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Li Q, Geng S, Luo H, Wang W, Mo YQ, Luo Q, Wang L, Song GB, Sheng JP, Xu B. Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy. Signal Transduct Target Ther 2024; 9:266. [PMID: 39370455 PMCID: PMC11456611 DOI: 10.1038/s41392-024-01953-7] [Citation(s) in RCA: 54] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 07/25/2024] [Accepted: 08/16/2024] [Indexed: 10/08/2024] Open
Abstract
Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Its complexity is influenced by various signal transduction networks that govern cellular proliferation, survival, differentiation, and apoptosis. The pathogenesis of CRC is a testament to the dysregulation of these signaling cascades, which culminates in the malignant transformation of colonic epithelium. This review aims to dissect the foundational signaling mechanisms implicated in CRC, to elucidate the generalized principles underpinning neoplastic evolution and progression. We discuss the molecular hallmarks of CRC, including the genomic, epigenomic and microbial features of CRC to highlight the role of signal transduction in the orchestration of the tumorigenic process. Concurrently, we review the advent of targeted and immune therapies in CRC, assessing their impact on the current clinical landscape. The development of these therapies has been informed by a deepening understanding of oncogenic signaling, leading to the identification of key nodes within these networks that can be exploited pharmacologically. Furthermore, we explore the potential of integrating AI to enhance the precision of therapeutic targeting and patient stratification, emphasizing their role in personalized medicine. In summary, our review captures the dynamic interplay between aberrant signaling in CRC pathogenesis and the concerted efforts to counteract these changes through targeted therapeutic strategies, ultimately aiming to pave the way for improved prognosis and personalized treatment modalities in colorectal cancer.
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Affiliation(s)
- Qing Li
- The Shapingba Hospital, Chongqing University, Chongqing, China
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Shan Geng
- Central Laboratory, The Affiliated Dazu Hospital of Chongqing Medical University, Chongqing, China
| | - Hao Luo
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - Wei Wang
- Chongqing Municipal Health and Health Committee, Chongqing, China
| | - Ya-Qi Mo
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China
| | - Qing Luo
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Lu Wang
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China
| | - Guan-Bin Song
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.
| | - Jian-Peng Sheng
- College of Artificial Intelligence, Nanjing University of Aeronautics and Astronautics, Nanjing, China.
| | - Bo Xu
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China.
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Sikora H, Gruba N, Wysocka M, Piwkowska A, Lesner A. Optimization of fluorescent substrates for ADAM17 and their utility in the detection of diabetes. Anal Biochem 2023; 681:115337. [PMID: 37783443 DOI: 10.1016/j.ab.2023.115337] [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: 07/06/2023] [Revised: 09/28/2023] [Accepted: 09/29/2023] [Indexed: 10/04/2023]
Abstract
ADAM17 (a disintegrin and metalloproteinase 17) is a sheddase that releases various types of membrane-associated proteins, including adhesive molecules, cytokines and their receptors, and inflammatory mediators. Evidence suggests that the enzyme is involved in the proteolytic cleavage of antiaging transmembrane protein Klotho (KL). What is more, reduced serum and urinary KL levels are observed in the early stages of chronic kidney disease. This study aimed to optimise the ADAM17 specific and selective fluorescent substrates. Then, the obtained substrate was used to detect the enzyme in urine samples of patients diagnosed with diabetes. It turned out that in all cases we were able to detect proteolytic activity, which was the opposite of the healthy samples.
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Affiliation(s)
- Honorata Sikora
- Department of Biomedical Chemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308, Gdańsk, Poland
| | - Natalia Gruba
- Department of Environmental Technology, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63 Street, PL, 80-308, Gdańsk, Poland.
| | - Magdalena Wysocka
- Department of Biomedical Chemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308, Gdańsk, Poland
| | - Agnieszka Piwkowska
- Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute Polish Academy of Sciences, Wita Stwosza 63, 80-308, Gdansk, Poland; Department of Molecular Biotechnology, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308, Gdansk, Poland
| | - Adam Lesner
- Department of Environmental Technology, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63 Street, PL, 80-308, Gdańsk, Poland
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Abudoubari S, Bu K, Mei Y, Maimaitiyiming A, An H, Tao N. Preliminary study on miRNA in prostate cancer. World J Surg Oncol 2023; 21:270. [PMID: 37641123 PMCID: PMC10464187 DOI: 10.1186/s12957-023-03151-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 08/16/2023] [Indexed: 08/31/2023] Open
Abstract
OBJECTIVE To screen for miRNAs differentially expressed in prostate cancer and prostate hyperplasia tissues and to validate their association with prostate cancer. METHODS Patients diagnosed by pathology in the Department of Urology of the First Affiliated Hospital of Xinjiang Medical University from October 2021 to June 2022 were selected, and their general clinical information, blood samples, and prostate tissue samples were collected. miRNA microarray technology was performed to obtain differentially expressed miRNAs in prostate cancer and hyperplasia tissues, and miRNAs to be studied were screened by microarray results and review of relevant literature. The detection of miRNA expression in the patients' blood and prostate tissue samples was measured. The miRNA-222-mimics were transfected into PC3 cells, and cell biology experiments such as CCK8, scratch, Transwell, and flow cytometry were performed to detect the effects of overexpressed miRNA-222 on the growth and proliferation, invasive ability, apoptotic ability, and metastatic ability of prostate cancer cells. RESULTS The results of the miRNA microarray showed that there were many differentially expressed miRNAs in prostate cancer and hyperplasia tissues, and four miRNAs, miRNA-144, miRNA-222, miRNA-1248, and miRNA-3651 were finally selected as the subjects by reviewing relevant literature. The results showed that the expression of miRNA-222 in prostate cancer tissues was lower than that in prostate hyperplasia tissues (P < 0.05). The expression of miRNA-222, miRNA-1248, and miRNA-3651 in blood samples of prostate cancer patients was lower than that in prostate hyperplasia patients (P < 0.05). The analysis results indicated that the f/t ratio and the relative expression of miRNA-222 and miRNA-1248 were independent influences of prostate cancer (P < 0.05), in which overexpression of miRNA-222 decreased the proliferative, invasive, and metastatic abilities of PC3 cells and enhanced the level of apoptosis of cancer cells. CONCLUSIONS Although there was no significant change in the overall incidence of prostate cancer in this study, significant changes occurred in the incidence of prostate cancer with different characteristics. In addition, the nomogram prediction model of prostate cancer-specific survival rate constructed based on four factors has a high reference value, which helps physicians to correctly assess the patient-specific survival rate and provides a reference basis for patient diagnosis and prognosis evaluation.
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Affiliation(s)
- Saimaitikari Abudoubari
- College of Public Health, Xinjiang Medical University, Urumqi, 830011, Xinjiang, China
- Department of Radiology, The First People's Hospital of Kashi Prefecture, Kashi, 844700, Xinjiang, China
| | - Ke Bu
- College of Public Health, Xinjiang Medical University, Urumqi, 830011, Xinjiang, China
| | - Yujie Mei
- College of Public Health, Xinjiang Medical University, Urumqi, 830011, Xinjiang, China
| | | | - Hengqing An
- The First Affiliated Hospital, Xinjiang Medical University, No. 393, Xinyi Road, Xinshi District, Urumqi, 830011, Xinjiang, China.
- Xinjiang Clinical Research Center for Genitourinary System, No. 393, Xinyi Road, Xinshi District, Urumqi, 830011, Xinjiang, China.
| | - Ning Tao
- College of Public Health, Xinjiang Medical University, Urumqi, 830011, Xinjiang, China.
