Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan; (S.K.); (D.Y.); (H.A.)
| | - Hirofumi Akita
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan; (S.K.); (D.Y.); (H.A.)
| | - Ayumu Asai
- Center of Medical Innovation and Translational Research (CoMIT), Osaka University Graduate School of Medicine, Suita, Yamadaoka 2-2, Osaka 565-0871, Japan; (Y.T.); (M.K.); (A.A.); (M.K.); (T.A.); (T.K.); (K.O.); (M.Y.); (T.H.); (Y.D.); (H.E.)
- Artificial Intelligence Research Center, The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan;
| | - Masamitsu Konno
- Center of Medical Innovation and Translational Research (CoMIT), Osaka University Graduate School of Medicine, Suita, Yamadaoka 2-2, Osaka 565-0871, Japan; (Y.T.); (M.K.); (A.A.); (M.K.); (T.A.); (T.K.); (K.O.); (M.Y.); (T.H.); (Y.D.); (H.E.)
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan; (S.K.); (D.Y.); (H.A.)
| | - Takahiro Arai
- Center of Medical Innovation and Translational Research (CoMIT), Osaka University Graduate School of Medicine, Suita, Yamadaoka 2-2, Osaka 565-0871, Japan; (Y.T.); (M.K.); (A.A.); (M.K.); (T.A.); (T.K.); (K.O.); (M.Y.); (T.H.); (Y.D.); (H.E.)
- Unitech Co., Ltd., Kashiwa 277-0005, Japan
| | - Toru Kitagawa
- Center of Medical Innovation and Translational Research (CoMIT), Osaka University Graduate School of Medicine, Suita, Yamadaoka 2-2, Osaka 565-0871, Japan; (Y.T.); (M.K.); (A.A.); (M.K.); (T.A.); (T.K.); (K.O.); (M.Y.); (T.H.); (Y.D.); (H.E.)
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan; (S.K.); (D.Y.); (H.A.)
- Kyowa-kai Medical Corporation, Osaka 540-0008, Japan
| | - Ken Ofusa
- Center of Medical Innovation and Translational Research (CoMIT), Osaka University Graduate School of Medicine, Suita, Yamadaoka 2-2, Osaka 565-0871, Japan; (Y.T.); (M.K.); (A.A.); (M.K.); (T.A.); (T.K.); (K.O.); (M.Y.); (T.H.); (Y.D.); (H.E.)
- Prophoenix Division, Food and Life-Science Laboratory, Idea Consultants, Inc., Osaka-city, Osaka 559-8519, Japan
| | - Masami Yabumoto
- Center of Medical Innovation and Translational Research (CoMIT), Osaka University Graduate School of Medicine, Suita, Yamadaoka 2-2, Osaka 565-0871, Japan; (Y.T.); (M.K.); (A.A.); (M.K.); (T.A.); (T.K.); (K.O.); (M.Y.); (T.H.); (Y.D.); (H.E.)
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan; (S.K.); (D.Y.); (H.A.)
- Kinshu-kai Medical Corporation, Osaka 558-0041, Japan
| | - Takaaki Hirotsu
- Center of Medical Innovation and Translational Research (CoMIT), Osaka University Graduate School of Medicine, Suita, Yamadaoka 2-2, Osaka 565-0871, Japan; (Y.T.); (M.K.); (A.A.); (M.K.); (T.A.); (T.K.); (K.O.); (M.Y.); (T.H.); (Y.D.); (H.E.)
- Hirotsu Bio Science Inc., Tokyo 107-0062, Japan
| | - Andrea Vecchione
- Department of Clinical and Molecular Medicine, University of Rome “Sapienza”, Santo Andrea Hospital, via di Grottarossa, 1035-00189 Rome, Italy;
| | - Masateru Taniguchi
- Artificial Intelligence Research Center, The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan;
| | - Yuichiro Doki
- Center of Medical Innovation and Translational Research (CoMIT), Osaka University Graduate School of Medicine, Suita, Yamadaoka 2-2, Osaka 565-0871, Japan; (Y.T.); (M.K.); (A.A.); (M.K.); (T.A.); (T.K.); (K.O.); (M.Y.); (T.H.); (Y.D.); (H.E.)
