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Doodmani SM, Safari MH, Akbari M, Farahani N, Alimohammadi M, Aref AR, Tajik F, Maghsoodlou A, Daneshi S, Tabari T, Taheriazam A, Entezari M, Nabavi N, Hashemi M. Metastasis and chemoresistance in breast cancer: Crucial function of ZEB1/2 proteins. Pathol Res Pract 2025; 267:155838. [PMID: 39954369 DOI: 10.1016/j.prp.2025.155838] [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: 10/14/2024] [Revised: 12/20/2024] [Accepted: 02/10/2025] [Indexed: 02/17/2025]
Abstract
Breast cancer remains one of the leading causes of mortality worldwide. While advancements in chemotherapy, immunotherapy, radiotherapy, and targeted therapies have significantly improved breast cancer treatment, many patients are diagnosed at advanced stages, where tumor cells exhibit aggressive behavior and therapy resistance. Understanding the mechanisms driving breast cancer progression is therefore critical. Metastasis is a major factor that drastically reduces patient prognosis and survival, accounting for most breast cancer-related deaths. ZEB proteins have emerged as key regulators of cancer metastasis. Beyond their role in metastasis, ZEB proteins also influence drug resistance. This review focuses on the role of ZEB1 and ZEB2 in regulating breast cancer metastasis. These proteins interact with components of the tumor microenvironment (TME) to drive cancer progression and metastasis. Additionally, ZEB proteins regulate angiogenesis through interactions with VEGF. Targeting ZEB proteins offers potential therapeutic benefits, particularly for aggressive breast cancer subtypes such as triple-negative breast cancer (TNBC), which often show poor therapeutic response. ZEB proteins also influence the sensitivity of breast cancer cells to chemotherapy, making them promising targets for enhancing treatment efficacy. Given their upregulation in breast cancer, ZEB proteins can serve as valuable diagnostic and prognostic markers.
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Affiliation(s)
- Seyed Mohammad Doodmani
- Department of Pathobiology, Faculty of Specialized Veterinary Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mohamad Hosein Safari
- Department of Internal Medicine, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
| | - Mohammadarian Akbari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences,Tehran, Iran
| | - Amir Reza Aref
- Department of Vitro Vision, DeepkinetiX, Inc, Boston, MA, USA
| | - Fatemeh Tajik
- Department of Surgery, University of California, Irvine Medical Center, Orange, CA, USA
| | - Amin Maghsoodlou
- Young Researchers and Elite Club, Damghan Branch, Islamic Azad University, Damghan, Iran
| | - Salman Daneshi
- Department of Public Health, School of Health, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Teimour Tabari
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia V8V 1P7, Canada
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Ferreira M, Morais M, Medeiros R, Teixeira AL. MicroRNAs as Promising Therapeutic Agents Against Prostate Cancer Resistant to Castration-Where Are We Now? Pharmaceutics 2024; 16:1347. [PMID: 39598472 PMCID: PMC11597238 DOI: 10.3390/pharmaceutics16111347] [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: 09/02/2024] [Revised: 10/17/2024] [Accepted: 10/19/2024] [Indexed: 11/29/2024] Open
Abstract
MicroRNAs are a conserved class of small, tissue-specific, non-coding RNAs that regulate gene expression to preserve cellular homeostasis. Proper miRNA expression is crucial for physiological balance because it affects numerous genetic pathways, including cell cycle control, proliferation, and apoptosis, through gene expression targeting. Deregulated miRNA expression has been implicated in several cancer types, including prostate cancer (PC), acting as tumor suppressors or oncogenes. Despite the availability of promising therapies to control tumor growth and progression, effective diagnostic and therapeutic strategies for different types of cancer are still lacking. PC continues to be a significant health challenge, particularly its castration-resistant (CRPC) form, which presents major therapeutic obstacles because of its resistance to conventional androgen deprivation treatments. This review explores miRNAs' critical roles in gene regulation and cancer biology, as well as various miRNA delivery systems, highlighting their potential and the challenges in effectively targeting cancer cells. It aims to provide a comprehensive overview of the status of miRNA research in the fight against CRPC, summarizing miRNA-based therapies' successes and limitations. It also highlights the promise of miRNAs as therapeutic agents for CRPC, underlining the need for further research to overcome existing challenges and move these therapies toward clinical applications.
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Affiliation(s)
- Mariana Ferreira
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal; (M.F.); (M.M.); (R.M.)
- ICBAS, Abel Salazar Institute for the Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal
| | - Mariana Morais
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal; (M.F.); (M.M.); (R.M.)
- ICBAS, Abel Salazar Institute for the Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal; (M.F.); (M.M.); (R.M.)
- ICBAS, Abel Salazar Institute for the Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal
- Biomedical Research Center (CEBIMED), Faculty of Health Sciences, Fernando Pessoa University (UFP), 4249-004 Porto, Portugal
- Research Department, LPCC-Portuguese League Against Cancer (NRNorte), 4200-172 Porto, Portugal
- Faculty of Medicine (FMUP), University of Porto, 4200-319 Porto, Portugal
| | - Ana Luísa Teixeira
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal; (M.F.); (M.M.); (R.M.)
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Liu B, Lu K, Yuan L, Li X, Lan L, Han S. Hsa-miR-181a-2-3p inhibits the oncogenicity of colon cancer by directly targeting STING. Aging (Albany NY) 2024; 16:11729-11743. [PMID: 39133165 PMCID: PMC11346793 DOI: 10.18632/aging.206059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 07/16/2024] [Indexed: 08/13/2024]
Abstract
OBJECTIVE Colon cancer is a common malignant tumor of the gastrointestinal system, which is characterized by high morbidity and mortality. The purpose of this study was to analyze the expression and biological role of miR-181a-2-3p in colon cancer and to investigate the molecular mechanism of its regulatory effect on colon cancer through stimulator of interferon genes (STING). METHODS Real-time reverse transcription polymerase chain reaction (qRT-PCR) assay was used to detect the expression of miR-181a-2-3p in colon cancer cell lines and normal intestinal epithelial cells. After overexpression of miR-181a-2-3p in colon cancer cell lines SW480 and HT29, cells were examined by CCK8, Transwell, and flow cytometry assays for alterations in proliferation, migration, apoptosis, and cell cycle. Target genes of miR-181a-2-3p were predicted by bioinformatics and validated by dual luciferase assays. Rescue experiments were performed to explore the role of STING in the effect of miR-181a-2-3p. The effect of miR-181a-2-3p on colon cancer proliferation in vivo was validated by nude mouse tumorigenicity assay. RESULTS miR-181a-2-3p was lowly expressed in both colon cancer tissues and cell lines. Overexpression of miR-181a-2-3p led to reduced proliferation and migration, increased apoptosis, and altered cell cycle in colon cancer cell lines SW480 and HT29. STING was a target gene of miR-181a-2-3p. Increased STING expression partially counteracted the effect of overexpression of miR-181a-2-3p on colon cancer cell lines. miR-181a-2-3p also suppressed colon cancer proliferation in vivo. CONCLUSION miR-181a-2-3p inhibits the proliferation and oncogenicity of colon cancer, and its molecular mechanism could be inhibited by STING.
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Affiliation(s)
- Bowei Liu
- Department of Gastroenterology, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, Henan 450003, China
| | - Kai Lu
- Clinical Medicine College, Xinxiang Medical University, Xinxiang, Henan 453000, China
| | - Lijie Yuan
- Department of Gastroenterology, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, Henan 450003, China
| | - Xiaofang Li
- Department of Gastroenterology, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, Henan 450003, China
| | - Ling Lan
- Department of Gastroenterology, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, Henan 450003, China
| | - Shuangyin Han
- Department of Gastroenterology, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, Henan 450003, China
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Ellakwa DES, Mushtaq N, Khan S, Jabbar A, Abdelmalek MA, Wadan AHS, Ellakwa TE, Raza A. Molecular functions of microRNAs in colorectal cancer: recent roles in proliferation, angiogenesis, apoptosis, and chemoresistance. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:5617-5630. [PMID: 38619588 DOI: 10.1007/s00210-024-03076-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 03/28/2024] [Indexed: 04/16/2024]
Abstract
MiRNAs (microRNAs) constitute a group of diminutive molecules of non-coding RNA intricately involved in regulating gene expression. This regulation is primarily accomplished through the binding of miRNAs to complementary sequences situated in the 3'-UTR of the messenger RNA (mRNA) target; as a result, they are degraded or repressed. The multifaceted biogenesis of miRNAs is characterized by a meticulously orchestrated sequence of events encompassing transcription, processing, transportation, and decay. Colorectal cancer stands as a pervasive and formidable ailment, afflicting millions across the globe. Colorectal cancer is not well diagnosed early, and metastasis rates are high, which results in low survival rates in advanced stages. The genesis and progression of colorectal cancer are subject to the influence of genetic and epigenetic factors, among which miRNAs play a pivotal role. When it comes to colorectal cancer, miRNAs have a dual character, depending on the genes they target, functioning as either tumor suppressors or oncogenes and the prevailing cellular milieu. Their impact extends to modulating critical facets of colorectal cancer pathogenesis, including proliferation, angiogenesis, apoptosis, chemoresistance, and radiotherapy response. The discernible potential of miRNAs which are used as biomarkers to diagnose colorectal cancer, prognosis, and treatment response has come to the forefront. Notably, miRNAs are easily found and detected readily in a variety of biological fluids, including saliva, blood, urine, and feces. This prominence is attributed to the inherent advantages of miRNAs over conventional biomarkers, including heightened stability, specificity, sensitivity, and accessibility. Various investigations have pinpointed miRNA signatures or panels capable of differentiating colorectal cancer patients from their healthy counterparts, predicting colorectal cancer stage and survival, and monitoring colorectal cancer recurrence and therapy response. Although there has been research on miRNAs in various diseases, there has been less research on miRNAs in cancer. Moreover, updated results of preclinical and clinical studies on miRNA biomarkers and drugs are required. Nevertheless, the integration of miRNAs as biomarkers for colorectal cancer is not devoid of challenges and limitations. These encompass the heterogeneity prevalent among colorectal cancer subtypes and stages, the variability in miRNA expression across different tissues and individuals, the absence of standardized methodologies for miRNA detection and quantification, and the imperative for validation through extensive clinical trials. Consequently, further research is imperative to conclusively establish the clinical utility and reliability of miRNAs as colorectal cancer biomarkers. MiR-21 demonstrates carcinogenic characteristics by targeting several tumor suppressor genes, which encourages cell division, invasion, and metastasis. On the other hand, by controlling the Wnt/β-catenin pathway, the tumor suppressor miRNA miR-34a prevents CRC cell proliferation, migration, and invasion. Furthermore, in colorectal cancer, the miR-200 family increases chemotherapy sensitivity while suppressing epithelial-mesenchymal transition (EMT). As an oncogene, the miR-17-92 cluster targets elements of the TGF-β signaling pathway to encourage the growth of CRC cells. Finally, miR-143/145, which is downregulated in CRC, influences apoptosis and the progression of the cell cycle. These miRNAs affect pathways like Wnt, TGF-β, PI3K-AKT, MAPK, and EMT, making them potential clinical biomarkers and therapeutic targets. This review summarizes recent research related to miRNAs, their role in tumor progression and metastasis, and their potential as biomarkers and therapeutic targets in colorectal cancer. In addition, we combined miRNAs' roles in tumorigenesis and development with the therapy of CRC patients, leading to novel perspectives on colorectal cancer diagnosis and treatment.
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Affiliation(s)
- Doha El-Sayed Ellakwa
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy for Girls, Al-Azhar University, Cairo, Egypt.
- Department of Biochemistry, Faculty of Pharmacy, Sinai University, Kantra Branch, Ismailia, Egypt.
| | - Nadia Mushtaq
- Department of Life Sciences, Lahore University of Management Sciences, Lahore, Pakistan
| | - Sahrish Khan
- Center for Applied Molecular Biology (CAMB), University of Punjab, Lahore, Pakistan
| | - Abdul Jabbar
- Department of Veterinary Medicine, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | | | | | - Takwa E Ellakwa
- Physical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Ali Raza
- Department of Veterinary Microbiology, Faculty of Veterinary Medicine, Ataturk University, Erzurum, Turkey
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Lenart M, Siemińska I, Szatanek R, Mordel A, Szczepanik A, Rubinkiewicz M, Siedlar M, Baj-Krzyworzeka M. Identification of miRNAs Present in Cell- and Plasma-Derived Extracellular Vesicles-Possible Biomarkers of Colorectal Cancer. Cancers (Basel) 2024; 16:2464. [PMID: 39001526 PMCID: PMC11240749 DOI: 10.3390/cancers16132464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 06/29/2024] [Accepted: 07/04/2024] [Indexed: 07/16/2024] Open
Abstract
Globally, an increasing prevalence of colorectal cancer (CRC) prompts a need for the development of new methods for early tumor detection. MicroRNAs (also referred to as miRNAs) are short non-coding RNA molecules that play a pivotal role in the regulation of gene expression. MiRNAs are effectively transferred to extracellular vesicle (EVs) membrane sacs commonly released by cells. Our study aimed to examine the expression of miRNAs in four CRC cell lines and EVs derived from them (tumor EVs) in comparison to the normal colon epithelium cell line and its EVs. EVs were isolated by ultracentrifugation from the culture supernatant of SW480, SW620, SW1116, HCT116 and normal CCD841CoN cell lines and characterized according to the MISEV2023 guidelines. MiRNAs were analyzed by small RNA sequencing and validated by quantitative PCR. The performed analysis revealed 22 common miRNAs highly expressed in CRC cell lines and effectively transferred to tumor EVs, including miR-9-5p, miR-182-5p, miR-196b-5p, miR-200b-5p, miR-200c-3p, miR-425-5p and miR-429, which are associated with development, proliferation, invasion and migration of colorectal cancer cells, as well as in vesicle maturation and transport-associated pathways. In parallel, normal cells expressed miRNAs, such as miR-369 and miR-143, which play a role in proinflammatory response and tumor suppression. The analysis of selected miRNAs in plasma-derived EVs and tumor samples from CRC patients showed the similarity of miRNA expression profile between the patients' samples and CRC cell lines. Moreover, miR-182-5p, miR-196-5p, miR-425-5p and miR-429 were detected in several EV samples isolated from patients' plasma. Our results suggest that miR-182-5p, miR-196b-5p and miR-429 are differentially expressed between EVs from CRC patients and healthy donors, which might have clinical implications.
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Affiliation(s)
- Marzena Lenart
- Department of Clinical Immunology, Medical College, Jagiellonian University, 30-663 Krakow, Poland
| | - Izabela Siemińska
- Department of Clinical Immunology, Medical College, Jagiellonian University, 30-663 Krakow, Poland
- Institute of Veterinary Sciences, University Center of Veterinary Medicine JU-AU, University of Agriculture in Krakow, 30-059 Krakow, Poland
| | - Rafał Szatanek
- Department of Clinical Immunology, Medical College, Jagiellonian University, 30-663 Krakow, Poland
| | - Anna Mordel
- Department of Clinical Immunology, University Children's Hospital of Cracow, 30-663 Krakow, Poland
| | - Antoni Szczepanik
- Third Department of Surgery, Faculty of Medicine, Jagiellonian University Medical College, 31-202 Krakow, Poland
| | - Mateusz Rubinkiewicz
- Second Department of Surgery, Jagiellonian University Medical College, 30-688 Krakow, Poland
| | - Maciej Siedlar
- Department of Clinical Immunology, Medical College, Jagiellonian University, 30-663 Krakow, Poland
| | - Monika Baj-Krzyworzeka
- Department of Clinical Immunology, Medical College, Jagiellonian University, 30-663 Krakow, Poland
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Das R, Mehta DK, Gupta N. Understanding the Potential of mRNA as Biomarker to Revolutionize Diagnosis of Colorectal Cancer. Drug Res (Stuttg) 2024; 74:102-112. [PMID: 38350633 DOI: 10.1055/a-2244-6572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2024]
Abstract
MicroRNA as potential biomarker for early diagnosis, differentiating various stages, interpreting the success of postoperative curative surgery and predicting early relapse of Colorectal cancer.In the realm of medical research, the quest to find effective biomarkers for various diseases has always been a top priority. Colorectal cancer (CRC), one of the leading causes of cancer-related deaths worldwide, is no exception. The emergence of microRNA (mRNA) as a potential biomarker for CRC has sparked immense interest among scientists and clinicians alike. mRNA, a molecule responsible for translating genetic information into functional proteins, presents a promising avenue for early detection and personalized treatment of this deadly disease. By analyzing the specific patterns and levels of mRNA expression in CRC cells, researchers have the ability to identify signatures that can aid in accurate diagnosis, predict patient prognosis, and even guide targeted therapies. This breakthrough in molecular biology not only enhances our understanding of CRC but also holds the potential to revolutionize the field of cancer diagnostics and treatment. In this article, we will delve deeper into the potential of mRNA as a biomarker for CRC, exploring its benefits and challenges in the field of cancer research.