- Xinjiang Clinical Research Center for Genitourinary System, No. 393, Xinyi Road, Xinshi District, Urumqi, 830011, Xinjiang, China.
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Phannasil P, Akekawatchai C, Jitrapakdee S. MicroRNA expression profiles associated with the metastatic ability of MDA‑MB‑231 breast cancer cells. Oncol Lett 2023; 26:339. [PMID: 37427352 PMCID: PMC10326657 DOI: 10.3892/ol.2023.13926] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 05/18/2023] [Indexed: 07/11/2023] Open
Abstract
Breast cancer is an important worldwide public health concern. The incidence rate of breast cancer increases every year. The primary cause of death is metastasis, a process by which cancer cells spread from a primary site to secondary organs. MicroRNAs (miRs/miRNAs) are small non-coding RNAs that control gene expression at the post-transcriptional level. Dysregulation of certain miRNAs is involved in carcinogenesis, cancer cell proliferation and metastasis. Therefore, the present study assessed miRNAs associated with breast cancer metastasis using two breast cancer cell lines, the low-metastatic MCF-7 and the highly metastatic MDA-MB-231. miRNA array analysis of both cell lines indicated that 46 miRNAs were differentially expressed when compared between the two cell lines. A total of 16 miRNAs were upregulated in MDA-MB-231 compared with MCF-7 cells, which suggested that their expression levels may be associated with the highly invasive phenotype of MDA-MB-231 cells. Among these miRNAs, miR-222-3p was selected for further study and its expression was confirmed by reverse transcription-quantitative PCR (RT-qPCR). Under both non-adherent and adherent culture conditions, the expression levels of miR-222-3p in the MDA-MB-231 cell line were higher than those noted in the MCF-7 cell line under the same conditions. Suppression of endogenous miR-222-3p expression in MDA-MB-231 cells using a miR-222-3p inhibitor resulted in a 20-40% reduction in proliferation, and a ~30% reduction in migration, which suggested that the aggressive phenotype of MDA-MB-231 cells was partly regulated by miR-222-3p. Bioinformatic analysis of miR-222-3p using TargetScan 8.0, miRDB and PicTar identified 25 common mRNA targets, such as cyclin-dependent kinase inhibitor 1B, ADP-ribosylation factor 4, iroquois homeobox 5 and Bcl2 modifying factor. The results of the present study indicated that miR-222-3p was potentially associated with the proliferation and migratory ability of the MDA-MB-231 cell line.
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Affiliation(s)
- Phatchariya Phannasil
- Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand
| | - Chareeporn Akekawatchai
- Department of Medical Technology, Faculty of Allied Health Sciences, Thammasat University, Pathumtani 12121, Thailand
| | - Sarawut Jitrapakdee
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
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Yang JT, Lee IN, Huang C, Huang HC, Wu YP, Chong ZY, Chen JC. ADAM17 Confers Temozolomide Resistance in Human Glioblastoma Cells and miR-145 Regulates Its Expression. Int J Mol Sci 2023; 24:ijms24097703. [PMID: 37175410 PMCID: PMC10178422 DOI: 10.3390/ijms24097703] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 04/13/2023] [Accepted: 04/18/2023] [Indexed: 05/15/2023] Open
Abstract
Glioblastoma (GBM) is a malignant brain tumor, commonly treated with temozolomide (TMZ). Upregulation of A disintegrin and metalloproteinases (ADAMs) is correlated to malignancy; however, whether ADAMs modulate TMZ sensitivity in GBM cells remains unclear. To explore the role of ADAMs in TMZ resistance, we analyzed changes in ADAM expression following TMZ treatment using RNA sequencing and noted that ADAM17 was markedly upregulated. Hence, we established TMZ-resistant cell lines to elucidate the role of ADAM17. Furthermore, we evaluated the impact of ADAM17 knockdown on TMZ sensitivity in vitro and in vivo. Moreover, we predicted microRNAs upstream of ADAM17 and transfected miRNA mimics into cells to verify their effects on TMZ sensitivity. Additionally, the clinical significance of ADAM17 and miRNAs in GBM was analyzed. ADAM17 was upregulated in GBM cells under serum starvation and TMZ treatment and was overexpressed in TMZ-resistant cells. In in vitro and in vivo models, ADAM17 knockdown conferred greater TMZ sensitivity. miR-145 overexpression suppressed ADAM17 and sensitized cells to TMZ. ADAM17 upregulation and miR-145 downregulation in clinical specimens are associated with disease progression and poor prognosis. Thus, miR-145 enhances TMZ sensitivity by inhibiting ADAM17. These findings offer insights into the development of therapeutic approaches to overcome TMZ resistance.
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Affiliation(s)
- Jen-Tsung Yang
- Department of Neurosurgery, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi 61363, Taiwan
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - I-Neng Lee
- Department of Medical Research, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan
| | - Cheng Huang
- Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Hsiu-Chen Huang
- Department of Applied Science, National Tsing Hua University South Campus, Hsinchu 30013, Taiwan
- Center for Teacher Education, National Tsing Hua University, Hsinchu 300044, Taiwan
| | - Yu-Ping Wu
- Department of Medical Research, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan
| | - Zhi-Yong Chong
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan
| | - Jui-Chieh Chen
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan
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Ilieva M, Panella R, Uchida S. MicroRNAs in Cancer and Cardiovascular Disease. Cells 2022; 11:3551. [PMID: 36428980 PMCID: PMC9688578 DOI: 10.3390/cells11223551] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/07/2022] [Accepted: 11/08/2022] [Indexed: 11/12/2022] Open
Abstract
Although cardiac tumor formation is rare, accumulating evidence suggests that the two leading causes of deaths, cancers, and cardiovascular diseases are similar in terms of pathogenesis, including angiogenesis, immune responses, and fibrosis. These similarities have led to the creation of new exciting field of study called cardio-oncology. Here, we review the similarities between cancer and cardiovascular disease from the perspective of microRNAs (miRNAs). As miRNAs are well-known regulators of translation by binding to the 3'-untranslated regions (UTRs) of messenger RNAs (mRNAs), we carefully dissect how a specific set of miRNAs are both oncomiRs (miRNAs in cancer) and myomiRs (muscle-related miRNAs). Furthermore, from the standpoint of similar pathogenesis, miRNAs categories related to the similar pathogenesis are discussed; namely, angiomiRs, Immune-miRs, and fibromiRs.
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Affiliation(s)
| | | | - Shizuka Uchida
- Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, DK-2450 Copenhagen SV, Denmark
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Dashti F, Mirazimi SMA, Rabiei N, Fathazam R, Rabiei N, Piroozmand H, Vosough M, Rahimian N, Hamblin MR, Mirzaei H. The role of non-coding RNAs in chemotherapy for gastrointestinal cancers. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:892-926. [PMID: 34760336 PMCID: PMC8551789 DOI: 10.1016/j.omtn.2021.10.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastrointestinal (GI) cancers, including colorectal, gastric, hepatic, esophageal, and pancreatic tumors, are responsible for large numbers of deaths around the world. Chemotherapy is the most common approach used to treat advanced GI cancer. However, chemoresistance has emerged as a critical challenge that prevents successful tumor elimination, leading to metastasis and recurrence. Chemoresistance mechanisms are complex, and many factors and pathways are involved. Among these factors, non-coding RNAs (ncRNAs) are critical regulators of GI tumor development and subsequently can induce resistance to chemotherapy. This occurs because ncRNAs can target multiple signaling pathways, affect downstream genes, and modulate proliferation, apoptosis, tumor cell migration, and autophagy. ncRNAs can also induce cancer stem cell features and affect the epithelial-mesenchymal transition. Thus, ncRNAs could possibly act as new targets in chemotherapy combinations to treat GI cancer and to predict treatment response.