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan; (S.K.); (D.Y.); (H.A.)
| | - Hidetoshi Eguchi
- Center of Medical Innovation and Translational Research (CoMIT), Osaka University Graduate School of Medicine, Suita, Yamadaoka 2-2, Osaka 565-0871, Japan; (Y.T.); (M.K.); (A.A.); (M.K.); (T.A.); (T.K.); (K.O.); (M.Y.); (T.H.); (Y.D.); (H.E.)
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan; (S.K.); (D.Y.); (H.A.)
| | - Hideshi Ishii
- Center of Medical Innovation and Translational Research (CoMIT), Osaka University Graduate School of Medicine, Suita, Yamadaoka 2-2, Osaka 565-0871, Japan; (Y.T.); (M.K.); (A.A.); (M.K.); (T.A.); (T.K.); (K.O.); (M.Y.); (T.H.); (Y.D.); (H.E.)
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan; (S.K.); (D.Y.); (H.A.)
- Correspondence: ; Tel.: +81-(0)6-6210-8406 (ext. 8405); Fax: +81-(0)6-6210-8407
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Wang X, Chai Z, Pan G, Hao Y, Li B, Ye T, Li Y, Long F, Xia L, Liu M. ExoBCD: a comprehensive database for exosomal biomarker discovery in breast cancer. Brief Bioinform 2020; 22:5860692. [PMID: 32591816 DOI: 10.1093/bib/bbaa088] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 03/08/2020] [Accepted: 04/26/2020] [Indexed: 12/24/2022] Open
Abstract
Effective and safe implementation of precision oncology for breast cancer is a vital strategy to improve patient outcomes, which relies on the application of reliable biomarkers. As 'liquid biopsy' and novel resource for biomarkers, exosomes provide a promising avenue for the diagnosis and treatment of breast cancer. Although several exosome-related databases have been developed, there is still lacking of an integrated database for exosome-based biomarker discovery. To this end, a comprehensive database ExoBCD (https://exobcd.liumwei.org) was constructed with the combination of robust analysis of four high-throughput datasets, transcriptome validation of 1191 TCGA cases and manual mining of 950 studies. In ExoBCD, approximately 20 900 annotation entries were integrated from 25 external sources and 306 exosomal molecules (49 potential biomarkers and 257 biologically interesting molecules). The latter could be divided into 3 molecule types, including 121 mRNAs, 172 miRNAs and 13 lncRNAs. Thus, the well-linked information about molecular characters, experimental biology, gene expression patterns, overall survival, functional evidence, tumour stage and clinical use were fully integrated. As a data-driven and literature-based paradigm proposed of biomarker discovery, this study also demonstrated the corroborative analysis and identified 36 promising molecules, as well as the most promising prognostic biomarkers, IGF1R and FRS2. Taken together, ExoBCD is the first well-corroborated knowledge base for exosomal studies of breast cancer. It not only lays a foundation for subsequent studies but also strengthens the studies of probing molecular mechanisms, discovering biomarkers and developing meaningful clinical use.
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Affiliation(s)
- Xuanyi Wang
- Key Laboratory of Clinical Laboratory Diagnostics, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Zixuan Chai
- Key Laboratory of Clinical Laboratory Diagnostics, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Guizhi Pan
- Key Laboratory of Clinical Laboratory Diagnostics, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Youjin Hao
- College of Life Sciences, Chongqing Normal University, Chongqing, China
| | - Bo Li
- College of Life Sciences, Chongqing Normal University, Chongqing, China
| | - Ting Ye
- Key Laboratory of Clinical Laboratory Diagnostics, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Yinghong Li
- Key Laboratory of Clinical Laboratory Diagnostics, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Fei Long
- Key Laboratory of Clinical Laboratory Diagnostics, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Lixin Xia
- Key Laboratory of Clinical Laboratory Diagnostics, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Mingwei Liu
- Key Laboratory of Clinical Laboratory Diagnostics, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
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Ishige F, Hoshino I, Iwatate Y, Chiba S, Arimitsu H, Yanagibashi H, Nagase H, Takayama W. MIR1246 in body fluids as a biomarker for pancreatic cancer. Sci Rep 2020; 10:8723. [PMID: 32457495 PMCID: PMC7250935 DOI: 10.1038/s41598-020-65695-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 05/08/2020] [Indexed: 01/28/2023] Open
Abstract
Pancreatic cancer is an aggressive tumor associated with poor survival, and early detection is important to improve patient outcomes. In the present study, we examined MIR1246 expression as a biomarker of pancreatic cancer. Total RNA was extracted from serum, urine and saliva samples from healthy subjects (n = 30) and patients with pancreatic cancer (n = 41, stage 0–IV). The MIR1246 level in each fluid was analyzed by quantitative reverse transcription-polymerase chain reaction. Significantly higher MIR1246 expression in serum and urine was observed in patients with cancer than in healthy controls. A significant positive correlation was found between serum and urine MIR1246 expression (r = 0.34). Receiver operating characteristic curves were constructed for MIR1246 in all three body fluids. The area under the curve for serum MIR1246 was 0.87 (sensitivity, 92.3%; specificity, 73.3%), and that for urine MIR1246 was 0.90 (sensitivity, 90.2%; specificity, 83.3%). With a cut-off of the control group’s mean plus twice the standard deviation, the sensitivities of MIR1246 in serum and urine for pancreatic cancer were 60.9 and 58.5%, respectively. Combining both serum and urine MIR1246 expression yielded a sensitivity of 85%. These results indicate that MIR246 may be a useful diagnostic biomarker for pancreatic cancer.