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Affiliation(s)
- Rina Das
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
| | - Dinesh Kumar Mehta
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
| | - Nidhi Gupta
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
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Maliborska S, Holotiuk V, Partykevych Y, Rossylna O. PROGNOSTIC SIGNIFICANCE OF microRNA-100, -125b, AND -200b IN PATIENTS WITH COLORECTAL CANCER. Exp Oncol 2024; 45:443-450. [PMID: 38328846 DOI: 10.15407/exp-oncology.2023.04.443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Indexed: 02/09/2024]
Abstract
BACKGROUND The discovery of new markers for colorectal cancer (CRC) is of paramount importance for improving the diagnosis, prognosis, and treatment of this disease. CRC is the third most common cancer worldwide and the second leading cause of cancer-related deaths. Early detection and treatment are crucial for improving patient outcomes, but current screening methods are not foolproof. Additionally, there is a need for better prognostic markers to identify patients at high risk of recurrence or metastasis, who may benefit from more aggressive treatment. OBJECTIVES To analyze the expression profile of miR-100, miR-125b, and miR-200b in the blood serum of CRC patients and assess its correlation with the clinicopathological factors of cancer course. MATERIALS AND METHODS Twenty blood serum samples from CRC patients were analyzed by the real-time polymerase chain reaction for miR-100, miR-125b, and miR-200b expressions. The results were normalized and then analyzed using statistical tests. RESULTS According to our results, miR-125b and -200b expressions correlate with T (r = -0.51 and 0.6, respectively, p < 0.05) and N (r = 0.47 and -0.52, respectively, p < 0.05). Also, miR-125b levels were 1.56 times higher and mir- 200b - 1.59 times lower in patients with metastases in the regional lymph nodes. CONCLUSIONS Observed levels of miR-125b and -200b in correlation with tumor stage and lymph node metastasis among CRC patients demonstrate their potential clinical utility as minimally invasive biomarkers for the prognosis of cancer course. Therefore, further validation studies with larger participant cohorts are necessary.
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Affiliation(s)
- S Maliborska
- Ivano-Frankivsk National Medical University, Department of Oncology, Ivano-Frankivsk, Ukraine
| | - V Holotiuk
- Ivano-Frankivsk National Medical University, Department of Oncology, Ivano-Frankivsk, Ukraine
| | - Y Partykevych
- Prykarpatsky Clinical Oncology Center of the Ivano-Frankivsk Regional Council", Ivano-Frankivsk, Ukraine
| | - O Rossylna
- Clinic for Personalized Diagnostics and Therapy Design "Oncotheranostics", Kyiv, Ukraine
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Nagainallur Ravichandran S, Das D, Dayananda EK, Dey A, Banerjee A, Sun-Zhang A, Zhang H, Sun XF, Pathak S. A Review on Emerging Techniques for Diagnosis of Colorectal Cancer. Cancer Invest 2024; 42:119-140. [PMID: 38404236 DOI: 10.1080/07357907.2024.2315443] [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: 06/11/2023] [Accepted: 02/02/2024] [Indexed: 02/27/2024]
Abstract
Common detection methods in practice for diagnosing colorectal cancer (CRC) are painful and invasive leading to less participation of individuals for CRC diagnosis. Whereas, improved or enhanced imaging systems and other minimally invasive techniques with shorter detection times deliver greater detail and less discomfort in individuals. Thus, this review is a summary of the diagnostic tests, ranging from the simple potential use in developing a flexible CRC treatment to the patient's potential benefits in receiving less invasive procedures and the advanced treatments that might provide a better assessment for the diagnosis of CRC and reduce the mortality related to CRC.
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Affiliation(s)
- Shruthi Nagainallur Ravichandran
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, India
| | - Diptimayee Das
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, India
| | - Erica Katriel Dayananda
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, India
| | - Amit Dey
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, India
| | - Antara Banerjee
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, India
| | - Alexander Sun-Zhang
- Department of Oncology-Pathology, BioClinicum, Karolinska Institutet, Stockholm, Sweden
| | - Hong Zhang
- Faculty of Medicine and Health, School of Medical Sciences, Orebro University, Örebro, Sweden
| | - Xiao-Feng Sun
- Division of Oncology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Surajit Pathak
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai, India
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Moeinafshar A, Nouri M, Shokrollahi N, Masrour M, Behnam A, Tehrani Fateh S, Sadeghi H, Miryounesi M, Ghasemi MR. Non-coding RNAs as potential therapeutic targets for receptor tyrosine kinase signaling in solid tumors: current status and future directions. Cancer Cell Int 2024; 24:26. [PMID: 38200584 PMCID: PMC10782702 DOI: 10.1186/s12935-023-03203-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 12/27/2023] [Indexed: 01/12/2024] Open
Abstract
This review article presents an in-depth analysis of the current state of research on receptor tyrosine kinase regulatory non-coding RNAs (RTK-RNAs) in solid tumors. RTK-RNAs belong to a class of non-coding RNAs (nc-RNAs) responsible for regulating the expression and activity of receptor tyrosine kinases (RTKs), which play a critical role in cancer development and progression. The article explores the molecular mechanisms through which RTK-RNAs modulate RTK signaling pathways and highlights recent advancements in the field. This include the identification of potential new RTK-RNAs and development of therapeutic strategies targeting RTK-RNAs. While the review discusses promising results from a variety of studies, encompassing in vitro, in vivo, and clinical investigations, it is important to acknowledge the challenges and limitations associated with targeting RTK-RNAs for therapeutic applications. Further studies involving various cancer cell lines, animal models, and ultimately, patients are necessary to validate the efficacy of targeting RTK-RNAs. The specificity of ncRNAs in targeting cellular pathways grants them tremendous potential, but careful consideration is required to minimize off-target effects, the article additionally discusses the potential clinical applications of RTK-RNAs as biomarkers for cancer diagnosis, prognosis, and treatment. In essence, by providing a comprehensive overview of the current understanding of RTK-RNAs in solid tumors, this review emphasizes their potential as therapeutic targets for cancer while acknowledging the associated challenges and limitations.
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Affiliation(s)
- Aysan Moeinafshar
- Center for Comprehensive Genetic Services, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Nouri
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nima Shokrollahi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahdi Masrour
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Center for Orthopedic Trans-Disciplinary Applied Research, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirmohammad Behnam
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sahand Tehrani Fateh
- Center for Comprehensive Genetic Services, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Sadeghi
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Miryounesi
- Center for Comprehensive Genetic Services, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad-Reza Ghasemi
- Center for Comprehensive Genetic Services, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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10
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Zhao B, Wang W, Ye H, Wang J, Meng K, Yang T. A novel miRNA-based signature as predictive tool of survival outcome of colorectal cancer patients. Chem Biol Drug Des 2023; 102:1024-1033. [PMID: 37532274 DOI: 10.1111/cbdd.14301] [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: 12/01/2022] [Revised: 06/03/2023] [Accepted: 07/17/2023] [Indexed: 08/04/2023]
Abstract
It is great significance of identifying valuable biomarkers for early diagnosis and prognostic prediction of colorectal cancer (CRC) patients. This study aimed at developing and validating a miRNAs-based signature as prognostic tool for CRC patients. The miRNA expression profile of 624 CRC samples (613 tumor tissues and 11 normal tissues) was analyzed, and 523 differentially expressed miRNAs (DEmiRNAs) were identified, in which 191 were downregulated and 332 were upregulated. All patients were randomly divided into a training cohort (N = 308) and an internal validation cohort (N = 200). Using the least absolute shrinkage and selection operator (LASSO) and Cox regression model, a prognostic signature of 10 miRNAs (hsa-miR-149-5p, hsa-miR-193b-5p, hsa-miR-193a-3p, hsa-miR-3677-3p, hsa-miR-29a-3p, hsa-miR-200c-5p, hsa-miR-200a-5p, hsa-miR-6854-5p, hsa-miR-216a-5p and hsa-miR-891a-5p) was developed in the training cohort. The risk score was calculated by the product of the expression level and the coefficients of each miRNA. The prognostic value of 10 miRNAs-based signature for CRC patients was tested and validated. Survival analysis indicated that high-risk patients (> 1.10) had a worse overall survival (OS) than low-risk (≤ 1.10) patients (5-year OS rate for training cohort: 59.3% vs. 78.9%, p < .001; validation cohort: 48.3% vs. 69.3%, p = .011). The miRNA-based signature was an independent prognostic factor for CRC patients (HR for training cohort:2.476, 95% CI:1.202-5.098, p = .014; HR for validation cohort:2.050, 95% CI:1.087-3.869, p = .027). The AUC values for 3-year and 5-year OS prediction were 0.718 and 0.784 in the training cohort, 0.659 and 0.614 in the validation cohort, respectively. The 10 miRNAs-based signature provided a proper prognostic stratification for CRC patients, and it might be a promising tool for survival prediction.
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Affiliation(s)
- Bochao Zhao
- Department of Gastrointestinal Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Weiqiang Wang
- Department of Gastrointestinal Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Haikun Ye
- Department of Gastrointestinal Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Jingchao Wang
- Department of Gastrointestinal Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Kewei Meng
- Department of Gastrointestinal Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Tao Yang
- Department of Gastrointestinal Surgery, Tianjin First Central Hospital, Tianjin, China
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11
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Lu J, Kornmann M, Traub B. Role of Epithelial to Mesenchymal Transition in Colorectal Cancer. Int J Mol Sci 2023; 24:14815. [PMID: 37834263 PMCID: PMC10573312 DOI: 10.3390/ijms241914815] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 09/28/2023] [Accepted: 09/29/2023] [Indexed: 10/15/2023] Open
Abstract
The epithelial-mesenchymal transition (EMT) is a cellular reprogramming process that occurs during embryonic development and adult tissue homeostasis. This process involves epithelial cells acquiring a mesenchymal phenotype. Through EMT, cancer cells acquire properties associated with a more aggressive phenotype. EMT and its opposite, mesenchymal-epithelial transition (MET), have been described in more tumors over the past ten years, including colorectal cancer (CRC). When EMT is activated, the expression of the epithelial marker E-cadherin is decreased and the expression of the mesenchymal marker vimentin is raised. As a result, cells temporarily take on a mesenchymal phenotype, becoming motile and promoting the spread of tumor cells. Epithelial-mesenchymal plasticity (EMP) has become a hot issue in CRC because strong inducers of EMT (such as transforming growth factor β, TGF-β) can initiate EMT and regulate metastasis, microenvironment, and immune system resistance in CRC. In this review, we take into account the significance of EMT-MET in CRC and the impact of the epithelial cells' plasticity on the prognosis of CRC. The analysis of connection between EMT and colorectal cancer stem cells (CCSCs) will help to further clarify the current meager understandings of EMT. Recent advances affecting important EMT transcription factors and EMT and CCSCs are highlighted. We come to the conclusion that the regulatory network for EMT in CRC is complicated, with a great deal of crosstalk and alternate paths. More thorough research is required to more effectively connect the clinical management of CRC with biomarkers and targeted treatments associated with EMT.
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Affiliation(s)
| | | | - Benno Traub
- Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany; (J.L.); (M.K.)
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12
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Tariq L, Arafah A, Sehar N, Ali A, Khan A, Rasool I, Rashid SM, Ahmad SB, Beigh S, Dar TUH, Rehman MU. Novel insights on perils and promises of miRNA in understanding colon cancer metastasis and progression. Med Oncol 2023; 40:282. [PMID: 37639075 DOI: 10.1007/s12032-023-02099-2] [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: 05/23/2023] [Accepted: 06/19/2023] [Indexed: 08/29/2023]
Abstract
Colorectal cancer (CRC) is the third highest frequent malignancy and ultimate critical source of cancer-associated mortality around the world. Regardless of latest advances in molecular and surgical targeted medicines that have increased remedial effects in CRC patients, the 5-year mortality rate for CRC patients remains dismally low. Evidence suggests that microRNAs (miRNAs) execute an essential part in the development and spread of CRC. The miRNAs are a type of short non-coding RNA that exhibited to control the appearance of tumor suppressor genes and oncogenes. miRNA expression profiling is already being utilized in clinical practice as analytical and prognostic biomarkers to evaluate cancer patients' tumor genesis, advancement, and counteraction to drugs. By modulating their target genes, dysregulated miRNAs are linked to malignant characteristics (e.g., improved proliferative and invasive capabilities, cell cycle aberration, evasion of apoptosis, and promotion of angiogenesis). This review presents an updated summary of circulatory miRNAs, tumor-suppressive and oncogenic miRNAs, and the potential reasons for dysregulated miRNAs in CRC. Further we will explore the critical role of miRNAs in CRC drug resistance.
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Affiliation(s)
- Lubna Tariq
- Department of Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, 183254, India
| | - Azher Arafah
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Nouroz Sehar
- Centre for Translational and Clinical Research, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Aarif Ali
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Alusteng, Shuhama, Srinagar, Jammu and Kashmir, 190006, India
| | - Andleeb Khan
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, 45142, Jazan, Saudi Arabia
| | - Iyman Rasool
- Department of Pathology, Government Medical College (GMC-Srinagar), Karanagar, Srinagar, Jammu and Kashmir, 190006, India
| | - Shahzada Mudasir Rashid
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Alusteng, Shuhama, Srinagar, Jammu and Kashmir, 190006, India
| | - Sheikh Bilal Ahmad
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Alusteng, Shuhama, Srinagar, Jammu and Kashmir, 190006, India
| | - Saba Beigh
- Department of Public Health, Faculty of Applied Medical Science, Al Baha University, 65431, Al Baha, Saudi Arabia
| | - Tanveer Ul Hassan Dar
- Department of Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, 183254, India
| | - Muneeb U Rehman
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, 11451, Riyadh, Saudi Arabia.
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13
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Jelski W, Mroczko B. Potential Diagnostic Utility of microRNAs in Gastrointestinal Cancers. Cancer Manag Res 2023; 15:863-871. [PMID: 37636029 PMCID: PMC10460163 DOI: 10.2147/cmar.s421928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Accepted: 08/02/2023] [Indexed: 08/29/2023] Open
Abstract
Early detection of gastrointestinal cancers is beneficial for patient survival and prognosis. MiRNAs have been shown to be potential cancer biomarkers that can be used to diagnose cancers. MiRNAs are single-stranded, small non-coding RNAs that are involved in the post-transcriptional regulation of the expression of different oncogenes. Cancer tissues contain miRNAs that play a special role in the etiology of cancer development or limiting cancer suppression. Dysregulation of miRNAs occurs in a variety of malignancies, including gastrointestinal cancers. MiRNAs are stable and protected against degradation by RNase, which enables their detection in tissues and biological fluids. The results of many studies suggest that miRNAs have a relatively higher diagnostic efficiency in distinguishing cancer patients from healthy people. The researchers have identified many miRNA signature in the blood for the detection of gastrointestinal cancers. This review focuses on the role and potential utility of miRNAs in the early detection, prognosis and evaluation of the treatment effectiveness of gastrointestinal cancers.