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Affiliation(s)
- Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Nikta Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Fathazam
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negin Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Haleh Piroozmand
- Faculty of Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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Said MN, Muawia S, Helal A, Fawzy A, Allam RM, Shafik NF. Regulation of CDK inhibitor p27 by microRNA 222 in breast cancer patients. Exp Mol Pathol 2021; 123:104718. [PMID: 34752733 DOI: 10.1016/j.yexmp.2021.104718] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 10/13/2021] [Accepted: 11/01/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Breast cancer is the most common of all cancers and the second leading cause of cancer-related deaths among women worldwide. MicroRNAs regulate at least 60% of the human genes, including tumor suppressor genes and oncogenes, and can thereby affect cancer risk. In this study, the prognostic values of the CDK inhibitor p27 and miR-222 as biomarkers for breast cancer were evaluated. METHODS The real-time quantitative polymerase chain reaction method was employed to measure the expression level of miR-222, whereas the serum levels of the CDK inhibitor p27 were measured via enzyme-linked immunosorbent assay. The levels were determined in sera from 110 participants representing three different groups. RESULTS Patients with breast cancer exhibited significantly higher expression levels of miR-222 and lower levels of CDK inhibitor p27 than the control group. In addition, a statistically significant inverse correlation between miR-222 and the CDK inhibitor p27 was observed. The receiver operating characteristic curves plotted for serum p27 and miR-222 helped in significantly differentiating between breast cancer patients and controls but could not discriminate between those with stage II and stage III cancer. CONCLUSION Thus, a significant upregulation in the serum miR-222 levels was observed in cancer patients, and a significant inverse correlation was noted between the miR-222 and CDK inhibitor p27 expression levels. These findings indicate that miR-222 may be used as a useful noninvasive screening biomarker for human breast cancer. MICROABSTRACT Novel biomarkers for prognosis, prediction, and therapeutic purposes are essential as the prognosis and therapeutic targets of breast cancer are dependent on traditional markers, such as the tumor stage and hormonal receptor status. This study aimed to evaluate the diagnostic and prognostic values of the CDK inhibitor p27 and miR-222 in breast cancer. Our results indicated that miR-222 and the CDK inhibitor p27 may be used as noninvasive biomarkers to screen for human breast cancer but cannot discriminate between patients with early breast cancer and patients with advanced breast cancer.
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Affiliation(s)
- Michael Nabil Said
- Molecular Biology Department, Genetic Engineering and Biotechnology Research Institute, University of Sadat city, Egypt
| | - Shaden Muawia
- Molecular Biology Department, Genetic Engineering and Biotechnology Research Institute, University of Sadat city, Egypt
| | - Amany Helal
- Medical Oncology Department, National Cancer Institute, Cairo University, Egypt
| | - Amal Fawzy
- Clinical Pathology and Oncologic Laboratory Medicine Department, National Cancer Institute, Cairo University, Egypt
| | - Rasha Mahmoud Allam
- Cancer Epidemiology & Biostatistics Department, National Cancer Institute, Cairo University, Egypt
| | - Nevine F Shafik
- Clinical Pathology and Oncologic Laboratory Medicine Department, National Cancer Institute, Cairo University, Egypt.
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Yuan J, Zhang Q, Wu S, Yan S, Zhao R, Sun Y, Tian X, Zhou K. miRNA-223-3p modulates ibrutinib resistance through regulation of the CHUK/Nf-κb signaling pathway in mantle cell lymphoma. Exp Hematol 2021; 103:52-59.e2. [PMID: 34474146 DOI: 10.1016/j.exphem.2021.08.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 08/25/2021] [Accepted: 08/27/2021] [Indexed: 12/29/2022]
Abstract
Since the use of Bruton's tyrosine kinase (BTK) inhibitor ibrutinib in relapsed/refractory (R/R) mantle cell lymphoma (MCL), the problem of drug resistance has become increasingly prominent. Though it has been proven that the nonclassic nuclear factor κB pathway (nonclassic NF-κB pathway) correlates with ibrutinib resistance in MCL, the upstream regulator is unknown. In the present study, conserved helix-loop-helix ubiquitous kinase (CHUK) overexpression accelerated proliferation and suppressed apoptosis of MCL cells after ibrutinib treatment in vitro. The results of luciferase reporter assay, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blot revealed that CHUK was targeted and negatively regulated by miRNA-223-3p. miRNA-223-3p knockdown promoted proliferation and inhibited apoptosis of MCL cells after ibrutinib treatment in vitro and vivo, whereas CHUK knockdown reversed downregulated miRNA-223-3p-promoted cell proliferation after ibrutinib treatment in vitro. In conclusion, miRNA-223-3p modulates ibrutinib resistance through regulation of the CHUK/NF-κB signaling pathway in MCL, which is crucial in providing a marker to predict disease response.
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Affiliation(s)
- Jingjing Yuan
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Qing Zhang
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Shengsheng Wu
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Suran Yan
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Ran Zhao
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yajuan Sun
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Xiaoxu Tian
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Keshu Zhou
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
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10
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Huang X, Zhu X, Yu Y, Zhu W, Jin L, Zhang X, Li S, Zou P, Xie C, Cui R. Dissecting miRNA signature in colorectal cancer progression and metastasis. Cancer Lett 2020; 501:66-82. [PMID: 33385486 DOI: 10.1016/j.canlet.2020.12.025] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is the third most common cancer and leading cause of cancer related deaths worldwide. Despite recent advancements in surgical and molecular targeted therapies that improved the therapeutic efficacy in CRC, the 5 years survival rate of CRC patients still remains frustratingly poor. Accumulated evidences indicate that microRNAs (miRNAs) play a crucial role in the progression and metastasis of CRC. Dysregulated miRNAs are closely associated with cancerous phenotypes (e.g. enhanced proliferative and invasive ability, evasion of apoptosis, cell cycle aberration, and promotion of angiogenesis) by regulating their target genes. In this review, we provide an updated overview of tumor suppressive and oncogenic miRNAs, circulatory miRNAs, and the possible causes of dysregulated miRNAs in CRC. In addition, we discuss the important functions of miRNAs in drug resistance of CRC.
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Affiliation(s)
- Xiangjie Huang
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Xinping Zhu
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Yun Yu
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Wangyu Zhu
- Affiliated Zhoushan Hospital, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Libo Jin
- Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang, 325035, China; Wenzhou University-Wenzhou Medical University Collaborative Innovation Center of Biomedical, Wenzhou, Zhejiang, 325035, China
| | - Xiaodong Zhang
- First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Shaotang Li
- First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Peng Zou
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang, 325035, China; Wenzhou University-Wenzhou Medical University Collaborative Innovation Center of Biomedical, Wenzhou, Zhejiang, 325035, China
| | - Congying Xie
- First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Ri Cui
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang, 325035, China; Wenzhou University-Wenzhou Medical University Collaborative Innovation Center of Biomedical, Wenzhou, Zhejiang, 325035, China.