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Affiliation(s)
- Fumitaka Ishige
- Division of Hepatobiliarypancreatic Surgery, Chiba Cancer Center, Chuo-ku, Chiba, Japan
| | - Isamu Hoshino
- Division of Gastrointestinal Surgery, Chiba Cancer Center, Chuo-ku, Chiba, Japan.
| | - Yosuke Iwatate
- Division of Hepatobiliarypancreatic Surgery, Chiba Cancer Center, Chuo-ku, Chiba, Japan
| | - Satoshi Chiba
- Division of Hepatobiliarypancreatic Surgery, Chiba Cancer Center, Chuo-ku, Chiba, Japan
| | - Hidehito Arimitsu
- Division of Hepatobiliarypancreatic Surgery, Chiba Cancer Center, Chuo-ku, Chiba, Japan
| | - Hiroo Yanagibashi
- Division of Hepatobiliarypancreatic Surgery, Chiba Cancer Center, Chuo-ku, Chiba, Japan
| | - Hiroki Nagase
- Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chuo-ku, Chiba, Japan
| | - Wataru Takayama
- Division of Hepatobiliarypancreatic Surgery, Chiba Cancer Center, Chuo-ku, Chiba, Japan
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Solomon MC, Radhakrishnan RA. MicroRNA's - The vibrant performers in the oral cancer scenario. JAPANESE DENTAL SCIENCE REVIEW 2020; 56:85-89. [PMID: 32612717 PMCID: PMC7310692 DOI: 10.1016/j.jdsr.2020.04.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 03/11/2020] [Accepted: 04/13/2020] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are a family of small non-coding (18–22 nucleotide) RNA molecules. These molecules regulate gene expression by either inhibiting mRNA translation or by degrading mRNA. A single miRNA can control the expression of target genes, and the expression of a target gene can be regulated by multiple miRNAs. They are key regulators of various biological and pathological processes. These include cell proliferation, development and tumorigenesis. Novel studies have discovered definite signature miRNAs in the initiation and progression of cancers. Interestingly, miRNAs have also been found in fragile genomic sites that are associated with increased cancer risk. These micro RNAs regulate the expression of several genes that play a crucial role in the transition of normal oral mucosa through dysplasia to malignancy. The aim of this review is to recapitulate the current understanding of the many miRNAs that have been identified, the genes that they target and the role that they play in the carcinogenic pathway. The review also highlights the prospective role of miRNAs in the diagnosis, prognosis and treatment of oral cancers.