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Affiliation(s)
- Wojciech Jelski
- Department of Biochemical Diagnostics, Medical University, Bialystok, Poland
| | - Barbara Mroczko
- Department of Biochemical Diagnostics, Medical University, Bialystok, Poland
- Department of Neurodegeneration Diagnostics, Medical University, Bialystok, Poland
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14
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Zha B, Luo Y, Kamili M, Zha X. Non-coding RNAs and gastrointestinal cancers prognosis: an umbrella review of systematic reviews and meta-analyses of observational studies. Front Oncol 2023; 13:1193665. [PMID: 37546412 PMCID: PMC10399243 DOI: 10.3389/fonc.2023.1193665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 07/03/2023] [Indexed: 08/08/2023] Open
Abstract
Aim Provide an overview and a systematic evaluation of the evidence quality on the association between non-coding RNAs (ncRNAs) and prognosis value for gastrointestinal cancers (GICs). Methods We searched the literature from three electronic databases: Pubmed, Embase, and Web of science, then carefully screened and extracted the primary information and results from the included articles. We use A measurable systematic review and meta-analysis evaluation tool (AMSTAR2) to evaluate the quality of methodology and then use the Grading of Recommendations Assessment 2, Development and Evaluation guideline (GRADE) make sure the reliability of the meta-analysis. Results Overall, 182 meta-analyses from 58 studies were included in this study. Most of these studies are of low or very low quality. Using the scoring tool, we found that only two meta-analyses were rated as high reliability, and 17 meta-analyses were rated as medium reliability. Conclusions Although ncRNA has good prognostic value in some studies, only a tiny amount of evidence is highly credible at present. More research is needed in the future. PROSPERO registration number CRD42022382296.
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Affiliation(s)
- Bowen Zha
- The Sixth Clinical Medical College, Capital Medical University, Beijing, China
| | - Yuxi Luo
- The First Clinical Medical College, Capital Medical University, Beijing, China
| | - Muladili Kamili
- The Sixth Clinical Medical College, Capital Medical University, Beijing, China
| | - Xiaqin Zha
- Department of Blood Purification, University Affiliated Second Hospital, Nanchang, China
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15
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Chen H, Xie G, Luo Q, Yang Y, Hu S. Regulatory miRNAs, circRNAs and lncRNAs in cell cycle progression of breast cancer. Funct Integr Genomics 2023; 23:233. [PMID: 37432486 DOI: 10.1007/s10142-023-01130-z] [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: 05/14/2023] [Revised: 06/01/2023] [Accepted: 06/07/2023] [Indexed: 07/12/2023]
Abstract
Breast cancer is a complex and heterogeneous disease that poses a significant public health concern worldwide, and it remains a major challenge despite advances in treatment options. One of the main properties of cancer cells is the increased proliferative activity that has lost regulation. Dysregulation of various positive and negative modulators in the cell cycle has been identified as one of the driving factors of breast cancer. In recent years, non-coding RNAs have garnered much attention in the regulation of cell cycle progression, with microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs) being of particular interest. MiRNAs are a class of highly conserved and regulatory small non-coding RNAs that play a crucial role in the modulation of various cellular and biological processes, including cell cycle regulation. CircRNAs are a novel form of non-coding RNAs that are highly stable and capable of modulating gene expression at posttranscriptional and transcriptional levels. LncRNAs have also attracted considerable attention because of their prominent roles in tumor development, including cell cycle progression. Emerging evidence suggests that miRNAs, circRNAs and lncRNAs play important roles in the regulation of cell cycle progression in breast cancer. Herein, we summarized the latest related literatures in breast cancer that emphasize the regulatory roles of miRNAs, circRNAs and lncRNAs in cell cycle progress of breast cancer. Further understanding of the precise roles and mechanisms of non-coding RNAs in breast cancer cell cycle regulation could lead to the development of new diagnostic and therapeutic strategies for breast cancer.
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Affiliation(s)
- Huan Chen
- Department of Clinical Laboratory, Wuhan Institute of Technology Hospital, Wuhan Institute of Technology, Wuhan, China
| | - Guoping Xie
- Department of Clinical Laboratory, The Second Staff Hospital of Wuhan Iron and Steel (Group) Corporation, Wuhan, China
| | - Qunying Luo
- Department of Internal Medicine-Neurology, Huarun Wuhan Iron and Steel General Hospital, Wuhan, China
| | - Yisha Yang
- Luoyang Campus, Henan Vocational College of Agriculture, Luoyang, China
| | - Siheng Hu
- Department of Clinical Laboratory, Honggangcheng Street Community Health Service Center, Wuhan, China.
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16
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Pös O, Styk J, Buglyó G, Zeman M, Lukyova L, Bernatova K, Hrckova Turnova E, Rendek T, Csók Á, Repiska V, Nagy B, Szemes T. Cross-Kingdom Interaction of miRNAs and Gut Microbiota with Non-Invasive Diagnostic and Therapeutic Implications in Colorectal Cancer. Int J Mol Sci 2023; 24:10520. [PMID: 37445698 DOI: 10.3390/ijms241310520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/15/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Colorectal cancer (CRC) has one of the highest incidences among all types of malignant diseases, affecting millions of people worldwide. It shows slow progression, making it preventable. However, this is not the case due to shortcomings in its diagnostic and management procedure and a lack of effective non-invasive biomarkers for screening. Here, we discuss CRC-associated microRNAs (miRNAs) and gut microbial species with potential as CRC diagnostic and therapy biomarkers. We provide rich evidence of cross-kingdom miRNA-mediated interactions between the host and gut microbiome. miRNAs have emerged with the ability to shape the composition and dynamics of gut microbiota. Intestinal microbes can uptake miRNAs, which in turn influence microbial growth and provide the ability to regulate the abundance of various microbial species. In the context of CRC, targeting miRNAs could aid in manipulating the balance of the microbiota. Our findings suggest the need for correlation analysis between the composition of the gut microbiome and the miRNA expression profile.
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Affiliation(s)
- Ondrej Pös
- Comenius University Science Park, 841 04 Bratislava, Slovakia
- Geneton Ltd., 841 04 Bratislava, Slovakia
| | - Jakub Styk
- Comenius University Science Park, 841 04 Bratislava, Slovakia
- Geneton Ltd., 841 04 Bratislava, Slovakia
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia
| | - Gergely Buglyó
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Michal Zeman
- Comenius University Science Park, 841 04 Bratislava, Slovakia
| | - Lydia Lukyova
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, 842 05 Bratislava, Slovakia
| | - Kamila Bernatova
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, 842 05 Bratislava, Slovakia
| | - Evelina Hrckova Turnova
- Comenius University Science Park, 841 04 Bratislava, Slovakia
- Slovgen Ltd., 841 04 Bratislava, Slovakia
| | - Tomas Rendek
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia
| | - Ádám Csók
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Vanda Repiska
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia
- Medirex Group Academy, n.p.o., 949 05 Nitra, Slovakia
| | - Bálint Nagy
- Comenius University Science Park, 841 04 Bratislava, Slovakia
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Tomas Szemes
- Comenius University Science Park, 841 04 Bratislava, Slovakia
- Geneton Ltd., 841 04 Bratislava, Slovakia
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, 842 05 Bratislava, Slovakia
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17
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Wu Z, Fang ZX, Hou YY, Wu BX, Deng Y, Wu HT, Liu J. Exosomes in metastasis of colorectal cancers: Friends or foes? World J Gastrointest Oncol 2023; 15:731-756. [PMID: 37275444 PMCID: PMC10237026 DOI: 10.4251/wjgo.v15.i5.731] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 03/07/2023] [Accepted: 04/04/2023] [Indexed: 05/12/2023] Open
Abstract
Colorectal cancer (CRC), the third most common type of cancer worldwide, threaten human health and quality of life. With multidisciplinary, including surgery, chemotherapy and/or radiotherapy, patients with an early diagnosis of CRC can have a good prognosis. However, metastasis in CRC patients is the main risk factor causing cancer-related death. To elucidate the underlying molecular mechanisms of CRC metastasis is the difficult and research focus on the investigation of the CRC mechanism. On the other hand, the tumor microenvironment (TME) has been confirmed as having an essential role in the tumorigenesis and metastasis of malignancies, including CRCs. Among the different factors in the TME, exosomes as extracellular vesicles, function as bridges in the communication between cancer cells and different components of the TME to promote the progression and metastasis of CRC. MicroRNAs packaged in exosomes can be derived from different sources and transported into the TME to perform oncogenic or tumor-suppressor roles accordingly. This article focuses on CRC exosomes and illustrates their role in regulating the metastasis of CRC, especially through the packaging of miRNAs, to evoke exosomes as novel biomarkers for their impact on the metastasis of CRC progression.
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Affiliation(s)
- Zheng Wu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Ze-Xuan Fang
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yan-Yu Hou
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Bing-Xuan Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu Deng
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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18
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Chen W, Li T, Chen C, Zhang J, Ma Z, Hou W, Yao Y, Mao W, Liu C, Kong D, Tang S, Shen W. Three-dimensional ordered DNA network constructed by a biomarker pair for accurate monitoring of colorectal cancer. Biosens Bioelectron 2023; 232:115335. [PMID: 37087986 DOI: 10.1016/j.bios.2023.115335] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 03/31/2023] [Accepted: 04/17/2023] [Indexed: 04/25/2023]
Abstract
Precise and early screening of colorectal cancer (CRC) is one crucial yet challenging task for its treatment, and the analysis of multi-targets of CRC in a single assay with high accuracy is essential for pathological research and clinical diagnosis. Here, a CRC-related biomarker pair, microRNA-211 (miRNA-211) and H2S, was detected by constructing a three-dimensional (3D) ordered DNA network. First, trace amount of miRNA-211 could initiate a hybridization chain reaction-based amplification process. A highly ordered 3D DNA network was formed based on the organized assembly of DNA-cube frameworks that were constructed by DNA origamis and Ag nanoparticles (NPs) encapsulated inside. In the presence of the H2S, Ag NPs within the network can be etched to generate Ag2S quantum dots, which could be better visualized in fluorescence in situ cell imaging. Using the 3D DNA ordered network as the sensing platform, it can acquire dual analysis of biomolecule (miRNA-211) and inorganic gas (H2S) in vitro, overcoming the limitations of single type of biomarker detection in a single assay. This assay achieved a wide linearity range of H2S from 0.05 to 10 μM, and exhibited a low limit of detection of 4.78 nM. This strategy allows us to acquire the spatial distributions of H2S and miRNA expression levels in living CRC cells simultaneously, providing a highly sensitive and selective tool for early screening and monitoring of CRC.
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Affiliation(s)
- Wenhui Chen
- School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang, 212003, Jiangsu Province, PR China
| | - Tingting Li
- School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang, 212003, Jiangsu Province, PR China
| | - Chengbo Chen
- Department of Medicinal Chemistry, University of Washington, Seattle, WA, 98195, USA
| | - Jinghui Zhang
- School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang, 212003, Jiangsu Province, PR China
| | - Ziyu Ma
- School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang, 212003, Jiangsu Province, PR China
| | - Weilin Hou
- School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang, 212003, Jiangsu Province, PR China
| | - Yao Yao
- School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang, 212003, Jiangsu Province, PR China
| | - Wei Mao
- School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang, 212003, Jiangsu Province, PR China
| | - Chang Liu
- School of Grain Science and Technology, Jiangsu University of Science and Technology, Zhenjiang, 212003, Jiangsu Province, PR China
| | - Dezhao Kong
- School of Grain Science and Technology, Jiangsu University of Science and Technology, Zhenjiang, 212003, Jiangsu Province, PR China
| | - Sheng Tang
- School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang, 212003, Jiangsu Province, PR China.
| | - Wei Shen
- School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang, 212003, Jiangsu Province, PR China.
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19
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Mezher M, Abdallah S, Ashekyan O, Shoukari AA, Choubassy H, Kurdi A, Temraz S, Nasr R. Insights on the Biomarker Potential of Exosomal Non-Coding RNAs in Colorectal Cancer: An In Silico Characterization of Related Exosomal lncRNA/circRNA–miRNA–Target Axis. Cells 2023; 12:cells12071081. [PMID: 37048155 PMCID: PMC10093117 DOI: 10.3390/cells12071081] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 03/28/2023] [Accepted: 03/31/2023] [Indexed: 04/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancer types, ranking third after lung and breast cancers. As such, it demands special attention for better characterization, which may eventually result in the development of early detection strategies and preventive measures. Currently, components of bodily fluids, which may reflect various disease states, are being increasingly researched for their biomarker potential. One of these components is the circulating extracellular vesicles, namely, exosomes, which are demonstrated to carry various cargo. Of importance, the non-coding RNA cargo of circulating exosomes, especially long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and micro RNAs (miRNAs), may potentially serve as significant diagnostic and prognostic/predictive biomarkers. In this review, we present existing evidence on the diagnostic and prognostic/predictive biomarker value of exosomal non-coding RNAs in CRC. In addition, taking advantage of the miRNA sponging functionality of lncRNAs and circRNAs, we demonstrate an experimentally validated CRC exosomal non-coding RNA-regulated target gene axis benefiting from published miRNA sponging studies in CRC. Hence, we present a set of target genes and pathways downstream of the lncRNA/circRNA–miRNA–target axis along with associated significant Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, which may collectively serve to better characterize CRC and shed light on the significance of exosomal non-coding RNAs in CRC diagnosis and prognosis/prediction.
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Affiliation(s)
- Maria Mezher
- Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
| | - Samira Abdallah
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
| | - Ohanes Ashekyan
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
| | - Ayman Al Shoukari
- Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
| | - Hayat Choubassy
- Faculty of Sciences, Lebanese University, Beirut P.O. Box 6573, Lebanon
| | - Abdallah Kurdi
- Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut 1107 2020, Lebanon
| | - Sally Temraz
- Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
| | - Rihab Nasr
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
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20
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Altman J, Jones G, Ahmed S, Sharma S, Sharma A. Tear Film MicroRNAs as Potential Biomarkers: A Review. Int J Mol Sci 2023; 24:3694. [PMID: 36835108 PMCID: PMC9962948 DOI: 10.3390/ijms24043694] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 02/06/2023] [Accepted: 02/07/2023] [Indexed: 02/15/2023] Open
Abstract
MicroRNAs are non-coding RNAs that serve as regulatory molecules in a variety of pathways such as inflammation, metabolism, homeostasis, cell machinery, and development. With the progression of sequencing methods and modern bioinformatics tools, novel roles of microRNAs in regulatory mechanisms and pathophysiological states continue to expand. Advances in detection methods have further enabled larger adoption of studies utilizing minimal sample volumes, allowing the analysis of microRNAs in low-volume biofluids, such as the aqueous humor and tear fluid. The reported abundance of extracellular microRNAs in these biofluids has prompted studies to explore their biomarker potential. This review compiles the current literature reporting microRNAs in human tear fluid and their association with ocular diseases including dry eye disease, Sjögren's syndrome, keratitis, vernal keratoconjunctivitis, glaucoma, diabetic macular edema, and diabetic retinopathy, as well as non-ocular diseases, including Alzheimer's and breast cancer. We also summarize the known roles of these microRNAs and shed light on the future progression of this field.