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11
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Non-coding RNAs in drug resistance of head and neck cancers: A review. Biomed Pharmacother 2020; 127:110231. [PMID: 32428836 DOI: 10.1016/j.biopha.2020.110231] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 04/30/2020] [Accepted: 05/03/2020] [Indexed: 02/06/2023] Open
Abstract
Head and neck cancer (HNC), which includes epithelial malignancies of the upper aerodigestive tract (oral cavity, oropharynx, pharynx, hypopharynx, larynx, and thyroid), are slowly but consistently increasing, while the overall survival rate remains unsatisfactory. Because of the multifunctional anatomical intricacies of the head and neck, disease progression and therapy-related side effects often severely affect the patient's appearance and self-image, as well as their ability to breathe, speak, and swallow. Patients with HNC require a multidisciplinary approach involving surgery, radiation therapy, and chemotherapeutics. Chemotherapy is an important part of the comprehensive treatment of tumors, especially advanced HNC, but drug resistance is the main cause of poor clinical efficacy. The most important determinant of this phenomenon is still largely unknown. Recent studies have shown that non-coding RNAs have a crucial role in HNC drug resistance. In addition, they can serve as biomarkers in the diagnosis, treatment, and prognosis of HNCs. In this review, we summarize the relationship between non-coding RNAs and drug resistance of HNC, and discuss their potential clinical application in overcoming HNC chemoresistance.
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12
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Amini S, Abak A, Sakhinia E, Abhari A. MicroRNA-221 and MicroRNA-222 in Common Human Cancers: Expression, Function, and Triggering of Tumor Progression as a Key Modulator. Lab Med 2020; 50:333-347. [PMID: 31049571 DOI: 10.1093/labmed/lmz002] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Revised: 09/28/2018] [Accepted: 01/19/2019] [Indexed: 12/15/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of short (~22 nucleotides [nt]), single-stranded RNA oligonucleotides that are regulatory in nature and are often dysregulated in various diseases, including cancer. miRNAs can act as oncomiRs (miRNAs associated with cancer) or tumor suppressor miRNAs and have the potential to be a diagnostic, prognostic, noninvasive biomarker for these diseases. MicroRNA-221 (miR-221) and microRNA-222 (miR-222) are homologous miRNAs, located on the human chromosome Xp11.3, which factored significantly in impairment in the regulation of a wide range of cancers. In this review, we have highlighted the most consistently reported dysregulated miRNAs that trigger human tissues to express cancerous features and surveyed the role of those miRNAs in metastasis, apoptosis, angiogenesis, and tumor prognosis. Also, we applied the causes of drug resistance and the role of coordinated actions of these miRNAs to epigenetic changes and selected miRNAs as a potential type of cancer treatment.
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Affiliation(s)
- Sima Amini
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Atefe Abak
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ebrahim Sakhinia
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Tabriz Genetic Analysis Center (TGAC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Abhari
- Department of Biochemistry and Clinical Laboratory, Division of Clinical Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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13
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Withers SB, Dewhurst T, Hammond C, Topham CH. MiRNAs as Novel Adipokines: Obesity-Related Circulating MiRNAs Influence Chemosensitivity in Cancer Patients. Noncoding RNA 2020; 6:ncrna6010005. [PMID: 31979312 PMCID: PMC7151601 DOI: 10.3390/ncrna6010005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 01/08/2020] [Accepted: 01/11/2020] [Indexed: 12/12/2022] Open
Abstract
Adipose tissue is an endocrine organ, capable of regulating distant physiological processes in other tissues via the release of adipokines into the bloodstream. Recently, circulating adipose-derived microRNAs (miRNAs) have been proposed as a novel class of adipokine, due to their capacity to regulate gene expression in tissues other than fat. Circulating levels of adipokines are known to be altered in obese individuals compared with typical weight individuals and are linked to poorer health outcomes. For example, obese individuals are known to be more prone to the development of some cancers, and less likely to achieve event-free survival following chemotherapy. The purpose of this review was twofold; first to identify circulating miRNAs which are reproducibly altered in obesity, and secondly to identify mechanisms by which these obesity-linked miRNAs might influence the sensitivity of tumors to treatment. We identified 8 candidate circulating miRNAs with altered levels in obese individuals (6 increased, 2 decreased). A second literature review was then performed to investigate if these candidates might have a role in mediating resistance to cancer treatment. All of the circulating miRNAs identified were capable of mediating responses to cancer treatment at the cellular level, and so this review provides novel insights which can be used by future studies which aim to improve obese patient outcomes.
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Affiliation(s)
- Sarah B. Withers
- Biomedical Research Centre, School of Science, Engineering and Environment, Peel Building, University of Salford, Salford M5 4WT, UK; (S.B.W.); (T.D.); (C.H.)
- Salford Royal Foundation Trust, Clinical Sciences Building, Stott Lane, Salford M6 8HD, UK
| | - Toni Dewhurst
- Biomedical Research Centre, School of Science, Engineering and Environment, Peel Building, University of Salford, Salford M5 4WT, UK; (S.B.W.); (T.D.); (C.H.)
| | - Chloe Hammond
- Biomedical Research Centre, School of Science, Engineering and Environment, Peel Building, University of Salford, Salford M5 4WT, UK; (S.B.W.); (T.D.); (C.H.)
| | - Caroline H. Topham
- Biomedical Research Centre, School of Science, Engineering and Environment, Peel Building, University of Salford, Salford M5 4WT, UK; (S.B.W.); (T.D.); (C.H.)
- Correspondence: ; Tel.: +44-(0)-161-295-4292
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14
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Liu C, Zhang Y, Liang S, Ying Y. Aldehyde dehydrogenase 1, a target of miR-222, is expressed at elevated levels in cervical cancer. Exp Ther Med 2020; 19:1673-1680. [PMID: 32104219 PMCID: PMC7027150 DOI: 10.3892/etm.2020.8425] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 09/04/2019] [Indexed: 02/06/2023] Open
Abstract
The aim of the present study was to investigate the expression of microRNA-222 (miR-222) and aldehyde dehydrogenase 1 (ALDH1) in tissues and peripheral blood of cervical cancer patients, and to elucidate their underlying mechanisms of action. Tumor tissues and tumor-adjacent tissues were obtained from 33 cervical cancer patients and peripheral blood was obtained from these patients and 28 healthy subjects. The expression of miR-222 and ALDH1 mRNA was evaluated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). To examine the levels of ALDH1 protein in tissues and blood, western blotting and ELISA were used. To confirm a direct interaction between miR-222 and ALDH1 mRNA, a dual luciferase reporter assay was performed. HeLA cells were transfected with agomiR-222 and expression of ALDH1 in the cells was measured by RT-qPCR and western blotting. MTT assay was preform to investigate the proliferation of HeLA cells. Expression of ALDH1 mRNA and protein was elevated in cervical cancer tissues and peripheral blood from patients compared with tumor-adjacent tissues and healthy controls, while the expression of miR-222 was reduced. Upregulation of miR-222 inhibited HeLA cell proliferation possibly due to a reduction in the expression of ALDH1. A dual luciferase reporter assay showed that miR-222 can bind with the 3′-untranslated seed region of ALDH1 mRNA to regulate its expression. miR-222 regulation of ALDH1 expression may play a role in the prevention of cervical cancer.