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Affiliation(s)
- Monica Charlotte Solomon
- Department of Oral Pathology and Microbiology, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Raghu Anekal Radhakrishnan
- Department of Oral Pathology and Microbiology, Manipal College of Dental Sciences, Manipal, Wellcome Trust/DBT India Alliance Fellow, Director, International Relations, Manipal Academy of Higher Education, Manipal, Karnataka, India
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Zhao F, Wei C, Cui MY, Xia QQ, Wang SB, Zhang Y. Prognostic value of microRNAs in pancreatic cancer: a meta-analysis. Aging (Albany NY) 2020; 12:9380-9404. [PMID: 32420903 PMCID: PMC7288910 DOI: 10.18632/aging.103214] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 04/17/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND The prognostic impact of microRNA (miRNA) expression levels in pancreatic cancer (PC) has been estimated for years, but the outcomes are controversial and heterogeneous. Therefore, we comprehensively reviewed the evidence collected on miRNA expression in PC to determine this effect. RESULTS PC patients with high miR-21 (HR=2.61, 95%CI=1.68-4.04), miR-451a (HR=2.23, 95%CI=1.23-4.04) or miR-1290 (HR=1.43, 95%CI=1.04-1.95) levels in blood had significantly poorer OS (P<0.05). Furthermore, PC patients with high miR-10b (HR=1.73, 95%CI=1.09-2.76), miR-17-5p (HR=1.91, 95%CI=1.30-2.80), miR-21 (HR=1.90, 95%CI=1.61-2.25), miR-23a (HR=2.18, 95%CI=1.52-3.13), miR-155 (HR=2.22, 95%CI=1.27-3.88), miR-203 (HR=1.65, 95%CI=1.14-2.40), miR-221 (HR=1.72, 95%CI=1.08-2.74), miR-222 levels (HR=1.72, 95%CI=1.02-2.91) or low miR-29c (HR=1.39, 95%CI=1.08-1.79), miR-126 (HR=1.55, 95%CI=1.23-1.95), miR-218 (HR=2.62, 95%CI=1.41-4.88) levels in tissues had significantly shorter OS (P<0.05). CONCLUSIONS In summary, blood miR-21, miR-451a, miR-1290 and tissue miR-10b, miR-17-5p, miR-21, miR-23a, miR-29c, miR-126, miR-155, miR-203, miR-218, miR-221, miR-222 had significant prognostic value. METHODS We searched PubMed, EMBASE, Web of Science and Cochrane Database of Systematic Reviews to recognize eligible studies, and 57 studies comprising 5445 PC patients and 15 miRNAs were included to evaluate the associations between miRNA expression levels and overall survival (OS) up to June 1, 2019. Summary hazard ratios (HR) with 95% confidence intervals (CI) were calculated to assess the effect.
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Affiliation(s)
- Fei Zhao
- , Department of Traditional Chinese Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Chao Wei
- College of Integrated Traditional Chinese and Western Medicine, Jining Medical University, Jining, Shandong, China
| | - Meng-Ying Cui
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Qiang-Qiang Xia
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Shuai-Bin Wang
- Department of Urology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yue Zhang
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35233, USA
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA
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Quandt E, Ribeiro MPC, Clotet J. Atypical cyclins in cancer: New kids on the block? Semin Cell Dev Biol 2020; 107:46-53. [PMID: 32417219 DOI: 10.1016/j.semcdb.2020.04.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 04/15/2020] [Accepted: 04/27/2020] [Indexed: 12/13/2022]
Abstract
Atypical cyclins have recently emerged as a new subfamily of cyclins characterized by common structural features and interactor pattern. Interestingly, atypical cyclins are phylogenetically close to canonical cyclins, which have well-established roles in cell cycle regulation and cancer. Therefore, although the function of atypical cyclins is still poorly characterized, it seems likely that they are involved in cancer pathogenesis as well. Here, we coupled gene expression and prognostic significance analysis to bibliographic search in order to provide new insights into the role of atypical cyclins in cancer. The information gathered suggests that atypical cyclins intervene in critical processes to sustain cancer growth and have potential to become novel prognostic markers and drug targets in cancer.
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Affiliation(s)
- Eva Quandt
- Faculty of Medicine and Health Sciences, Universitat Internacional De Catalunya, 08195, Sant Cugat Del Vallès, Barcelona, Spain
| | - Mariana P C Ribeiro
- Faculty of Medicine and Health Sciences, Universitat Internacional De Catalunya, 08195, Sant Cugat Del Vallès, Barcelona, Spain.
| | - Josep Clotet
- Faculty of Medicine and Health Sciences, Universitat Internacional De Catalunya, 08195, Sant Cugat Del Vallès, Barcelona, Spain.