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Affiliation(s)
- Jeremy Altman
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Garrett Jones
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Saleh Ahmed
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Shruti Sharma
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
- Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Ashok Sharma
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
- Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
- Department of Population Health Sciences, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
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21
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Horak J, Kubecek O, Siskova A, Honkova K, Chvojkova I, Krupova M, Manethova M, Vodenkova S, García-Mulero S, John S, Cecka F, Vodickova L, Petera J, Filip S, Vymetalkova V. Differences in genome, transcriptome, miRNAome, and methylome in synchronous and metachronous liver metastasis of colorectal cancer. Front Oncol 2023; 13:1133598. [PMID: 37182133 PMCID: PMC10172672 DOI: 10.3389/fonc.2023.1133598] [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: 12/29/2022] [Accepted: 03/20/2023] [Indexed: 05/16/2023] Open
Abstract
Despite distant metastases being the critical factor affecting patients' survival, they remain poorly understood. Our study thus aimed to molecularly characterize colorectal cancer liver metastases (CRCLMs) and explore whether molecular profiles differ between Synchronous (SmCRC) and Metachronous (MmCRC) colorectal cancer. This characterization was performed by whole exome sequencing, whole transcriptome, whole methylome, and miRNAome. The most frequent somatic mutations were in APC, SYNE1, TP53, and TTN genes. Among the differently methylated and expressed genes were those involved in cell adhesion, extracellular matrix organization and degradation, neuroactive ligand-receptor interaction. The top up-regulated microRNAs were hsa-miR-135b-3p and -5p, and the hsa-miR-200-family while the hsa-miR-548-family belonged to the top down-regulated. MmCRC patients evinced higher tumor mutational burden, a wider median of duplications and deletions, and a heterogeneous mutational signature than SmCRC. Regarding chronicity, a significant down-regulation of SMOC2 and PPP1R9A genes in SmCRC compared to MmCRC was observed. Two miRNAs were deregulated between SmCRC and MmCRC, hsa-miR-625-3p and has-miR-1269-3p. The combined data identified the IPO5 gene. Regardless of miRNA expression levels, the combined analysis resulted in 107 deregulated genes related to relaxin, estrogen, PI3K-Akt, WNT signaling pathways, and intracellular second messenger signaling. The intersection between our and validation sets confirmed the validity of our results. We have identified genes and pathways that may be considered as actionable targets in CRCLMs. Our data also provide a valuable resource for understanding molecular distinctions between SmCRC and MmCRC. They have the potential to enhance the diagnosis, prognostication, and management of CRCLMs by a molecularly targeted approach.
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Affiliation(s)
- Josef Horak
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia
- Department of Medical Genetics, Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Ondrej Kubecek
- Department of Oncology and Radiotherapy, Faculty of Medicine and University Hospital in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Anna Siskova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czechia
| | - Katerina Honkova
- Department of Genetic Toxicology and Epigenetics, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia
| | - Irena Chvojkova
- Department of Genetic Toxicology and Epigenetics, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia
| | - Marketa Krupova
- The Fingerland Department of Pathology, University Hospital in Hradec Kralove, Hradec Kralove, Czechia
| | - Monika Manethova
- The Fingerland Department of Pathology, University Hospital in Hradec Kralove, Hradec Kralove, Czechia
| | - Sona Vodenkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia
| | - Sandra García-Mulero
- Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO)-Oncobell Programme, Bellvitge Biomedical Research Institute Oncobell Programme, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), Oncobell Programme, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
| | - Stanislav John
- Department of Oncology and Radiotherapy, Faculty of Medicine and University Hospital in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Filip Cecka
- Department of Surgery, Faculty of Medicine and University Hospital in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Ludmila Vodickova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czechia
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia
| | - Jiri Petera
- Department of Oncology and Radiotherapy, Faculty of Medicine and University Hospital in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Stanislav Filip
- Department of Oncology and Radiotherapy, Faculty of Medicine and University Hospital in Hradec Kralove, Charles University, Hradec Kralove, Czechia
- *Correspondence: Veronika Vymetalkova, ; Stanislav Filip,
| | - Veronika Vymetalkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czechia
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia
- *Correspondence: Veronika Vymetalkova, ; Stanislav Filip,
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22
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El-Daly SM, Gouhar SA, Abd Elmageed ZY. Circulating microRNAs as Reliable Tumor Biomarkers: Opportunities and Challenges Facing Clinical Application. J Pharmacol Exp Ther 2023; 384:35-51. [PMID: 35809898 PMCID: PMC9827506 DOI: 10.1124/jpet.121.000896] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 06/23/2022] [Accepted: 06/24/2022] [Indexed: 01/13/2023] Open
Abstract
MicroRNAs (miRNAs) are involved in the development of human malignancies, and cells have the ability to secrete these molecules into extracellular compartments. Thus, cell-free miRNAs (circulating miRNAs) can potentially be used as biomarkers to evaluate pathophysiological changes. Although circulating miRNAs have been proposed as potential noninvasive tumor biomarkers for diagnosis, prognosis, and response to therapy, their routine application in the clinic is far from being achieved. This review focuses on the recent progress regarding the value of circulating miRNAs as noninvasive biomarkers, with specific consideration of their relevant clinical applications. In addition, we provide an in-depth analysis of the technical challenges that impact the assessment of circulating miRNAs. We also highlight the significance of integrating circulating miRNAs with the standard laboratory biomarkers to boost sensitivity and specificity. The current status of circulating miRNAs in clinical trials as tumor biomarkers is also covered. These insights and general guidelines will assist researchers in experimental practice to ensure quality standards and repeatability, thus improving future studies on circulating miRNAs. SIGNIFICANCE STATEMENT: Our review will boost the knowledge behind the inconsistencies and contradictory results observed among studies investigating circulating miRNAs. It will also provide a solid platform for better-planned strategies and standardized techniques to optimize the assessment of circulating cell-free miRNAs.
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Affiliation(s)
- Sherien M El-Daly
- Medical Biochemistry Department, Medicine and Clinical Studies Research Institute, National Research Centre, Dokki, Cairo, Egypt (S.M.E-D., S.A.G.); Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt (S.M.E-D.); and Department of Biomedical Sciences, Discipline of Pharmacology, Edward Via College of Osteopathic Medicine, University of Louisiana-Monroe, Monroe, Louisiana (Z.Y.A.)
| | - Shaimaa A Gouhar
- Medical Biochemistry Department, Medicine and Clinical Studies Research Institute, National Research Centre, Dokki, Cairo, Egypt (S.M.E-D., S.A.G.); Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt (S.M.E-D.); and Department of Biomedical Sciences, Discipline of Pharmacology, Edward Via College of Osteopathic Medicine, University of Louisiana-Monroe, Monroe, Louisiana (Z.Y.A.)
| | - Zakaria Y Abd Elmageed
- Medical Biochemistry Department, Medicine and Clinical Studies Research Institute, National Research Centre, Dokki, Cairo, Egypt (S.M.E-D., S.A.G.); Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt (S.M.E-D.); and Department of Biomedical Sciences, Discipline of Pharmacology, Edward Via College of Osteopathic Medicine, University of Louisiana-Monroe, Monroe, Louisiana (Z.Y.A.)
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23
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Zhou Z, Cao Q, Diao Y, Wang Y, Long L, Wang S, Li P. Non-coding RNA-related antitumor mechanisms of marine-derived agents. Front Pharmacol 2022; 13:1053556. [PMID: 36532760 PMCID: PMC9752855 DOI: 10.3389/fphar.2022.1053556] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Accepted: 11/21/2022] [Indexed: 09/26/2023] Open
Abstract
In the last two decades, natural active substances have attracted great attention in developing new antitumor drugs, especially in the marine environment. A series of marine-derived compounds or derivatives with potential antitumor effects have been discovered and developed, but their mechanisms of action are not well understood. Emerging studies have found that several tumor-related signaling pathways and molecules are involved in the antitumor mechanisms of marine-derived agents, including noncoding RNAs (ncRNAs). In this review, we provide an update on the regulation of marine-derived agents associated with ncRNAs on tumor cell proliferation, apoptosis, cell cycle, invasion, migration, drug sensitivity and resistance. Herein, we also describe recent advances in marine food-derived ncRNAs as antitumor agents that modulate cross-species gene expression. A better understanding of the antitumor mechanisms of marine-derived agents mediated, regulated, or sourced by ncRNAs will provide new biomarkers or targets for potential antitumor drugs from preclinical discovery and development to clinical application.
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Affiliation(s)
- Zhixia Zhou
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Qianqian Cao
- Qingdao Central Hospital, Central Hospital Affiliated to Qingdao University, Qingdao, China
| | - Yujing Diao
- Qingdao Central Hospital, Central Hospital Affiliated to Qingdao University, Qingdao, China
| | - Yin Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Linhai Long
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Shoushi Wang
- Qingdao Central Hospital, Central Hospital Affiliated to Qingdao University, Qingdao, China
| | - Peifeng Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
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24
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Sattar RSA, Verma R, Nimisha, Kumar A, Dar GM, Apurva, Sharma AK, Kumari I, Ahmad E, Ali A, Mahajan B, Saluja SS. Diagnostic and prognostic biomarkers in colorectal cancer and the potential role of exosomes in drug delivery. Cell Signal 2022; 99:110413. [PMID: 35907519 DOI: 10.1016/j.cellsig.2022.110413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 07/13/2022] [Accepted: 07/15/2022] [Indexed: 11/03/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer with the second most frequent cause of death worldwide. One fourth to one fifth of the CRC cases are detected at advance stage. Early detection of colorectal cancer might help in decreasing mortality and morbidity worldwide. CRC being a heterogeneous disease, new non-invasive approaches are needed to complement and improve the screening and management of CRC. Reliable and early detectable biomarkers would improve diagnosis, prognosis, therapeutic responses, and will enable the prediction of drug response and recurrence risk. Over the past decades molecular research has demonstrated the potentials of CTCs, ctDNAs, circulating mRNAs, ncRNAs, and exosomes as tumor biomarkers. Non-invasive screening approaches using fecal samples for identification of altered gut microbes in CRC is also gaining attention. Exosomes can be potential candidates that can be employed in the drug delivery system. Further, the integration of in vitro, in vivo and in silico models that involve CRC biomarkers will help to understand the interactions occurring at the cellular level. This review summarizes recent update on CRC biomarkers and their application along with the nanoparticles followed by the application of organoid culture in CRC.
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Affiliation(s)
- Real Sumayya Abdul Sattar
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Renu Verma
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Nimisha
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Arun Kumar
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Ghulam Mehdi Dar
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Apurva
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Abhay Kumar Sharma
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Indu Kumari
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Ejaj Ahmad
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Asgar Ali
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Bhawna Mahajan
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India; Department of Biochemistry, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Sundeep Singh Saluja
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India; Department of GI Surgery, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India.
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25
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Ge T, Gu X, Jia R, Ge S, Chai P, Zhuang A, Fan X. Crosstalk between metabolic reprogramming and epigenetics in cancer: updates on mechanisms and therapeutic opportunities. CANCER COMMUNICATIONS (LONDON, ENGLAND) 2022; 42:1049-1082. [PMID: 36266736 PMCID: PMC9648395 DOI: 10.1002/cac2.12374] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 09/19/2022] [Accepted: 10/10/2022] [Indexed: 11/24/2022]
Abstract
Reversible, spatial, and temporal regulation of metabolic reprogramming and epigenetic homeostasis are prominent hallmarks of carcinogenesis. Cancer cells reprogram their metabolism to meet the high bioenergetic and biosynthetic demands for vigorous proliferation. Epigenetic dysregulation is a common feature of human cancers, which contributes to tumorigenesis and maintenance of the malignant phenotypes by regulating gene expression. The epigenome is sensitive to metabolic changes. Metabolism produces various metabolites that are substrates, cofactors, or inhibitors of epigenetic enzymes. Alterations in metabolic pathways and fluctuations in intermediate metabolites convey information regarding the intracellular metabolic status into the nucleus by modulating the activity of epigenetic enzymes and thus remodeling the epigenetic landscape, inducing transcriptional responses to heterogeneous metabolic requirements. Cancer metabolism is regulated by epigenetic machinery at both transcriptional and post‐transcriptional levels. Epigenetic modifiers, chromatin remodelers and non‐coding RNAs are integral contributors to the regulatory networks involved in cancer metabolism, facilitating malignant transformation. However, the significance of the close connection between metabolism and epigenetics in the context of cancer has not been fully deciphered. Thus, it will be constructive to summarize and update the emerging new evidence supporting this bidirectional crosstalk and deeply assess how the crosstalk between metabolic reprogramming and epigenetic abnormalities could be exploited to optimize treatment paradigms and establish new therapeutic options. In this review, we summarize the central mechanisms by which epigenetics and metabolism reciprocally modulate each other in cancer and elaborate upon and update the major contributions of the interplays between epigenetic aberrations and metabolic rewiring to cancer initiation and development. Finally, we highlight the potential therapeutic opportunities for hematological malignancies and solid tumors by targeting this epigenetic‐metabolic circuit. In summary, we endeavored to depict the current understanding of the coordination between these fundamental abnormalities more comprehensively and provide new perspectives for utilizing metabolic and epigenetic targets for cancer treatment.
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Affiliation(s)
- Tongxin Ge
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, P. R. China.,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P. R. China
| | - Xiang Gu
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, P. R. China.,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P. R. China
| | - Renbing Jia
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, P. R. China.,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P. R. China
| | - Shengfang Ge
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, P. R. China.,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P. R. China
| | - Peiwei Chai
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, P. R. China.,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P. R. China
| | - Ai Zhuang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, P. R. China.,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P. R. China
| | - Xianqun Fan
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, P. R. China.,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P. R. China
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26
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Noncoding RNAs Emerging as Drugs or Drug Targets: Their Chemical Modification, Bio-Conjugation and Intracellular Regulation. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27196717. [PMID: 36235253 PMCID: PMC9573214 DOI: 10.3390/molecules27196717] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 10/06/2022] [Accepted: 10/07/2022] [Indexed: 11/07/2022]
Abstract
With the increasing understanding of various disease-related noncoding RNAs, ncRNAs are emerging as novel drugs and drug targets. Nucleic acid drugs based on different types of noncoding RNAs have been designed and tested. Chemical modification has been applied to noncoding RNAs such as siRNA or miRNA to increase the resistance to degradation with minimum influence on their biological function. Chemical biological methods have also been developed to regulate relevant noncoding RNAs in the occurrence of various diseases. New strategies such as designing ribonuclease targeting chimeras to degrade endogenous noncoding RNAs are emerging as promising approaches to regulate gene expressions, serving as next-generation drugs. This review summarized the current state of noncoding RNA-based theranostics, major chemical modifications of noncoding RNAs to develop nucleic acid drugs, conjugation of RNA with different functional biomolecules as well as design and screening of potential molecules to regulate the expression or activity of endogenous noncoding RNAs for drug development. Finally, strategies of improving the delivery of noncoding RNAs are discussed.
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27
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Curcumin Targeting Non-Coding RNAs in Colorectal Cancer: Therapeutic and Biomarker Implications. Biomolecules 2022; 12:biom12101339. [PMID: 36291546 PMCID: PMC9599102 DOI: 10.3390/biom12101339] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/12/2022] [Accepted: 09/18/2022] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer is one of the most common gastrointestinal malignancies, with high incidence rates, a low rate of early diagnosis, and complex pathogenesis. In recent years, there has been progress made in its diagnosis and treatment methods, but tumor malignant proliferation and metastasis after treatment still seriously affect the survival and prognosis of patients. Therefore, it is an extremely urgent task of current medicine to find new anti-tumor drugs with high efficiency and safety and low toxicity. Curcumin has shown potent anti-tumor and anti-inflammatory effects and is considered a hot spot in the research and development of anti-tumor drugs due to its advantages of precise efficacy, lower toxic side effects, and less drug resistance. Recent studies have revealed that curcumin has anti-tumor effects exerted on the epigenetic regulation of tumor-promoting/tumor-suppressing gene expression through the alteration of expression levels of non-coding RNAs (e.g., lncRNAs, miRNAs, and circRNAs). Herein, we summarize the interaction between curcumin and non-coding RNAs on the occurrence and development of colorectal cancer. The information complied in this review will serve as a scientific and reliable basis and viewpoint for the clinical application of non-coding RNAs in colorectal cancer.