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Affiliation(s)
- Changde Liu
- Clinical Laboratory, The Hui People Hospital of Beijing, Beijing 100054, P.R. China
| | - Yan Zhang
- Clinical Laboratory, Yuquan Hospital of Tsinghua University, Beijing 100049, P.R. China
| | - Shanghua Liang
- Department of Pathology, Beijing Dian Medical Testing Laboratory Co., Beijing 102609, P.R. China
| | - Yuhua Ying
- Department of Gynaecology, Yuquan Hospital of Tsinghua University, Beijing 100049, P.R. China
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15
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Hon KW, Othman N, Hanif EAM, Nasir SN, Razak NSA, Jamal R, Abu N. Predictive biomarkers of drug resistance in colorectal cancer—Recent updates. DRUG RESISTANCE IN COLORECTAL CANCER: MOLECULAR MECHANISMS AND THERAPEUTIC STRATEGIES 2020:135-151. [DOI: 10.1016/b978-0-12-819937-4.00008-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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16
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Andrei L, Kasas S, Ochoa Garrido I, Stanković T, Suárez Korsnes M, Vaclavikova R, Assaraf YG, Pešić M. Advanced technological tools to study multidrug resistance in cancer. Drug Resist Updat 2020; 48:100658. [DOI: 10.1016/j.drup.2019.100658] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 09/26/2019] [Accepted: 09/27/2019] [Indexed: 02/06/2023]
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17
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Role of miR-221/222 in Tumor Development and the Underlying Mechanism. JOURNAL OF ONCOLOGY 2019; 2019:7252013. [PMID: 31929798 PMCID: PMC6942871 DOI: 10.1155/2019/7252013] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 10/22/2019] [Accepted: 11/01/2019] [Indexed: 12/24/2022]
Abstract
MicroRNA-221/222 (miRNA-221/222, miR-221/222) is a noncoding microRNA which is widely distributed in eukaryotic organisms and deeply involved in the posttranscriptional regulation of gene expressions. According to recent studies, abnormal expressions of miR-221/222 are closely related to the occurrence and development of various kinds of malignant tumors. The role of miR-221/222 in tumor development and their potential molecular mechanism in various cancers, including liver cancer, colorectal cancer, cervical cancer, ovarian cancer, and endometrial carcinoma, are summarized and reviewed in this paper. Moreover, the potential translational biomarker role of abnormal miR-221/222 level in tumor or blood circulation for tumor diagnosis is also discussed.
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18
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The emerging role of noncoding RNAs in colorectal cancer chemoresistance. Cell Oncol (Dordr) 2019; 42:757-768. [DOI: 10.1007/s13402-019-00466-8] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2019] [Indexed: 02/06/2023] Open
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19
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Current Evidence on miRNAs as Potential Theranostic Markers for Detecting Chemoresistance in Colorectal Cancer: A Systematic Review and Meta-Analysis of Preclinical and Clinical Studies. Mol Diagn Ther 2019; 23:65-82. [PMID: 30726546 DOI: 10.1007/s40291-019-00381-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Findings from observational clinical studies examining the relationship between biomarker expression and theranosis in colorectal cancer (CRC) have been conflicting. OBJECTIVE We conducted this systematic review and meta-analysis to summarise the existing evidence to demonstrate the involvement of microRNAs (miRNAs) in chemoresistance and sensitivity in CRC through drug genetic pathways. METHODS Using PRISMA guidelines, we systematically searched PubMed and Science Direct for relevant studies that took place between 2012 and 2017. A random-effects model of meta-analysis was applied to evaluate the pooled effect size of hazard ratios (HRs) across the included studies. Cochran's Q test and the I2 statistic were used to detect heterogeneity. A funnel plot was used to assess potential publication bias. RESULTS Of the 4700 studies found, 39 studies comprising 2822 patients with CRC met the inclusion criteria. The included studies used one or a combination of 14 chemotherapy drugs, including 5-fluorouracil and oxaliplatin. Of the 60 miRNAs, 28 were associated with chemosensitivity, 20 with chemoresistance, and one with differential expression and radiosensitivity; ten miRNAs were not associated with any impact on chemotherapy. The results outline the importance of 34 drug-regulatory pathways of chemoresistance and sensitivity in CRC. The mean effect size was 0.689 (95% confidence interval 0.428-1.110), indicating that the expression of miRNAs decreased the likelihood of death by about 32%. CONCLUSION Studies have consistently shown that multiple miRNAs could act as clinical predictors of chemoresistance and sensitivity. An inclusion of supplementary miRNA estimation in CRC routine practice needs to be considered to evaluate the efficacy of chemotherapy after confirming our findings with large-scale prospective cohort studies. PROSPERO REGISTRATION NUMBER CRD42017082196.
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20
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Mousavi S, Moallem R, Hassanian SM, Sadeghzade M, Mardani R, Ferns GA, Khazaei M, Avan A. Tumor-derived exosomes: Potential biomarkers and therapeutic target in the treatment of colorectal cancer. J Cell Physiol 2019; 234:12422-12432. [PMID: 30637729 DOI: 10.1002/jcp.28080] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Accepted: 12/07/2018] [Indexed: 12/13/2022]
Abstract
Colorectal cancer (CRC) is the third most common cause of cancer-related death in men and women in many countries. Early detection of CRC helps to prevent the advanced stages of the disease, and may thereby improve the survival of these patients. A noninvasive test with high specificity and sensitivity is required for this. Exosomes are lipid bilayer membrane nanovesicles that are released into most body fluids and especially in the microenvironment of cancer. They carry various proteins, lipids, and nucleic materials such as DNA, RNA, messenger RNA (mRNA), and microRNA (miRNA), and may also alter the function of target cells. In this review, we aimed to describe the biogenesis, composition, function, and the role of tumor-derived exosomes in cancer progression. Moreover, their applications in tumor diagnosis and treatment are described, with a particular focus on CRC.
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Affiliation(s)
- Sousan Mousavi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Roya Moallem
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahsa Sadeghzade
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ramin Mardani
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Division of Medical Education, Brighton & Sussex Medical School, Brighton, Sussex, UK
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Physiology and School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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21
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Hon KW, Abu N, Ab Mutalib NS, Jamal R. miRNAs and lncRNAs as Predictive Biomarkers of Response to FOLFOX Therapy in Colorectal Cancer. Front Pharmacol 2018; 9:846. [PMID: 30127741 PMCID: PMC6088237 DOI: 10.3389/fphar.2018.00846] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 07/13/2018] [Indexed: 12/22/2022] Open
Abstract
Chemotherapy is one of the options for cancer treatment. FOLFOX is one of the widely used chemotherapeutic regimens used to treat primarily colorectal cancer and other cancers as well. However, the emergence of chemo-resistance clones during cancer treatment has become a critical challenge in the clinical setting. It is crucial to identify the potential biomarkers and therapeutics targets which could lead to an improvement in the success rate of the proposed therapies. Since non-coding RNAs have been known to be important players in the cellular system, the interest in their functional roles has intensified. Non-coding RNAs (ncRNAs) as regulators at the post-transcriptional level could be very promising to provide insights in overcoming chemo-resistance to FOLFOX. Hence, this mini review attempts to summarize the potential of ncRNAs correlating with chemo-sensitivity/resistance to FOLFOX.
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Affiliation(s)
- Kha Wai Hon
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Nadiah Abu
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Nurul-Syakima Ab Mutalib
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Rahman Jamal
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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22
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Exosome-mediated miR-222 transferring: An insight into NF-κB-mediated breast cancer metastasis. Exp Cell Res 2018; 369:129-138. [PMID: 29778754 DOI: 10.1016/j.yexcr.2018.05.014] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 05/16/2018] [Indexed: 02/06/2023]
Abstract
The subtypes of distant-organ metastasis led to treatment failure and poor prognosis are major obstacles in the management of patients with advanced breast cancer (BCa). Emerging evidences demonstrated that exosomes act as mediators for intercellular communication between various types of cells in the local tumor microenvironment. The present study aims to investigate whether BCa-derived exosomes are capable of cell-cell transferring miR-222 for BCa metastatic progression. Results showed that exosomal miR-222 is highly expressed in BCa patients with lymphatic metastasis. Consistently, the elevated levels of exosomal miR-222 are closely correlated with the high aggressivity of BCa cell lines. miR-222 promoting the aggressivity of BCa cells was confirmed in vitro and in vivo. Mechanistically, miR-222 directly targets PDLIM2, a tumor suppressor gene, leading to activation of NF-κB signal pathway. In conclusion, the levels of exosomal miR-222 are correlated with BCa metastatic progression. Exosome-transferred miR-222 promotes migration and invasion of BCa cells. miR-222 contributes to tumorigenicity of BCa cells through down-regulation of PDLIM2 and consequently activating NF-κB.