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Yang J, Lian Y, Yang R, Lian Y, Wu J, Liu J, Wang K, Xu H. Upregulation of lncRNA LINC00460 Facilitates GC Progression through Epigenetically Silencing CCNG2 by EZH2/LSD1 and Indicates Poor Outcomes. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 19:1164-1175. [PMID: 32059342 PMCID: PMC7016164 DOI: 10.1016/j.omtn.2019.12.041] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 12/11/2019] [Accepted: 12/29/2019] [Indexed: 01/24/2023]
Abstract
Non-protein-coding functional elements in the human genome in the postgenomic biology field have been drawing great attention in recent years. Thousands of long non-coding RNAs (lncRNAs) have been found to be expressed in various tumors. Yet only a small proportion of these lncRNAs have been well characterized. We have demonstrated that LINC00460 could affect cell proliferation through epigenetic regulation of KLF2 and CUL4A in human colorectal cancer. However, the clinical significance and biological role of LINC00460 in gastric cancer (GC) remain largely unknown. In this research, we discovered that LINC00460 is remarkably upregulated in GC tissues compared to the non-tumor tissues. Additionally, LINC00460 served as an independent prognostic marker in GC. Functionally, proliferation of GC cells could be regulated by LINC00460 both in vitro and in vivo. RNA sequencing (RNA-seq) analysis for the whole transcriptome indicated that LINC00460 may serve as a key regulatory factor in the tumorigenesis of GC. What's more, the biological function of LINC00460 was mediated, to certain extent, by the direct interaction with enhancer of zeste homolog 2 (EZH2) and lysine (K)-specific demethylase 1A (LSD1) proteins. Further analyses indicated that LINC00460 promoted GC proliferation at least partly through the downregulation of tumor suppressor-gene Cyclin G2 (CCNG2), which is mediated by EZH2 and LSD1. In conclusion, our results suggested that LINC00460 acted as an oncogene in GC to inhibit the expression of CCNG2 at least partly by binding with EZH2 and LSD1. Our study could provide additional insights into the development of novel target therapeutic methods for GC.
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Affiliation(s)
- Jiebin Yang
- Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen, Fujian, P.R. China; Department of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian, P.R. China
| | - Yikai Lian
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, P.R. China; School of Medicine, Xiamen University, Xiamen, Fujian, P.R. China
| | - Renzhi Yang
- School of Medicine, Xiamen University, Xiamen, Fujian, P.R. China
| | - Yifan Lian
- Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen, Fujian, P.R. China; School of Medicine, Xiamen University, Xiamen, Fujian, P.R. China
| | - Jingtong Wu
- Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen, Fujian, P.R. China; School of Medicine, Xiamen University, Xiamen, Fujian, P.R. China
| | - Jingjing Liu
- Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen, Fujian, P.R. China
| | - Keming Wang
- Department of Oncology, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
| | - Hongzhi Xu
- Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen, Fujian, P.R. China.
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Hsieh PL, Liao YW, Pichler M, Yu CC. MicroRNAs as Theranostics Targets in Oral Carcinoma Stem Cells. Cancers (Basel) 2020; 12:cancers12020340. [PMID: 32028645 PMCID: PMC7072536 DOI: 10.3390/cancers12020340] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 01/30/2020] [Accepted: 01/31/2020] [Indexed: 12/25/2022] Open
Abstract
Oral cancer belongs to head and neck squamous cell carcinoma and has been recognized as one of the most prevalent malignancies worldwide. Recent studies have suggested that cancer stem cells (CSCs) may participate in tumor initiation, metastasis and even recurrence, so the regulation of CSCs has drawn significant attention over the past decade. Among various molecules that are associated with CSCs, non-coding RNAs (ncRNAs) have been indicated as key players in the acquisition and maintenance of cancer stemness. In addition, accumulating studies have shown that the aberrant expression of these ncRNAs may serve as surrogate diagnostic markers or even therapeutic targets for cancer treatment. The current study reviews the previous work by us and others to summarize how these ncRNAs affect oral cancer stemness and their potential theranostic applications. A better understanding of the implication of these ncRNAs in oral tumorigenesis will facilitate the translation of basic ncRNA research into clinical application in the future.
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Affiliation(s)
- Pei-Ling Hsieh
- Department of Anatomy, School of Medicine, China Medical University, Taichung 404, Taiwan;
| | - Yi-Wen Liao
- School of Dentistry, Chung Shan Medical University, Taichung 40201, Taiwan;
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
| | - Martin Pichler
- Research Unit of Non-Coding RNAs and Genome Editing, Division of Clinical Oncology, Department of Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, 8036 Graz, Austria;
| | - Cheng-Chia Yu
- School of Dentistry, Chung Shan Medical University, Taichung 40201, Taiwan;
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
- Institute of Oral Sciences, Chung Shan Medical University, Taichung 40201, Taiwan
- Correspondence: ; Tel.: +886-4-24718668
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