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28
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Klicka K, Grzywa TM, Mielniczuk A, Klinke A, Włodarski PK. The role of miR-200 family in the regulation of hallmarks of cancer. Front Oncol 2022; 12:965231. [PMID: 36158660 PMCID: PMC9492973 DOI: 10.3389/fonc.2022.965231] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 08/04/2022] [Indexed: 11/16/2022] Open
Abstract
MiRNAs are short non-coding RNAs that regulate gene expression post-transcriptionally contributing to the development of different diseases including cancer. The miR-200 family consists of five members, miR-200a, miR-200b, miR-200c, miR-141, and miR-429. Their expression is dysregulated in cancer tissue and their level is altered in the body fluids of cancer patients. Moreover, the levels of miR-200 family members correlate with clinical parameters such as cancer patients' survival which makes them potentially useful as diagnostic and prognostic biomarkers. MiRNAs can act as either oncomiRs or tumor suppressor miRNAs depending on the target genes and their role in the regulation of key oncogenic signaling pathways. In most types of cancer, the miR-200 family acts as tumor suppressor miRNA and regulates all features of cancer. In this review, we summarized the expression pattern of the miR-200 family in different types of cancer and their potential utility as biomarkers. Moreover, we comprehensively described the role of miR-200 family members in the regulation of all hallmarks of cancer proposed by Hanahan and Weinberg with the focus on the epithelial-mesenchymal transition, invasiveness, and metastasis of tumor cells.
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Affiliation(s)
- Klaudia Klicka
- Department of Methodology, Medical University of Warsaw, Warsaw, Poland
- Doctoral School, Medical University of Warsaw, Warsaw, Poland
| | - Tomasz M. Grzywa
- Department of Methodology, Medical University of Warsaw, Warsaw, Poland
- Department of Immunology, Medical University of Warsaw, Warsaw, Poland
- Laboratory of Experimental Medicine, Medical University of Warsaw, Warsaw, Poland
| | | | - Alicja Klinke
- Department of Methodology, Medical University of Warsaw, Warsaw, Poland
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Yang CK, Hsu HC, Liu YH, Tsai WS, Ma CP, Chen YT, Tan BCM, Lai YY, Chang IYF, Yang C, Yang CY, Yu JS, Liu H. EV-miRome-wide profiling uncovers miR-320c for detecting metastatic colorectal cancer and monitoring the therapeutic response. Cell Oncol (Dordr) 2022; 45:621-638. [PMID: 35849310 PMCID: PMC9424175 DOI: 10.1007/s13402-022-00688-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2022] [Indexed: 11/28/2022] Open
Abstract
PURPOSE Molecular composition of circulating small extracellular vesicles (EVs) does not merely reflect the cells of origin, but also is enriched in specific biomolecules directly associated with the cellular transformation. However, while most of the currently identified EV-miRs are only geared towards one-dimensional disease detection, their application for long-term tracking and treatment response monitoring has been largely elusive. METHODS We established and optimized a rapid, sensitive and robust liquid biopsy sampling method, and further used small RNA sequencing to comprehensively catalogue EV-miRomes in association with the progression and outcome of metastatic colorectal cancer (mCRC). RESULTS By cross-comparison of EV-miRomes (n = 290) from multi-stage and longitudinal cohorts, we uncovered a 15-EV-miR signature with dual detection and long-term monitoring of tumor size progression for mCRC. From this panel, EV-miR-320c was uncovered as a strong clinical marker - aside from its diagnostic power and a therapeutic monitoring performance superior to carcinoembryonic antigen (CEA), its high expression has also been linked to lower overall survival and a greater likelihood of disease recurrence. Further, integrative analyses of tissue transcriptomic and liquid biopsy implicated this 15-EV-miR signature in programming the mesenchymal-epithelial transition (MET) for distant localization of the metastasized cells and also in creating a tumor-favoring metastatic niche. CONCLUSION Our clinically-oriented delineation of the mCRC-associated circulating EV-miRomes systematically revealed the functional significance of these liquid biopsy markers and further strengthen their translational potential in mCRC therapeutic monitoring.
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Affiliation(s)
- Chan-Keng Yang
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Hung-Chih Hsu
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yu-Hao Liu
- Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wen-Sy Tsai
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Chung-Pei Ma
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Yi-Tung Chen
- Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Bertrand Chin-Ming Tan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Research Center for Emerging Viral Infections, Chang Gung University, Taoyuan, Taiwan
- Department of Neurosurgery, Lin-Kou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ying-Yu Lai
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ian Yi-Feng Chang
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
- Department of Neurosurgery, Lin-Kou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chi Yang
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Chia-Yu Yang
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
- Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Jau-Song Yu
- Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
- Liver Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Hsuan Liu
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
- Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
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Hao M, Wang K, Ding Y, Li H, Liu Y, Ding L. Which patients are prone to suffer liver metastasis? A review of risk factors of metachronous liver metastasis of colorectal cancer. Eur J Med Res 2022; 27:130. [PMID: 35879739 PMCID: PMC9310475 DOI: 10.1186/s40001-022-00759-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 07/09/2022] [Indexed: 12/07/2022] Open
Abstract
BACKGROUND In recent years, with the increasing incidence of colorectal cancer (CRC) and its high fatality rate, CRC has seized the attention of the world. And liver metastasis, as the main cause of death of CRC, has become the leading cause of treatment failure in CRC, especially metachronous liver metastasis, have caused patients who underwent bowel resection to experience multiple tortures. MAIN BODY Metachronous liver metastasis has severely affected the quality of life and prognosis of patients. Therefore, in this review, we discuss risk factors for metachronous liver metastasis of CRC, which is the premise for effective intervention for CRC patients who suffer metachronous liver metastasis after undergoing surgery, as well as the signaling pathways associated with CRC. CONCLUSION The occurrence of metachronous liver metastasis is closely related to histology-based prognostic biomarkers, serum-based biomarkers, tumor microenvironment, pre-metastatic niche, liquid biopsy and tissue-based biomarkers. Further research is required to explore the risk factors associated with liver metastasis of CRC.
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Affiliation(s)
- Mengdi Hao
- Department of Oncology Surgery, Beijing Shijitan Hospital, Capital Medical University, Tieyilu 10 Yangfangdian, Haidian, Beijing, 100038, People's Republic of China
- Department of Oncology Surgery, Ninth School of Clinical Medicine, Peking University, Beijing, China
| | - Kun Wang
- Department of Oncology Surgery, Beijing Shijitan Hospital, Capital Medical University, Tieyilu 10 Yangfangdian, Haidian, Beijing, 100038, People's Republic of China
- Department of Oncology Surgery, Ninth School of Clinical Medicine, Peking University, Beijing, China
| | - Yuhan Ding
- Department of Oncology Surgery, Beijing Shijitan Hospital, Capital Medical University, Tieyilu 10 Yangfangdian, Haidian, Beijing, 100038, People's Republic of China
- Department of Oncology Surgery, Ninth School of Clinical Medicine, Peking University, Beijing, China
| | - Huimin Li
- Department of Oncology Surgery, Beijing Shijitan Hospital, Capital Medical University, Tieyilu 10 Yangfangdian, Haidian, Beijing, 100038, People's Republic of China
- Department of Oncology Surgery, Ninth School of Clinical Medicine, Peking University, Beijing, China
| | - Yin Liu
- Department of Oncology Surgery, Beijing Shijitan Hospital, Capital Medical University, Tieyilu 10 Yangfangdian, Haidian, Beijing, 100038, People's Republic of China
- Department of Oncology Surgery, Ninth School of Clinical Medicine, Peking University, Beijing, China
| | - Lei Ding
- Department of Oncology Surgery, Beijing Shijitan Hospital, Capital Medical University, Tieyilu 10 Yangfangdian, Haidian, Beijing, 100038, People's Republic of China.
- Department of Oncology Surgery, Ninth School of Clinical Medicine, Peking University, Beijing, China.
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Sundararajan V, Burk UC, Bajdak-Rusinek K. Revisiting the miR-200 Family: A Clan of Five Siblings with Essential Roles in Development and Disease. Biomolecules 2022; 12:781. [PMID: 35740906 PMCID: PMC9221129 DOI: 10.3390/biom12060781] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/29/2022] [Accepted: 06/01/2022] [Indexed: 12/07/2022] Open
Abstract
Over two decades of studies on small noncoding RNA molecules illustrate the significance of microRNAs (miRNAs/miRs) in controlling multiple physiological and pathological functions through post-transcriptional and spatiotemporal gene expression. Among the plethora of miRs that are essential during animal embryonic development, in this review, we elaborate the indispensable role of the miR-200 family (comprising miR-200a, -200b, 200c, -141, and -429) in governing the cellular functions associated with epithelial homeostasis, such as epithelial differentiation and neurogenesis. Additionally, in pathological contexts, miR-200 family members are primarily involved in tumor-suppressive roles, including the reversal of the cancer-associated epithelial-mesenchymal transition dedifferentiation process, and are dysregulated during organ fibrosis. Moreover, recent eminent studies have elucidated the crucial roles of miR-200s in the pathophysiology of multiple neurodegenerative diseases and tissue fibrosis. Lastly, we summarize the key studies that have recognized the potential use of miR-200 members as biomarkers for the diagnosis and prognosis of cancers, elaborating the application of these small biomolecules in aiding early cancer detection and intervention.
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Affiliation(s)
- Vignesh Sundararajan
- Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, Singapore 117599, Singapore;
| | - Ulrike C. Burk
- Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany;
| | - Karolina Bajdak-Rusinek
- Department of Medical Genetics, Faculty of Medical Sciences, Medical University of Silesia, 40-752 Katowice, Poland
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Wada Y, Shimada M, Morine Y, Ikemoto T, Saito Y, Baba H, Mori M, Goel A. A blood-based noninvasive miRNA signature for predicting survival outcomes in patients with intrahepatic cholangiocarcinoma. Br J Cancer 2022; 126:1196-1204. [PMID: 35079106 PMCID: PMC9023447 DOI: 10.1038/s41416-022-01710-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 11/17/2021] [Accepted: 01/14/2022] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND The prognosis in patients with intrahepatic cholangiocarcinoma (ICC) is generally poor. To improve treatment selection, we sought to identify microRNA (miRNA) signature associated with survival outcomes in ICC. METHODS We first analysed the miRNA expression profiles of primary ICC from two public datasets to identify a miRNA panel to detect patients for short-term survival. We then analysed 309 specimens, including 241 FFPE samples from two clinical cohorts (training: n = 177; validation: n = 64) and matched plasma samples (n = 68), and developed a risk-stratification model incorporating the panel and CA 19-9 levels to predict survival outcomes in ICC. RESULTS We identified a 7-miRNA panel that robustly classified patients with poor outcomes in the discovery cohorts (AUC = 0.80 and 0.88, respectively). We subsequently trained this miRNA panel in a clinical cohort (AUC = 0.83) and evaluated its performance in an independent validation cohort (AUC = 0.82) and plasma samples from the additional validation cohort (AUC = 0.78). Patients in both clinical cohorts who were classified as high-risk had significantly worse prognosis (p < 0.01). The risk-stratification model demonstrated superior performance compared to models (AUC = 0.85). CONCLUSIONS We established a novel miRNA signature that could robustly predict survival outcomes in resected tissues and liquid biopsies to improve the clinical management of patients with ICC.
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Affiliation(s)
- Yuma Wada
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA
- Department of Surgery, Tokushima University, Tokushima, Japan
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
| | - Mitsuo Shimada
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Yuji Morine
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Tetsuya Ikemoto
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Yu Saito
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Masaki Mori
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA.
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Yu S, Zhou Y, Niu L, Qiao Y, Yan Y. Mesenchymal stem cell-derived exosome mir-342-3p inhibits metastasis and chemo-resistance of breast cancer through regulating ID4. Genes Genomics 2022; 44:539-550. [PMID: 35023068 DOI: 10.1007/s13258-021-01200-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/27/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND The mesenchymal stem cell-derived exosome (MSCs-exo) carrying microRNAs have been proved to regulate tumor biological activities. Clarifying molecular mechanism and identifying predictive microRNAs will be of great value in anti-tumor therapy improvement. OBJECTIVE We aimed to investigate the regulatory role of microRNA-342-3p (miR-342-3p) in MSCs-exo on breast cancer. METHODS Breast cancer tissues and cell lines were used to evaluate miR-342-3p expression in patients with or without lymph node/distal organ metastasis. The impact of MSCs-exo expression on tumor cell chemo-resistance and invasion/migration was measured. Dual-luciferase reporter gene assay was applied to identify binding site. Inhibitor of differentiation 4 (ID4) siRNA and miR-342-3p inhibitor transfection was conducted to further explore the miR-342-3p/ID4 axis on chemo-resistance and metastasis of breast cancer cells. RESULTS Breast cancer cells revealed significantly lower level of miR-342-3p in patients with metastatic diseases. miR-342-3p suppressed invasive and chemo-resistant behavior of breast cancer tumor cells. Binding site between miR-342-3p and ID4 was proved. ID4 could reverse the influence of miR-342-3p on chemo-resistance. The tumor inhibition effect of IDA siRNA in vivo was also identified. CONCLUSIONS This study demonstrated that miR-342-3p acted as potential tumor suppressor by inhibiting metastasis and chemo-resistance of breast cancer cells through targeting ID4. This study might provide potential therapy targets for the treatment of breast cancer.
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Affiliation(s)
- Shuyao Yu
- Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, No.277, Yanta West Road, Shaanxi Province, 710061, Xi'an, China
| | - Yuhui Zhou
- Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, No.277, Yanta West Road, Shaanxi Province, 710061, Xi'an, China
| | - Ligang Niu
- Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, No.277, Yanta West Road, Shaanxi Province, 710061, Xi'an, China
| | - Yan Qiao
- Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, No.277, Yanta West Road, Shaanxi Province, 710061, Xi'an, China
| | - Yu Yan
- Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, No.277, Yanta West Road, Shaanxi Province, 710061, Xi'an, China.