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23
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Panneerselvam J, Srivastava A, Muralidharan R, Wang Q, Zheng W, Zhao L, Chen A, Zhao YD, Munshi A, Ramesh R. IL-24 modulates the high mobility group (HMG) A1/miR222 /AKT signaling in lung cancer cells. Oncotarget 2018; 7:70247-70263. [PMID: 27602961 PMCID: PMC5342550 DOI: 10.18632/oncotarget.11838] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 08/24/2016] [Indexed: 01/10/2023] Open
Abstract
Interleukin (IL)-24, a novel tumor suppressor/cytokine exhibits antitumor activity against a broad-spectrum of human cancer cells. In a recent study, we showed that IL-24 inhibited AKT in lung cancer cells. However, the molecular mechanism of AKT inhibition by IL-24 remains elusive.The high mobility group (HMG) A1 a member of the non-histone chromosomal proteins and commonly referred to as architectural transcription factor, regulates transcription of various genes involved in cell growth and survival. Overexpression of HMGA1 has been shown to be associated with tumor progression and metastasis in several cancers, including human lung cancer. A recent study demonstrated that HMGA1 activates AKT function by reducing the activity of the protein phosphatase, phosphatase 2A subunit B (PPP2R2A) via the oncogenic micro (mi) RNA-222. Based on this report we hypothesized that IL-24-mediated AKT inhibition involved the HMGA1/miR-222 axis.To test our hypothesis, in the present study we used a H1299 lung cancer cell line that expressed exogenous human IL-24 when induced with doxycycline (DOX). Induction of IL-24 expression in the tumor cells markedly reduced HMGA1 mRNA and protein levels. Using a mechanistic approach, we found that IL-24 reduced miR-222-3p and -5p levels, as determined by qRT-PCR. Associated with HMGA1 and miR-222 inhibition was a marked increase in PPP2R2A, with a concomitant decrease in phosphorylated AKTT308/S473 expression. SiRNA-mediated knockdown of HMGA1 in combination with IL-24 significantly reduced AKT T308/S473 protein expression and greatly reduced cell migration and invasion compared with individual treatments. Further combination of IL-24 and a miR-222-3p inhibitor significantly increased PPP2R2A expression.Our results demonstrate for the first time that IL-24 inhibits AKT via regulating the HMGA1/miR-222 signaling node in human lung cancer cells and acts as an effective tumor suppressor. Thus, a therapy combining IL-24 with HMGA1 siRNA or miR-222-3p inhibitor should present effective treatment of lung cancer.
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Affiliation(s)
- Janani Panneerselvam
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.,Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
| | - Akhil Srivastava
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.,Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
| | - Ranganayaki Muralidharan
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.,Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
| | - Qi Wang
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.,Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
| | - Wei Zheng
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
| | - Lichao Zhao
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.,Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
| | - Alshine Chen
- Department of Biostatistics and Epidemiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.,Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
| | - Yan D Zhao
- Department of Biostatistics and Epidemiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.,Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
| | - Anupama Munshi
- Department of Radiation Oncology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.,Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
| | - Rajagopal Ramesh
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.,Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.,Graduate Program in Biomedical Sciences, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
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24
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Circulating Plasma Levels of miR-20b, miR-29b and miR-155 as Predictors of Bevacizumab Efficacy in Patients with Metastatic Colorectal Cancer. Int J Mol Sci 2018; 19:ijms19010307. [PMID: 29361687 PMCID: PMC5796251 DOI: 10.3390/ijms19010307] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 01/15/2018] [Accepted: 01/18/2018] [Indexed: 12/28/2022] Open
Abstract
Targeting angiogenesis in the treatment of colorectal cancer (CRC) is a common strategy, for which potential predictive biomarkers have been studied. miRNAs are small non-coding RNAs involved in several processes including the angiogenic pathway. They are very stable in biological fluids, which turns them into potential circulating biomarkers. In this study, we considered a case series of patients with metastatic (m) CRC treated with a bevacizumab (B)-based treatment, enrolled in the prospective multicentric Italian Trial in Advanced Colorectal Cancer (ITACa). We then analyzed a panel of circulating miRNAs in relation to the patient outcome. In multivariate analysis, circulating basal levels of hsa-miR-20b-5p, hsa-miR-29b-3p and hsa-miR-155-5p resulted in being significantly associated with progression-free survival (PFS) (p = 0.027, p = 0.034 and p = 0.039, respectively) and overall survival (OS) (p = 0.044, p = 0.024 and p = 0.032, respectively). We also observed that an increase in hsa-miR-155-5p at the first clinical evaluation was significantly associated with shorter PFS (HR 3.03 (95% CI 1.06-9.09), p = 0.040) and OS (HR 3.45 (95% CI 1.18-10.00), p = 0.024), with PFS and OS of 9.5 (95% CI 6.8-18.7) and 15.9 (95% CI 8.4-not reached), respectively, in patients with an increase ≥30% of hsa-miR-155-5p and 22.3 (95% CI 10.2-25.5) and 42.9 (24.8-not reached) months, respectively, in patients without such increase. In conclusion, our results highlight the potential usefulness of circulating basal levels of hsa-miR-20b-5p, hsa-miR-29b-3p and hsa-miR-155-5p in predicting the outcome of patients with mCRC treated with B. In addition, the variation of circulating hsa-miR-155-5p could also be indicative of the patient survival.
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25
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Petrovic N, Ergun S. miRNAs as Potential Treatment Targets and Treatment Options in Cancer. Mol Diagn Ther 2018; 22:157-168. [DOI: 10.1007/s40291-017-0314-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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26
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Shirafkan N, Mansoori B, Mohammadi A, Shomali N, Ghasbi M, Baradaran B. MicroRNAs as novel biomarkers for colorectal cancer: New outlooks. Biomed Pharmacother 2018; 97:1319-1330. [DOI: 10.1016/j.biopha.2017.11.046] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 11/04/2017] [Accepted: 11/07/2017] [Indexed: 12/19/2022] Open
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27
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Strubberg AM, Madison BB. MicroRNAs in the etiology of colorectal cancer: pathways and clinical implications. Dis Model Mech 2017; 10:197-214. [PMID: 28250048 PMCID: PMC5374322 DOI: 10.1242/dmm.027441] [Citation(s) in RCA: 111] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) are small single-stranded RNAs that repress mRNA translation
and trigger mRNA degradation. Of the ∼1900 miRNA-encoding genes present
in the human genome, ∼250 miRNAs are reported to have changes in
abundance or altered functions in colorectal cancer. Thousands of studies have
documented aberrant miRNA levels in colorectal cancer, with some miRNAs reported
to actively regulate tumorigenesis. A recurrent phenomenon with miRNAs is their
frequent participation in feedback loops, which probably serve to reinforce or
magnify biological outcomes to manifest a particular cellular phenotype. Here,
we review the roles of oncogenic miRNAs (oncomiRs), tumor suppressive miRNAs
(anti-oncomiRs) and miRNA regulators in colorectal cancer. Given their stability
in patient-derived samples and ease of detection with standard and novel
techniques, we also discuss the potential use of miRNAs as biomarkers in the
diagnosis of colorectal cancer and as prognostic indicators of this disease.