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Raue R, Frank AC, Fuhrmann DC, de la Cruz-Ojeda P, Rösser S, Bauer R, Cardamone G, Weigert A, Syed SN, Schmid T, Brüne B. MicroRNA-200c Attenuates the Tumor-Infiltrating Capacity of Macrophages. BIOLOGY 2022; 11:biology11030349. [PMID: 35336722 PMCID: PMC8945044 DOI: 10.3390/biology11030349] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 02/17/2022] [Accepted: 02/18/2022] [Indexed: 12/12/2022]
Abstract
Simple Summary The tumor microenvironment determines the prognosis and outcome for cancer patients. Herein, tumor-associated macrophages are not only highly abundant, but also play a crucial role in shaping a tumor-supporting microenvironment. Both their recruitment to the tumor as well as their functional polarization toward a pro-tumorigenic phenotype are mediated by tumor-derived factors including microRNAs. However, the impact of most microRNAs on the tumor cell-macrophage crosstalk remains to be elucidated. Thus, we reached out to investigate the role of hsa-miR-200c-3p (miR-200c) in tumor cell–macrophage interactions, as it was shown to be differentially expressed during cancer progression and metastasis. miR-200c was highly expressed in MCF7 breast tumor cells compared to macrophages. Furthermore, we identified a CD36-dependent uptake of miR-200c, derived from apoptotic tumor cells, into macrophages. In macrophages, elevated miR-200c levels reduced the expression of numerous migration-associated mRNAs, consequently reducing the capacity of macrophages to infiltrate into tumor spheroids. Finally, a distinct signature of miR-200c-repressed, predicted targets was identified, which strongly correlated with tumor infiltration. Targeting the miR-200c transfer from dying tumor cells to macrophages might therefore provide the opportunity to specifically modulate tumor-associated macrophage recruitment. Abstract Macrophages constitute a major part of the tumor-infiltrating immune cells. Within the tumor microenvironment, they acquire an alternatively activated, tumor-supporting phenotype. Factors released by tumor cells are crucial for the recruitment of tumor-associated macrophages. In the present project, we aimed to understand the role of hsa-miR-200c-3p (miR-200c) in the interplay between tumor cells and macrophages. To this end, we employed a coculture system of MCF7 breast tumor cells and primary human macrophages and observed the transfer of miR-200c from apoptotic tumor cells to macrophages, which required intact CD36 receptor in macrophages. We further comprehensively determined miR-200c targets in macrophages by mRNA-sequencing and identified numerous migration-associated mRNAs to be downregulated by miR-200c. Consequently, miR-200c attenuated macrophage infiltration into 3-dimensional tumor spheroids. miR-200c-mediated reduction in infiltration further correlated with a miR-200c migration signature comprised of the four miR-200c-repressed, predicted targets PPM1F, RAB11FIB2, RDX, and MSN.
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Affiliation(s)
- Rebecca Raue
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (R.R.); (A.-C.F.); (D.C.F.); (S.R.); (R.B.); (G.C.); (A.W.); (S.N.S.); (B.B.)
| | - Ann-Christin Frank
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (R.R.); (A.-C.F.); (D.C.F.); (S.R.); (R.B.); (G.C.); (A.W.); (S.N.S.); (B.B.)
| | - Dominik C. Fuhrmann
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (R.R.); (A.-C.F.); (D.C.F.); (S.R.); (R.B.); (G.C.); (A.W.); (S.N.S.); (B.B.)
| | - Patricia de la Cruz-Ojeda
- Institute of Biomedicine of Seville (IBiS), Hospital University “Virgen del Rocío”/CSIC/University of Seville, 41013 Seville, Spain;
| | - Silvia Rösser
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (R.R.); (A.-C.F.); (D.C.F.); (S.R.); (R.B.); (G.C.); (A.W.); (S.N.S.); (B.B.)
| | - Rebekka Bauer
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (R.R.); (A.-C.F.); (D.C.F.); (S.R.); (R.B.); (G.C.); (A.W.); (S.N.S.); (B.B.)
| | - Giulia Cardamone
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (R.R.); (A.-C.F.); (D.C.F.); (S.R.); (R.B.); (G.C.); (A.W.); (S.N.S.); (B.B.)
| | - Andreas Weigert
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (R.R.); (A.-C.F.); (D.C.F.); (S.R.); (R.B.); (G.C.); (A.W.); (S.N.S.); (B.B.)
- German Cancer Consortium (DKTK), Partner Site Frankfurt, 60590 Frankfurt, Germany
- Frankfurt Cancer Institute, Goethe-University Frankfurt, 60596 Frankfurt, Germany
| | - Shahzad Nawaz Syed
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (R.R.); (A.-C.F.); (D.C.F.); (S.R.); (R.B.); (G.C.); (A.W.); (S.N.S.); (B.B.)
| | - Tobias Schmid
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (R.R.); (A.-C.F.); (D.C.F.); (S.R.); (R.B.); (G.C.); (A.W.); (S.N.S.); (B.B.)
- Correspondence:
| | - Bernhard Brüne
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (R.R.); (A.-C.F.); (D.C.F.); (S.R.); (R.B.); (G.C.); (A.W.); (S.N.S.); (B.B.)
- German Cancer Consortium (DKTK), Partner Site Frankfurt, 60590 Frankfurt, Germany
- Frankfurt Cancer Institute, Goethe-University Frankfurt, 60596 Frankfurt, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology, 60596 Frankfurt, Germany
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Jorgensen BG, Ro S. MicroRNAs and 'Sponging' Competitive Endogenous RNAs Dysregulated in Colorectal Cancer: Potential as Noninvasive Biomarkers and Therapeutic Targets. Int J Mol Sci 2022; 23:2166. [PMID: 35216281 PMCID: PMC8876324 DOI: 10.3390/ijms23042166] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 01/28/2022] [Accepted: 02/02/2022] [Indexed: 12/13/2022] Open
Abstract
The gastrointestinal (GI) tract in mammals is comprised of dozens of cell types with varied functions, structures, and histological locations that respond in a myriad of ways to epigenetic and genetic factors, environmental cues, diet, and microbiota. The homeostatic functioning of these cells contained within this complex organ system has been shown to be highly regulated by the effect of microRNAs (miRNA). Multiple efforts have uncovered that these miRNAs are often tightly influential in either the suppression or overexpression of inflammatory, apoptotic, and differentiation-related genes and proteins in a variety of cell types in colorectal cancer (CRC). The early detection of CRC and other GI cancers can be difficult, attributable to the invasive nature of prophylactic colonoscopies. Additionally, the levels of miRNAs associated with CRC in biofluids can be contradictory and, therefore, must be considered in the context of other inhibiting competitive endogenous RNAs (ceRNA) such as lncRNAs and circRNAs. There is now a high demand for disease treatments and noninvasive screenings such as testing for bloodborne or fecal miRNAs and their inhibitors/targets. The breadth of this review encompasses current literature on well-established CRC-related miRNAs and the possibilities for their use as biomarkers in the diagnoses of this potentially fatal GI cancer.
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Affiliation(s)
| | - Seungil Ro
- Department of Physiology & Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA;
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Wada Y, Shimada M, Morine Y, Ikemoto T, Saito Y, Zhu Z, Wang X, Etxart A, Park Y, Bujanda L, Park IJ, Goel A. Circulating miRNA Signature Predicts Response to Preoperative Chemoradiotherapy in Locally Advanced Rectal Cancer. JCO Precis Oncol 2021; 5:PO.21.00015. [PMID: 34913022 PMCID: PMC8668014 DOI: 10.1200/po.21.00015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 08/22/2021] [Accepted: 10/15/2021] [Indexed: 11/20/2022] Open
Abstract
UNLABELLED Patients with locally advanced rectal cancer (LARC) are recommended to receive preoperative chemoradiotherapy (PCRT) followed by surgery. Response to PCRT varies widely: 60%-70% of patients with LARC do not derive therapeutic benefit from PCRT, whereas 15%-20% of patients achieve pathologic complete response (pCR). We sought to develop a liquid biopsy assay for identifying response to PCRT in patients with LARC. MATERIALS AND METHODS We analyzed two genome-wide microRNA (miRNA) expression profiling data sets from tumor tissue samples for in silico discovery (GSE68204) and validation (GSE29298). We prioritized biomarkers in pretreatment plasma specimens from clinical training (n = 41; 15 responders and 26 nonresponders) and validation (n = 65; 29 responders and 36 nonresponders) cohorts of patients with LARC. We developed an integrated miRNA panel and established a risk assessment model, which was combined with the miRNA panel and carcinoembryonic antigen levels. RESULTS Our comprehensive discovery effort identified an 8-miRNA panel that robustly predicted response to PCRT, with an excellent accuracy in the discovery (area under the curve [AUC] = 0.95) and validation (AUC = 0.92) cohorts. We successfully established a circulating miRNA panel with remarkable diagnostic accuracy in the clinical training (AUC = 0.82) and validation (AUC = 0.81) cohorts. Moreover, the predictive accuracy of the panel was significantly superior to conventional clinical factors in both cohorts (P < .01) and the risk assessment model was superior (AUC = 0.83). Finally, we applied our model to detect patients with pathologic complete response and showed that it was dramatically superior to currently used pathologic features (AUC = 0.92). CONCLUSION Our novel risk assessment signature for predicting response to PCRT has a potential for clinical translation as a liquid biopsy assay in patients with LARC.
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Affiliation(s)
- Yuma Wada
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA
- Department of Surgery, Tokushima University, Tokushima, Japan
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX
| | - Mitsuo Shimada
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Yuji Morine
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Tetsuya Ikemoto
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Yu Saito
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Zhongxu Zhu
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Xin Wang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Ane Etxart
- Department of Surgery, Donostia Hospital University, Instituto Biodonostia, San Sebastián, Spain
| | - Yangsoon Park
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Luis Bujanda
- Gastroenterology Department, Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Universidad del País Vasco (UPV/EHU), San Sebastián, Spain
| | - In Ja Park
- Division of Colon and Rectal Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX
- City of Hope Comprehensive Cancer Center, Duarte, CA
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Cavallari I, Ciccarese F, Sharova E, Urso L, Raimondi V, Silic-Benussi M, D’Agostino DM, Ciminale V. The miR-200 Family of microRNAs: Fine Tuners of Epithelial-Mesenchymal Transition and Circulating Cancer Biomarkers. Cancers (Basel) 2021; 13:5874. [PMID: 34884985 PMCID: PMC8656820 DOI: 10.3390/cancers13235874] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 12/13/2022] Open
Abstract
The miR-200 family of microRNAs (miRNAs) includes miR-200a, miR-200b, miR-200c, miR-141 and miR-429, five evolutionarily conserved miRNAs that are encoded in two clusters of hairpin precursors located on human chromosome 1 (miR-200b, miR-200a and miR-429) and chromosome 12 (miR-200c and miR-141). The mature -3p products of the precursors are abundantly expressed in epithelial cells, where they contribute to maintaining the epithelial phenotype by repressing expression of factors that favor the process of epithelial-to-mesenchymal transition (EMT), a key hallmark of oncogenic transformation. Extensive studies of the expression and interactions of these miRNAs with cell signaling pathways indicate that they can exert both tumor suppressor- and pro-metastatic functions, and may serve as biomarkers of epithelial cancers. This review provides a summary of the role of miR-200 family members in EMT, factors that regulate their expression, and important targets for miR-200-mediated repression that are involved in EMT. The second part of the review discusses the potential utility of circulating miR-200 family members as diagnostic/prognostic biomarkers for breast, colorectal, lung, ovarian, prostate and bladder cancers.
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Affiliation(s)
- Ilaria Cavallari
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Francesco Ciccarese
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Evgeniya Sharova
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Loredana Urso
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padova, Italy
| | - Vittoria Raimondi
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Micol Silic-Benussi
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Donna M. D’Agostino
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
- Department of Biomedical Sciences, University of Padua, 35131 Padova, Italy
| | - Vincenzo Ciminale
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padova, Italy
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Hu X, Chen Q, Guo H, Li K, Fu B, Chen Y, Zhao H, Wei M, Li Y, Wu H. Identification of Target PTEN-Based miR-425 and miR-576 as Potential Diagnostic and Immunotherapeutic Biomarkers of Colorectal Cancer With Liver Metastasis. Front Oncol 2021; 11:657984. [PMID: 34490081 PMCID: PMC8418231 DOI: 10.3389/fonc.2021.657984] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 07/28/2021] [Indexed: 12/19/2022] Open
Abstract
A major complication of colorectal cancer (CRC), one of the most common and fatal types of cancers, is secondary liver metastasis. For patients with this fate, there are very few biomarkers available in clinical application, and the disease remains incurable. Recently, increasing studies demonstrated that tumorigenesis and development are closely related to immune escape, indicating that the roles of immune-related indicators might have been neglected in the past in colorectal cancer liver metastases (CRLM). Here, we unveil that elevated miR-425 and miR-576 promote CRLM through inhibiting PTEN-mediated cellular immune function. Specifically, miR-425 and miR-576 were identified for their significant upregulation in CRLM compared with the primary CRC tissues based on GSE81581 (n = 8) and GSE44121 (n = 18) datasets. Besides, we determined that the two microRNAs (miRNAs) coparticipated in restraining P53 and transforming growth factor beta (TGF-β) signaling pathways associated with tumor metastasis, and both shortened the overall survival of the patients with metastatic susceptibility. Notably, in situ hybridization on relatively large samples of paired CRC tissues (n = 157) not only substantiated that the expression of miR-425 and miR-576 was dramatically upregulated in CRLM but also revealed that they were closely related to tumor deterioration, especially liver metastases. Moreover, we further confirmed that the combination of miR-425 and miR-576 was an effective predictive model for liver metastases and poor clinical outcomes. Mechanically, downregulated PTEN (GSE81558, n = 6) was verified to be a shared target of miR-425 and miR-576 acting as metastasis-related oncogenes, on account of the presence of binding sites (+2928-+2934 and +4371-+4378, respectively) and the collaborative suppression of P53/TGF-β signaling in CRLM, which was further confirmed in CRC cells (HCT116 and SW480) based on systematic molecular biology experiments. Importantly, the target PTEN was strongly associated with microsatellite instability, tumor microenvironment, and immune cell infiltration. Thus, we speculate that miR-425 and miR-576 are novel biomarkers for CRLM prevention and immunotherapy and upstream inhibitors of the PTEN-P53/TGF-β function axis.
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Affiliation(s)
- Xiaoyun Hu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China.,Department of Gene Detection, Liaoning Medical Diagnosis and Treatment Center, Shenyang, China
| | - Qiuchen Chen
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China.,Department of Gene Detection, Liaoning Medical Diagnosis and Treatment Center, Shenyang, China
| | - Hao Guo
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China.,Department of Gene Detection, Liaoning Medical Diagnosis and Treatment Center, Shenyang, China
| | - Kuo Li
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China.,Department of Gene Detection, Liaoning Medical Diagnosis and Treatment Center, Shenyang, China
| | - Boshi Fu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China.,Department of Gene Detection, Liaoning Medical Diagnosis and Treatment Center, Shenyang, China
| | - Yu Chen
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China.,Department of Gene Detection, Liaoning Medical Diagnosis and Treatment Center, Shenyang, China
| | - Haishan Zhao
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China.,Department of Gene Detection, Liaoning Medical Diagnosis and Treatment Center, Shenyang, China
| | - Minjie Wei
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China.,Department of Gene Detection, Liaoning Medical Diagnosis and Treatment Center, Shenyang, China
| | - Yalun Li
- Department of Anorectal Surgery, First Hospital of China Medical University, Shenyang, China
| | - Huizhe Wu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China.,Department of Gene Detection, Liaoning Medical Diagnosis and Treatment Center, Shenyang, China
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A Prehepatectomy Circulating Exosomal microRNA Signature Predicts the Prognosis and Adjuvant Chemotherapeutic Benefits in Colorectal Liver Metastasis. Cancers (Basel) 2021; 13:cancers13174258. [PMID: 34503068 PMCID: PMC8428239 DOI: 10.3390/cancers13174258] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 08/14/2021] [Accepted: 08/16/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Exosomal miRNAs are associated with colorectal cancer liver metastasis (CRLM)-related biological behavior and prognosis. However, an exosomal miRNA signature predicting postoperative survival and the value of adjuvant chemotherapy for CRLM remains elusive. Using miRNA sequencing and the LASSO model, we constructed an miRNA signature comprising four exosomes. The signature showed a good predictive performance for patient outcome and the advantage of adjuvant chemotherapy after hepatectomy in two institutions’ training and validation cohorts. In addition, we found that the four miRNAs could target signaling molecules playing crucial roles in colorectal cancer metastasis, vesicle-related processing, and T cell activation. Furthermore, the exosomal miRNA score also increased with the decreasing Immunoscore. We believe that our signature can predict the prognosis and guide adjuvant chemotherapy decisions after liver metastasectomy in CRLM patients, further improving the predictive performance of the current CRLM predictive model system. Abstract Background: The clinical risk score (CRS) for prediction and treatment decision in colorectal liver metastasis (CRLM) is important, but imprecise. Exosomal miRNAs play critical roles in CRLM-related biological behavior. However, an exosomal miRNA score system for predicting posthepatectomy survival and the adjuvant chemotherapy benefit of CRLM remains elusive. Methods: miRNA sequencing was used to identify differentially expressed miRNAs, and the LASSO model was used to select miRNAs to construct the intent model. The predictive performance of the model was evaluated by the area under the ROC curve (AUC) in the training, internal validation, and external validation cohorts. Results: Sixteen differentially expressed exosomal miRNAs were identified, and four miRNAs were selected for model construction. Our model performed well in predicting prognosis with five-year AUCs of 0.70 (95% CI: 0.59–0.81), 0.70 (0.61–0.81), and 0.72 (057–0.86) in the training, internal, and external validation cohorts, respectively. miRNA classifier high-risk patients had better survival benefit from adjuvant chemotherapy regardless of CRS. All four miRNAs target signaling molecules play crucial roles in colorectal cancer metastasis, vesicle-related processing, and T cell activation. It also negatively correlated with the liver metastasis Immunoscore. Conclusion: We developed a circulating exosomal miRNA signature that can predict the prognosis and guide adjuvant chemotherapy decisions after hepatectomy in CRLM.