MiRNAs also represent attractive candidates for targeted therapies because their
function can be manipulated through the use of synthetic antagonists and miRNA
mimics. Summary: This Review provides an overview of some important
microRNAs and their roles in colorectal cancer.
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Affiliation(s)
- Ashlee M Strubberg
- Division of Gastroenterology, Washington University School of Medicine, Washington University, Saint Louis, MO 63110, USA
| | - Blair B Madison
- Division of Gastroenterology, Washington University School of Medicine, Washington University, Saint Louis, MO 63110, USA
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Xu K, Chen G, Qiu Y, Yuan Z, Li H, Yuan X, Sun J, Xu J, Liang X, Yin P. miR-503-5p confers drug resistance by targeting PUMA in colorectal carcinoma. Oncotarget 2017; 8:21719-21732. [PMID: 28423513 PMCID: PMC5400618 DOI: 10.18632/oncotarget.15559] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Accepted: 01/22/2017] [Indexed: 01/04/2023] Open
Abstract
The development of multidrug-resistance (MDR) is a major contributor to death in colorectal carcinoma (CRC). Here, we investigated the possible role of microRNA (miR)-503-5p in drug resistant CRC cells. Unbiased microRNA array screening revealed that miR-503-5p is up-regulated in two oxaliplatin (OXA)-resistant CRC cell lines. Overexpression of miR-503-5p conferred resistance to OXA-induced apoptosis and inhibition of tumor growth in vitro and in vivo through down-regulation of PUMA expression. miR-503-5p knockdown sensitized chemoresistant CRC cells to OXA. Our studies indicated that p53 suppresses miR-503-5p expression and that deletion of p53 upregulates miR-503-5p expression. Inhibition of miR-503-5p in p53 null cells increased their sensitivity to OXA treatment. Importantly, analysis of patient samples showed that expression of miR-503-5p negatively correlates with PUMA in CRC. These results indicate that a p53/miR-503-5p/PUMA signaling axis regulates the CRC response to chemotherapy, and suggest that miR-503-5p plays an important role in the development of MDR in CRC by modulating PUMA expression.
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Affiliation(s)
- Ke Xu
- Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China.,Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Medicine, Shanghai 200062, PR China
| | - Guo Chen
- Department of Radiation Oncology, School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia 30322, USA
| | - Yanyan Qiu
- Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China.,Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Medicine, Shanghai 200062, PR China.,Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China State
| | - Zeting Yuan
- Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China
| | - Hongchang Li
- Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China State
| | - Xia Yuan
- Department of Pharmacy, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China
| | - Jian Sun
- Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China.,Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Medicine, Shanghai 200062, PR China
| | - Jianhua Xu
- Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Medicine, Shanghai 200062, PR China
| | - Xin Liang
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, PR China
| | - Peihao Yin
- Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Medicine, Shanghai 200062, PR China.,Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China State
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microRNAs as cancer therapeutics: A step closer to clinical application. Cancer Lett 2017; 407:113-122. [DOI: 10.1016/j.canlet.2017.04.007] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 03/31/2017] [Accepted: 04/05/2017] [Indexed: 12/12/2022]
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Gao H, Cong X, Zhou J, Guan M. MicroRNA-222 influences migration and invasion through MIA3 in colorectal cancer. Cancer Cell Int 2017; 17:78. [PMID: 28855850 PMCID: PMC5576312 DOI: 10.1186/s12935-017-0447-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 08/22/2017] [Indexed: 12/17/2022] Open
Abstract
Background miR-222 has been reported to be overexpressed in colorectal cancer and it influences cancer cell proliferation, drug resistance and metastasis. However, the underlying molecular mechanism of miR-222 in colorectal cancer cell invasion and migration has not been thoroughly elucidated to date. Methods The cell cycle distribution and apoptosis were assessed by flow cytometry. Cell migration and invasion were analyzed by Transwell assays. The possible target gene of miR-222 was searched and identified by bioinformatics, dual luciferase reporter assay and western blot analysis. The siRNA method was used to confirm the function of the target gene. Results Overexpression of miR-222 effectively promotes migration and invasion of colorectal cancer (CRC) cells in vitro. Bioinformatics and the dual luciferase reporter assay revealed that miR-222 specifically targeted the 3′-UTR of melanoma inhibitory activity member 3 (MIA3), down-regulating its expression at the protein level. Inhibition of MIA3 by siRNA enhanced the migration and invasion of CRC cell lines. Conclusions Our study showed that miR-222 enhances the migration and invasion in CRC cells, primarily by down-regulation of MIA3. Electronic supplementary material The online version of this article (doi:10.1186/s12935-017-0447-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Heli Gao
- Department of Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Xuejing Cong
- Department of Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Jianfeng Zhou
- Department of Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Mei Guan
- Department of Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
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Zhang Y, Wang J. MicroRNAs are important regulators of drug resistance in colorectal cancer. Biol Chem 2017; 398:929-938. [PMID: 28095367 PMCID: PMC5911396 DOI: 10.1515/hsz-2016-0308] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 01/08/2017] [Indexed: 12/13/2022]
Abstract
Despite of continuous development of cancer treatment over the past decades, drug resistance is still one of the major hurdles of effective therapy for advanced colorectal cancer (CRC) worldwide and the understanding of its underlying mechanisms remains limited. Data which have emerged suggests that many microRNAs (miRNAs) may contribute to drug resistance in CRC. Major findings on miRNA functions in drug resistance of CRC are systemically reviewed here, with the goal of providing new updates to broaden our comprehension of its mechanisms and evidence to utilize miRNAs as potential therapeutic targets for CRC treatment.
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MicroRNAs with prognostic significance in bladder cancer: a systematic review and meta-analysis. Sci Rep 2017; 7:5619. [PMID: 28717125 PMCID: PMC5514092 DOI: 10.1038/s41598-017-05801-3] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Accepted: 06/05/2017] [Indexed: 01/11/2023] Open
Abstract
The aim of this study was to systematically review articles that investigated the prognostic significance of different microRNAs in bladder cancer (BC). We systematically searched PubMed, Web of Science, and Embase to identify relevant studies until March 2016. After screening, 26 studies that involved 2753 patients were included. Results suggested that many miRs expression aberration may predict prognosis in patients with BC. There are six miRs (miR-21, miR-143, miR-155, miR-200, miR-214, and miR-222) were reported by at least two studies, and we performed meta-analysis in the corresponding studies. Accordingly, we found that high miR-21 expression was associated with poor overall survival [OS; hazard ratio (HR) = 3.94, 95% CI 2.08–7.44]. High miR-143 expression was associated with poor progression-free survival (PFS; HR = 3.78, 95% CI 1.61–8.89). High miR-155 expression was associated with poor PFS (HR = 8.10, 95% CI 2.92–22.48). High miR-222 expression was associated with poor OS (HR = 3.39, 95% CI 1.10–10.41). Meanwhile, low miR-214 expression was correlated with poor RFS(HR = 0.34, 95% CI 0.22–0.53). Our comprehensive systematic review concluded that microRNAs, particularly miR-21, miR-143, miR-155, miR-214, and miR-222, could serve as meticulous follow-up markers for early detection of progression or recurrence and even useful therapeutic targets for the treatment in patients with BC.