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Xiao W, Zhou H, Chen B, Shen B, Zhou J. miR-582-5p inhibits migration and chemo-resistant capabilities of colorectal cancer cells by targeting TNKS2. Genes Genomics 2021; 44:747-756. [PMID: 34357507 DOI: 10.1007/s13258-021-01141-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 07/14/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Metastasis and chemo-resistance are still important factors that limit the overall efficacy of colorectal cancer treatment. Understanding the detailed molecular mechanism and identifying potential biomarkers are of great value in prognosis prediction and risk stratification. OBJECTIVE We investigated the role of miR-582-5p in colorectal cancer pathogenesis, progression and chemo-resistance. Furthermore, we explored the underlying molecular mechanism of miR-582-5p in modulation of malignant behaviors of colorectal cancer cells. METHODS Clinical samples and colorectal cancer cell lines were applied to explore miR-582-5p expression level and its significance on tumor cell metastasis and chemo-resistance. Transwell study and cellular survivability study were performed to explore the influences of miR-582-5p expression modulation on tumor cell chemo-resistance and invasion/migration. Dual-luciferase reporter gene assay was conducted to explore the influences of miR-582-5p on its target gene TNKS2. RESULTS Colorectal cancer patients with lymph node or distal organ metastatic diseases exhibited significantly lower level of miR-582-5p. In vitro studies have indicated that miR-582-5p inhibition significantly increased migration and chemo-resistant capabilities of tumor cells. And dual-luciferase reporter gene assay demonstrated that miR-582-5p exhibited its influences on the biological behavior of tumor cells by targeting TNKS2. CONCLUSIONS Our study demonstrated for the first time that miR-582-5p played an important role for colorectal tumor cell metastasis and chemo-resistance. Our research also indicated that miR-582-5p and its target gene TNKS2 could be novel biomarkers for metastatic disease prediction, overall prognosis evaluation, as well as potential therapeutic target for colorectal cancer patients.
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Affiliation(s)
- Weixing Xiao
- Department of Hepatobiliary Surgery, Jiaxing Hospital of Traditional Chinese Medicine, No. 1501 Zhongshan East Road, Jiaxing, 314000, Zhejiang, China
| | - Haijun Zhou
- Department of Hepatobiliary Surgery, Jiaxing Hospital of Traditional Chinese Medicine, No. 1501 Zhongshan East Road, Jiaxing, 314000, Zhejiang, China.
| | - Bingrong Chen
- Department of Hepatobiliary Surgery, Jiaxing Hospital of Traditional Chinese Medicine, No. 1501 Zhongshan East Road, Jiaxing, 314000, Zhejiang, China
| | - Bin Shen
- Department of Hepatobiliary Surgery, Jiaxing Hospital of Traditional Chinese Medicine, No. 1501 Zhongshan East Road, Jiaxing, 314000, Zhejiang, China
| | - Jun Zhou
- Department of Hepatobiliary Surgery, Jiaxing Hospital of Traditional Chinese Medicine, No. 1501 Zhongshan East Road, Jiaxing, 314000, Zhejiang, China
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Wada Y, Shimada M, Murano T, Takamaru H, Morine Y, Ikemoto T, Saito Y, Balaguer F, Bujanda L, Pellise M, Kato K, Saito Y, Ikematsu H, Goel A. A Liquid Biopsy Assay for Noninvasive Identification of Lymph Node Metastases in T1 Colorectal Cancer. Gastroenterology 2021; 161:151-162.e1. [PMID: 33819484 PMCID: PMC10360659 DOI: 10.1053/j.gastro.2021.03.062] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 03/02/2021] [Accepted: 03/22/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS We recently reported use of tissue-based transcriptomic biomarkers (microRNA [miRNA] or messenger RNA [mRNA]) for identification of lymph node metastasis (LNM) in patients with invasive submucosal colorectal cancers (T1 CRC). In this study, we translated our tissue-based biomarkers into a blood-based liquid biopsy assay for noninvasive detection of LNM in patients with high-risk T1 CRC. METHODS We analyzed 330 specimens from patients with high-risk T1 CRC, which included 188 serum samples from 2 clinical cohorts-a training cohort (N = 46) and a validation cohort (N = 142)-and matched formalin-fixed paraffin-embedded samples (N = 142). We performed quantitative reverse-transcription polymerase chain reaction, followed by logistic regression analysis, to develop an integrated transcriptomic panel and establish a risk-stratification model combined with clinical risk factors. RESULTS We used comprehensive expression profiling of a training cohort of LNM-positive and LMN-negative serum specimens to identify an optimized transcriptomic panel of 4 miRNAs (miR-181b, miR-193b, miR-195, and miR-411) and 5 mRNAs (AMT, forkhead box A1 [FOXA1], polymeric immunoglobulin receptor [PIGR], matrix metalloproteinase 1 [MMP1], and matrix metalloproteinase 9 [MMP9]), which robustly identified patients with LNM (area under the curve [AUC], 0.86; 95% confidence interval [CI], 0.72-0.94). We validated panel performance in an independent validation cohort (AUC, 0.82; 95% CI, 0.74-0.88). Our risk-stratification model was more accurate than the panel and an independent predictor for identification of LNM (AUC, 0.90; univariate: odds ratio [OR], 37.17; 95% CI, 4.48-308.35; P < .001; multivariate: OR, 17.28; 95% CI, 1.82-164.07; P = .013). The model limited potential overtreatment to only 18% of all patients, which is dramatically superior to pathologic features that are currently used (92%). CONCLUSIONS A novel risk-stratification model for noninvasive identification of T1 CRC has the potential to avoid unnecessary operations for patients classified as high-risk by conventional risk-classification criteria.
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Affiliation(s)
- Yuma Wada
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas; Department of Surgery, Tokushima University, Tokushima, Japan; Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, California
| | - Mitsuo Shimada
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Tatsuro Murano
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, Chiba, Japan
| | | | - Yuji Morine
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Tetsuya Ikemoto
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Yu Saito
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Francesc Balaguer
- Gastroenterology Department, Hospital Clinic de Barcelona, Barcelona, Spain; Department of Gastroenterology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Luis Bujanda
- Gastroenterology Department, Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Universidad del País Vasco (UPV)/Euskal Herriko Unibertsitatea (EHU), San Sebastián, Spain
| | - Maria Pellise
- Gastroenterology Department, Hospital Clinic de Barcelona, Barcelona, Spain; Department of Gastroenterology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Ken Kato
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan; Clinical Research Support Office, Clinical Research Coordinating Section, Biobank Translational Research Support Section, National Cancer Center Hospital, Tokyo, Japan
| | - Yutaka Saito
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Hiroaki Ikematsu
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, Chiba, Japan
| | - Ajay Goel
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas; Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, California.
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Pan F, Zhang D, Li N, Liu M. Circular RNA circFAT1(e2) Promotes Colorectal Cancer Tumorigenesis via the miR-30e-5p/ITGA6 Axis. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2021; 2021:9980459. [PMID: 34257702 PMCID: PMC8257361 DOI: 10.1155/2021/9980459] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/25/2021] [Accepted: 06/06/2021] [Indexed: 01/22/2023]
Abstract
circRNAs (circular RNAs) are a family of noncoding RNAs and have diverse physiological and pathological functions. However, the functions and mechanisms of circRNAs in the development and progression of colorectal cancer (CRC) remain largely unknown. Here, we aimed to explore the functions and roles of circFAT1(e2) in CRC. qRT-PCR revealed that circFAT1(e2) in CRC tumor tissues was upregulated compared with that in adjacent normal tissues and was also upregulated in CRC cell lines. Small interfering RNAs (siRNAs) against circFAT1(e2) were used to decrease the expression of circFAT1(e2) in HCT116 and RKO cells in vitro. The roles of circFAT1(e2) in CRC cell metastasis and proliferation were then determined by transwell and CCK-8 assays. The results showed that circFAT1(e2) silencing markedly suppressed CRC growth. Moreover, we identified circFAT1(e2) as a promoter of CRC metastasis. Knockdown of circFAT1(e2) evidently reduced HCT116 and RKO cell migration and invasion. Furthermore, the regulatory relationship between circFAT1(e2) and its target miRNAs was verified by a luciferase reporter assay. We demonstrated that circFAT1(e2) could sponge miR-30e-5p, which regulated the expression level of integrin α6 (ITGA6), the downstream target gene of miR-30e-5p. Rescue assays demonstrated that knockdown of miR-30e-5p enhanced CRC proliferation and migration via ITGA6. Taken together, our results reveal the novel oncogenic roles of circFAT1(e2) in CRC through the miR-30e-5p/ITGA6 axis.
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Affiliation(s)
- Fei Pan
- Department of General Practice, Minhang Hospital, Fudan University, 170 Xinsong Road, 201199 Shanghai, China
| | - Dongqing Zhang
- Department of General Practice, Minhang Hospital, Fudan University, 170 Xinsong Road, 201199 Shanghai, China
| | - Na Li
- Department of General Practice, Minhang Hospital, Fudan University, 170 Xinsong Road, 201199 Shanghai, China
| | - Mei Liu
- Department of General Practice, Minhang Hospital, Fudan University, 170 Xinsong Road, 201199 Shanghai, China
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Pidíková P, Herichová I. miRNA Clusters with Up-Regulated Expression in Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13122979. [PMID: 34198662 PMCID: PMC8232258 DOI: 10.3390/cancers13122979] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/05/2021] [Accepted: 06/09/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary As miRNAs show the capacity to be used as CRC biomarkers, we analysed experimentally validated data about frequently up-regulated miRNA clusters in CRC tissue. We identified 15 clusters that showed increased expression in CRC: miR-106a/363, miR-106b/93/25, miR-17/92a-1, miR-181a-1/181b-1, miR-181a-2/181b-2, miR-181c/181d, miR-183/96/182, miR-191/425, miR-200c/141, miR-203a/203b, miR-222/221, mir-23a/27a/24-2, mir-29b-1/29a, mir-301b/130b and mir-452/224. Cluster positions in the genome are intronic or intergenic. Most clusters are regulated by several transcription factors, and by long non-coding RNAs. In some cases, co-expression of miRNA with other cluster members or host gene has been proven. miRNA expression patterns in cancer tissue, blood and faeces were compared. The members of the selected clusters target 181 genes. Their functions and corresponding pathways were revealed with the use of Panther analysis. Clusters miR-17/92a-1, miR-106a/363, miR-106b/93/25 and miR-183/96/182 showed the strongest association with metastasis occurrence and poor patient survival, implicating them as the most promising targets of translational research. Abstract Colorectal cancer (CRC) is one of the most common malignancies in Europe and North America. Early diagnosis is a key feature of efficient CRC treatment. As miRNAs can be used as CRC biomarkers, the aim of the present study was to analyse experimentally validated data on frequently up-regulated miRNA clusters in CRC tissue and investigate their members with respect to clinicopathological characteristics of patients. Based on available data, 15 up-regulated clusters, miR-106a/363, miR-106b/93/25, miR-17/92a-1, miR-181a-1/181b-1, miR-181a-2/181b-2, miR-181c/181d, miR-183/96/182, miR-191/425, miR-200c/141, miR-203a/203b, miR-222/221, mir-23a/27a/24-2, mir-29b-1/29a, mir-301b/130b and mir-452/224, were selected. The positions of such clusters in the genome can be intronic or intergenic. Most clusters are regulated by several transcription factors, and miRNAs are also sponged by specific long non-coding RNAs. In some cases, co-expression of miRNA with other cluster members or host gene has been proven. miRNA expression patterns in cancer tissue, blood and faeces were compared. Based on experimental evidence, 181 target genes of selected clusters were identified. Panther analysis was used to reveal the functions of the target genes and their corresponding pathways. Clusters miR-17/92a-1, miR-106a/363, miR-106b/93/25 and miR-183/96/182 showed the strongest association with metastasis occurrence and poor patient survival, implicating them as the most promising targets of translational research.
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Shoji Y, Furuhashi S, Kelly DF, Bilchik AJ, Hoon DSB, Bustos MA. Current status of gastrointestinal tract cancer brain metastasis and the use of blood-based cancer biomarker biopsy. Clin Exp Metastasis 2021; 39:61-69. [PMID: 33950411 DOI: 10.1007/s10585-021-10094-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 03/25/2021] [Indexed: 12/24/2022]
Abstract
Brain metastasis (BM) frequently occurs in patients with cutaneous melanoma, lung, and breast cancer; although, BM rarely arises from cancers of the gastrointestinal tract (GIT). The reported incidence of GIT cancer BM is less than 4%. In the last few years, effective systemic therapy has prolonged the survival of GIT patients and consequently, the incidence of developing BM is rising. Therefore, the epidemiology and biology of BM arising from GIT cancer requires a more comprehensive understanding. In spite of the development of new therapeutic agents for patients with metastatic GIT cancers, survival for patients with BM still remains poor, with a median survival after diagnosis of less than 4 months. Limited evidence suggests that early detection of isolated intra-cranial lesions will enable surgical resection plus systemic and/or radiation therapy, which may lead to an increase in overall survival. Novel diagnostic methods such as blood-based biomarker biopsies may play a crucial role in the early detection of BM. Circulating tumor cells and circulating cell-free nucleic acids are known to serve as blood biomarkers for early detection and treatment response monitoring of multiple cancers. Blood biopsy may improve early diagnosis and treatment monitoring of GIT cancers BM, thus prolonging patients' survivals.
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Affiliation(s)
- Yoshiaki Shoji
- Division of Molecular Oncology, Department of Translational Molecular Medicine, Saint John's Cancer Institute at Providence Saint John's Health Center, 2200 Santa Monica Blvd, Santa Monica, CA, 90404, USA
| | - Satoru Furuhashi
- Division of Molecular Oncology, Department of Translational Molecular Medicine, Saint John's Cancer Institute at Providence Saint John's Health Center, 2200 Santa Monica Blvd, Santa Monica, CA, 90404, USA
| | - Daniel F Kelly
- Pacific Neuroscience Institute, Saint John's Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA
| | - Anton J Bilchik
- Department of Surgical Oncology, Saint John's Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA
| | - Dave S B Hoon
- Division of Molecular Oncology, Department of Translational Molecular Medicine, Saint John's Cancer Institute at Providence Saint John's Health Center, 2200 Santa Monica Blvd, Santa Monica, CA, 90404, USA
| | - Matias A Bustos
- Division of Molecular Oncology, Department of Translational Molecular Medicine, Saint John's Cancer Institute at Providence Saint John's Health Center, 2200 Santa Monica Blvd, Santa Monica, CA, 90404, USA.
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Ning T, Li J, He Y, Zhang H, Wang X, Deng T, Liu R, Li H, Bai M, Fan Q, Zhu K, Ying G, Ba Y. Exosomal miR-208b related with oxaliplatin resistance promotes Treg expansion in colorectal cancer. Mol Ther 2021; 29:2723-2736. [PMID: 33905821 PMCID: PMC8417448 DOI: 10.1016/j.ymthe.2021.04.028] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 07/15/2020] [Accepted: 04/20/2021] [Indexed: 02/07/2023] Open
Abstract
Oxaliplatin resistance is a challenge in the treatment of colorectal cancer (CRC) patients. Regulatory T cells (Tregs) are well known for their immunosuppressive roles, and targeting Tregs is an effective way to improve chemosensitivity. Exosome-delivered microRNA (miRNA) might be used as a potential biomarker for predicting chemosensitivity. However, the relationship between Tregs and exosomal miRNAs remains largely unknown. TaqMan low-density array was performed to screen the differentially expressed serum miRNAs from pooled serum of patients who had FOLFOX treatment. Differential expression was validated using qRT-PCR in individual samples. Exosomes were isolated by sequential differential centrifugation, and they were verified by transmission electron microscopy. The RNA and protein levels were determined by quantitative real-time PCR and western blotting. A mouse xenograft model was adopted to evaluate the correlation between exosome-derived miR-208b and Tregs in vivo. We demonstrated that circulating miR-208b is a non-invasive marker for predicting FOLFOX sensitivity in CRC. miR-208b in colon cancer was secreted by tumor cells in the pattern of exosomes, and oxaliplatin-resistant cells showed the most obvious phenomenon of miR-208b increase. Colon cancer cell-secreted miR-208b was sufficiently delivered into recipient T cells to promote Treg expansion by targeting programmed cell death factor 4 (PDCD4). Furthermore, in vivo studies indicated that Treg expansion mediated by cancer cell-secreted miR-208b resulted in tumor growth and oxaliplatin resistance. Our results demonstrate that tumor-secreted miR-208b promotes Treg expansion by targeting PDCD4, and it may be related to a decrease of oxaliplatin-based chemosensitivity in CRC. These findings highlight a potential role of exosomal miR-208b as a predictive biomarker for oxaliplatin-based therapy response, and they provide a novel target for immunotherapy.
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Affiliation(s)
- Tao Ning
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Jialu Li
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yi He
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Haiyang Zhang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Xinyi Wang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Ting Deng
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Rui Liu
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Hongli Li
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Ming Bai
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Qian Fan
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Kegan Zhu
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Guoguang Ying
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
| | - Yi Ba
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
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Park JW, Jeong JM, Cho KS, Cho SY, Cheon JH, Choi DH, Park SJ, Kim HK. MiR-30a and miR-200c differentiate cholangiocarcinomas from gastrointestinal cancer liver metastases. PLoS One 2021; 16:e0250083. [PMID: 33852640 PMCID: PMC8046207 DOI: 10.1371/journal.pone.0250083] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 03/30/2021] [Indexed: 11/19/2022] Open
Abstract
Prior studies have demonstrated the utility of microRNA assays for predicting some cancer tissue origins, but these assays need to be further optimized for predicting the tissue origins of adenocarcinomas of the liver. We performed microRNA profiling on 195 frozen primary tumor samples using 14 types of tumors that were either adenocarcinomas or differentiated from adenocarcinomas. The 1-nearest neighbor method predicted tissue-of-origin in 33 samples of a test set, with an accuracy of 93.9% at feature selection p values ranging from 10-4 to 10-10. According to binary decision tree analyses, the overexpression of miR-30a and the underexpression of miR-200 family members (miR-200c and miR-141) differentiated intrahepatic cholangiocarcinomas from extrahepatic adenocarcinomas. When binary decision tree analyses were performed using the test set, the prediction accuracy was 84.8%. The overexpression of miR-30a and the reduced expressions of miR-200c, miR-141, and miR-425 could distinguish intrahepatic cholangiocarcinomas from liver metastases from the gastrointestinal tract.
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Affiliation(s)
- Jun Won Park
- National Cancer Center of Korea, Goyang, Republic of Korea
- Department of Biomedical Convergence, Kangwon National University, Kangwon, Republic of Korea
| | - Jong Min Jeong
- National Cancer Center of Korea, Goyang, Republic of Korea
| | - Kye Soo Cho
- National Cancer Center of Korea, Goyang, Republic of Korea
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Soo Young Cho
- National Cancer Center of Korea, Goyang, Republic of Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Dong Ho Choi
- Departments of Surgery, Hanyang University School of Medicine, Seoul, Republic of Korea
| | - Sang Jae Park
- National Cancer Center of Korea, Goyang, Republic of Korea
| | - Hark Kyun Kim
- National Cancer Center of Korea, Goyang, Republic of Korea
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47
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Fan CW, Lu R, Fang C, Zhang XL, Lv ZY, Li Y, Zhang H, Zhou ZG, Mo XM, Sun XF. Expression profile, molecular functions, and prognostic significance of miRNAs in primary colorectal cancer stem cells. Aging (Albany NY) 2021; 13:12067-12085. [PMID: 33793420 PMCID: PMC8109135 DOI: 10.18632/aging.202914] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 03/13/2021] [Indexed: 02/05/2023]
Abstract
MicroRNAs (miRNAs) are known to drive the pathogenesis of colorectal cancer (CRC) via the regulation of cancer stem cells (CSCs). We studied the miRNA expression profile of primary CSCs isolated from patients with CRC (pCRCSCs). Compared to pCRCSC-derived differentiated cells, 98 differentially expressed miRNAs were identified in pCRCSCs. Target genes encoding pCRCSC-related miRNAs were identified using a combination of miRNA target databases and miRNA-mRNA regulatory networks from the same patient. The pCRCSC-related miRNA target genes were associated with pathways contributing to malignant phenotypes, including I-kappa B kinase/NF-kappa B signaling, signal transduction by p53 class mediator, Ras signaling, and cGMP-PKG signaling. The pCRCSC-related miRNA expression signature was independently associated with poor overall survival in both the training and validation cohorts. We have thus identified several pCRCSC-related miRNAs with oncogenic potential that could serve as prognostic biomarkers for CRC.
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Affiliation(s)
- Chuan-Wen Fan
- Institute of Digestive Surgery, Sichuan University, and Department of Gastrointestinal Surgery, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China.,Department of Gastrointestinal Surgery and Breast and Thyroid Surgery, Minimally Invasive Surgery, West China Fourth Hospital, Sichuan University, Chengdu, China.,Department of Oncology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.,Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu, China
| | - Ran Lu
- Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu, China
| | - Chao Fang
- Institute of Digestive Surgery, Sichuan University, and Department of Gastrointestinal Surgery, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Xue-Li Zhang
- School of Medicine, Institute of Medical Sciences, Örebro University, Örebro, Sweden
| | - Zhao-Ying Lv
- Institute of Digestive Surgery, Sichuan University, and Department of Gastrointestinal Surgery, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Yuan Li
- Institute of Digestive Surgery, Sichuan University, and Department of Gastrointestinal Surgery, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Hong Zhang
- School of Medicine, Institute of Medical Sciences, Örebro University, Örebro, Sweden
| | - Zong-Guang Zhou
- Institute of Digestive Surgery, Sichuan University, and Department of Gastrointestinal Surgery, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Xian-Ming Mo
- Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiao-Feng Sun
- Department of Oncology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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48
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Zeng Z, Lu J, Wang Y, Sheng H, Wang Y, Chen Z, Wu Q, Zheng J, Chen Y, Yang D, Yu K, Mo H, Hu J, Hu P, Liu Z, Ju H, Xu R. The lncRNA XIST/miR-125b-2-3p axis modulates cell proliferation and chemotherapeutic sensitivity via targeting Wee1 in colorectal cancer. Cancer Med 2021; 10:2423-2441. [PMID: 33666372 PMCID: PMC7982616 DOI: 10.1002/cam4.3777] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 12/26/2020] [Accepted: 12/30/2020] [Indexed: 01/03/2023] Open
Abstract
Background Numerous reports on microRNAs have illustrated their role in tumor growth and metastasis. Recently, a new prognostic factor, miR‐125b‐2‐3p, has been identified for predicting chemotherapeutic sensitivity in advanced colorectal cancer (CRC). However, the specific mechanisms and biological functions of miR‐125b‐2‐3p in advanced CRC under chemotherapy have yet to be elucidated. Methods MiR‐125b‐2‐3p expression was detected by real‐time PCR (RT‐PCR) in CRC tissues. The effects of miR‐125b‐2‐3p on the growth, metastasis, and drug sensitivity of CRC cells were tested in vitro and in vivo. Based on multiple databases, the upstream competitive endogenous RNAs (ceRNAs) and the downstream genes for miR‐125b‐2‐3p were predicted by bioinformatic analysis, followed by the experiments including luciferase reporter assays, western blot assays, and so on. Results MiR‐125b‐2‐3p was significantly lowly expressed in the tissues and cell lines of CRC. Higher expression of miR‐125b‐2‐3p was associated with relatively lower proliferation rates and fewer metastases. Moreover, overexpressed miR‐125b‐2‐3p remarkably improved chemotherapeutic sensitivity of CRC in vivo and in vitro. Mechanistically, miR‐125b‐2‐3p was absorbed by long noncoding RNA (lncRNA) XIST regulating WEE1 G2 checkpoint kinase (WEE1) expression. The upregulation of miR‐125b‐2‐3p inhibited the proliferation and epithelial‐mesenchymal transition (EMT) of CRC induced by lncRNA XIST. Conclusions Lower miR‐125b‐2‐3p expression resulted in lower sensitivity of CRC to chemotherapy and was correlated with poorer survival of CRC patients. LncRNA XIST promoted CRC metastasis acting as a ceRNA for miR‐125b‐2‐3p to mediate WEE1 expression. LncRNA XIST‐miR‐125b‐2‐3p‐WEE1 axis not only regulated CRC growth and metastasis but also contributed to chemotherapeutic resistance to CRC.
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Affiliation(s)
- Zhao‐lei Zeng
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Jia‐huan Lu
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Yun Wang
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Medical OncologySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Hui Sheng
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Ying‐nan Wang
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Zhan‐hong Chen
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Diseasethe Third Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Qi‐nian Wu
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
- Department of PathologySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Jia‐Bo Zheng
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Yan‐xing Chen
- Department of Medical OncologySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Dong‐dong Yang
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Kai Yu
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Hai‐yu Mo
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Jia‐jia Hu
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Pei‐shan Hu
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Ze‐xian Liu
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Huai‐qiang Ju
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Rui‐Hua Xu
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Medical OncologySun Yat‐sen University Cancer CenterGuangzhouChina
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Dos Santos IL, Penna KGBD, Dos Santos Carneiro MA, Libera LSD, Ramos JEP, Saddi VA. Tissue micro-RNAs associated with colorectal cancer prognosis: a systematic review. Mol Biol Rep 2021; 48:1853-1867. [PMID: 33598796 DOI: 10.1007/s11033-020-06075-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 12/10/2020] [Indexed: 01/05/2023]
Abstract
Colorectal cancer (CRC) is a multifactorial disease commonly diagnosed worldwide, with high mortality rates. Several studies demonstrate important associations between differential expression of micro-RNAs (miRs) and the prognosis of CRC. The present study aimed to identify differentially expressed tissue miRs associated with prognostic factors in CRC patients, through a systematic review of the Literature. Using the PubMed database, Cochrane Library and Web of Science, studies published in English evaluating miRs differentially expressed in tumor tissue and significantly associated with the prognostic aspects of CRC were selected. All the included studies used RT-PCR (Taqman or SYBR Green) for miR expression analysis and the period of publication was from 2009 to 2018. A total of 115 articles accomplished the inclusion criteria and were included in the review. The studies investigated the expression of 100 different miRs associated with prognostic aspects in colorectal cancer patients. The most frequent oncogenic miRs investigated were miR-21, miR-181a, miR-182, miR-183, miR-210 and miR-224 and the hyperexpression of these miRs was associated with distant metastasis, lymph node metastasis and worse survival in patients with CRC. The most frequent tumor suppressor miRs were miR-126, miR-199b and miR-22 and the hypoexpression of these miRs was associated with distant metastasis, worse prognosis and a higher risk of disease relapse (worse disease-free survival). Specific tissue miRs are shown to be promising prognostic biomarkers in patients with CRC, given their strong association with the prognostic aspects of these tumors, however, new studies are necessary to establish the sensibility and specificity of the individual miRs in order to use them in clinical practice.
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Affiliation(s)
- Igor Lopes Dos Santos
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil.
| | - Karlla Greick Batista Dias Penna
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
| | | | | | - Jéssica Enocencio Porto Ramos
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
| | - Vera Aparecida Saddi
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
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50
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Angius A, Scanu AM, Arru C, Muroni MR, Rallo V, Deiana G, Ninniri MC, Carru C, Porcu A, Pira G, Uva P, Cossu-Rocca P, De Miglio MR. Portrait of Cancer Stem Cells on Colorectal Cancer: Molecular Biomarkers, Signaling Pathways and miRNAome. Int J Mol Sci 2021; 22:1603. [PMID: 33562604 PMCID: PMC7915330 DOI: 10.3390/ijms22041603] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 02/02/2021] [Accepted: 02/02/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer death worldwide, and about 20% is metastatic at diagnosis and untreatable. Increasing evidence suggests that the heterogeneous nature of CRC is related to colorectal cancer stem cells (CCSCs), a small cells population with stemness behaviors and responsible for tumor progression, recurrence, and therapy resistance. Growing knowledge of stem cells (SCs) biology has rapidly improved uncovering the molecular mechanisms and possible crosstalk/feedback loops between signaling pathways that directly influence intestinal homeostasis and tumorigenesis. The generation of CCSCs is probably connected to genetic changes in members of signaling pathways, which control self-renewal and pluripotency in SCs and then establish function and phenotype of CCSCs. Particularly, various deregulated CCSC-related miRNAs have been reported to modulate stemness features, controlling CCSCs functions such as regulation of cell cycle genes expression, epithelial-mesenchymal transition, metastasization, and drug-resistance mechanisms. Primarily, CCSC-related miRNAs work by regulating mainly signal pathways known to be involved in CCSCs biology. This review intends to summarize the epigenetic findings linked to miRNAome in the maintenance and regulation of CCSCs, including their relationships with different signaling pathways, which should help to identify specific diagnostic, prognostic, and predictive biomarkers for CRC, but also develop innovative CCSCs-targeted therapies.
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Affiliation(s)
- Andrea Angius
- Institute of Genetic and Biomedical Research (IRGB), CNR, Cittadella Universitaria di Cagliari, 09042 Monserrato, Italy;
| | - Antonio Mario Scanu
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
| | - Caterina Arru
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (C.A.); (C.C.); (G.P.)
| | - Maria Rosaria Muroni
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
| | - Vincenzo Rallo
- Institute of Genetic and Biomedical Research (IRGB), CNR, Cittadella Universitaria di Cagliari, 09042 Monserrato, Italy;
| | - Giulia Deiana
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
| | - Maria Chiara Ninniri
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
| | - Ciriaco Carru
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (C.A.); (C.C.); (G.P.)
| | - Alberto Porcu
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
| | - Giovanna Pira
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (C.A.); (C.C.); (G.P.)
| | - Paolo Uva
- IRCCS G. Gaslini, 16147 Genoa, Italy;
| | - Paolo Cossu-Rocca
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
- Department of Diagnostic Services, “Giovanni Paolo II” Hospital, ASSL Olbia-ATS Sardegna, 07026 Olbia, Italy
| | - Maria Rosaria De Miglio
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
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