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Colorectal Cancer: From the Genetic Model to Posttranscriptional Regulation by Noncoding RNAs. BIOMED RESEARCH INTERNATIONAL 2017; 2017:7354260. [PMID: 28573140 PMCID: PMC5442347 DOI: 10.1155/2017/7354260] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 02/16/2017] [Indexed: 12/11/2022]
Abstract
Colorectal cancer is the third most common form of cancer in developed countries and, despite the improvements achieved in its treatment options, remains as one of the main causes of cancer-related death. In this review, we first focus on colorectal carcinogenesis and on the genetic and epigenetic alterations involved. In addition, noncoding RNAs have been shown to be important regulators of gene expression. We present a general overview of what is known about these molecules and their role and dysregulation in cancer, with a special focus on the biogenesis, characteristics, and function of microRNAs. These molecules are important regulators of carcinogenesis, progression, invasion, angiogenesis, and metastases in cancer, including colorectal cancer. For this reason, miRNAs can be used as potential biomarkers for diagnosis, prognosis, and efficacy of chemotherapeutic treatments, or even as therapeutic agents, or as targets by themselves. Thus, this review highlights the importance of miRNAs in the development, progression, diagnosis, and therapy of colorectal cancer and summarizes current therapeutic approaches for the treatment of colorectal cancer.
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Han SH, Kim HJ, Gwak JM, Kim M, Chung YR, Park SY. MicroRNA-222 Expression as a Predictive Marker for Tumor Progression in Hormone Receptor-Positive Breast Cancer. J Breast Cancer 2017; 20:35-44. [PMID: 28382093 PMCID: PMC5378578 DOI: 10.4048/jbc.2017.20.1.35] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 01/03/2017] [Indexed: 01/10/2023] Open
Abstract
Purpose The microRNA-221/222 (miR-221/222) gene cluster has been reported to be associated with the promotion of epithelial-mesenchymal transition (EMT), downregulation of estrogen receptor-α, and tamoxifen resistance in breast cancer. We studied the expression of miR-222 in human breast cancer samples to analyze its relationship with clinicopathologic features of the tumor, including estrogen receptor status, expression of EMT markers, and clinical outcomes. Methods Quantitative real-time polymerase chain reaction was performed to detect the expression of miR-222 in 197 invasive breast cancers. Expression of EMT markers (vimentin, smooth muscle actin, osteonectin, N-cadherin, and E-cadherin) was evaluated using immunohistochemistry. Results High miR-222 levels were associated with high T stage, high histologic grade, high Ki-67 proliferation index, and HER2 gene amplification. Its expression was significantly higher in the luminal B and human epidermal growth factor receptor 2-positive (HER2+) subtypes than in the luminal A and triple-negative subtypes. In the hormone receptor-positive subgroup, there was a significant negative correlation between miR-222 and estrogen receptor expression, and miR-222 expression was associated with EMT marker expression. In the group as a whole, high miR-222 expression was not associated with clinical outcome. However, subgroup analyses by hormone receptor status revealed that high miR-222 expression was a poor prognostic factor in the hormone receptor-positive subgroup, but not in the hormone receptor-negative subgroup. Conclusion This study showed that miR-222 is associated with down-regulation of the estrogen receptor, EMT, and tumor progression in hormone receptor-positive breast cancer, indicating that miR-222 might be associated with endocrine therapy resistance and poor clinical outcome in hormone receptor-positive breast cancer.
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Affiliation(s)
- Song-Hee Han
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hyun Jeong Kim
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jae Moon Gwak
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Mimi Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Yul Ri Chung
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - So Yeon Park
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea.; Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
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Fu Q, Cheng J, Zhang J, Zhang Y, Chen X, Xie J, Luo S. Downregulation of YEATS4 by miR-218 sensitizes colorectal cancer cells to L-OHP-induced cell apoptosis by inhibiting cytoprotective autophagy. Oncol Rep 2016; 36:3682-3690. [PMID: 27779719 DOI: 10.3892/or.2016.5195] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 06/10/2016] [Indexed: 11/06/2022] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Deregulation of microRNAs (miRNAs) has been reported to participate in CRC progression. In the present study, we observed downregulation of miR-218 and upregulation of YEATS domain containing 4 (YEATS4) in CRC tissues and in multidrug-resistant HCT-116/L-OHP cells compared with these levels in normal tissues and parental HCT-116 cells, respectively. The results indicated that miR-218 overexpression significantly decreased the IC50 value of oxaliplatin (L-OHP) in the HCT-116/L-OHP cells, and suppression of miR-218 significantly enhanced the IC50 of L-OHP in the HCT-116 cells. Flow cytometric analysis showed that miR-218 overexpression alone promoted cell apoptosis in the HCT-116/L-OHP cells, which was further enhanced in response to L-OHP, and miR-218 inhibition decreased cell apoptosis in the HCT-116 cells following treatment with L-OHP. Western blot analysis indicated that, compared with the small increase observed in HCT-116 cells, the relative LC3 II level in HCT-116/L-OHP cells after lysosome inhibition via chloroquine (CQ) was markedly upregulated following L-OHP treatment, suggesting induction of autophagy. Exposure of HCT-116/L-OHP cells to L-OHP after control mimic transfection increased autophagic flux, as reflected by increased LC3 II levels, while miR-218 overexpression partly reversed L-OHP-mediated LC3 II accumulation. Additionally, both miR-218 overexpression and CQ treatment promoted L-OHP-induced HCT-116/L-OHP cell apoptosis. Molecularly, our results confirmed that miR-218 directly targets the YEATS4 gene and inhibits YEATS4 expression. Furthermore, YEATS4 overexpression without the 3'-untranslated region (3'-UTR) restored miR-218-inhibited YEATS4 and LC3 II expression, and abolished miR-218-stimulated cell viability loss and cell apoptosis increase in response to L-OHP. In conclusion, miR-218 sensitized HCT-116/L-OHP cells to L-OHP-induced cell apoptosis via inhibition of cytoprotective autophagy by targeting YEATS4 expression.
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Affiliation(s)
- Qiang Fu
- Department of Gastrointestinal Surgery, Tumor Hospital of Henan Province (The Affiliated Tumor Hospital of Zhengzhou University), Zhengzhou, Henan 450008, P.R. China
| | - Jing Cheng
- Department of Medical Oncology, Zhengzhou Central Hospital (The Affiliated Central Hospital of Zhengzhou University), Zhengzhou, Henan 450007, P.R. China
| | - Jindai Zhang
- Department of Gastrointestinal Surgery, Tumor Hospital of Henan Province (The Affiliated Tumor Hospital of Zhengzhou University), Zhengzhou, Henan 450008, P.R. China
| | - Yonglei Zhang
- Department of Gastrointestinal Surgery, Tumor Hospital of Henan Province (The Affiliated Tumor Hospital of Zhengzhou University), Zhengzhou, Henan 450008, P.R. China
| | - Xiaobing Chen
- Department of Digestive Oncology, Tumor Hospital of Henan Province (The Affiliated Tumor Hospital of Zhengzhou University), Zhengzhou, Henan 450008, P.R. China
| | - Jianguo Xie
- Department of Gastrointestinal Surgery, Tumor Hospital of Henan Province (The Affiliated Tumor Hospital of Zhengzhou University), Zhengzhou, Henan 450008, P.R. China
| | - Suxia Luo
- Department of Digestive Oncology, Tumor Hospital of Henan Province (The Affiliated Tumor Hospital of Zhengzhou University), Zhengzhou, Henan 450008, P.R. China
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Fanale D, Castiglia M, Bazan V, Russo A. Involvement of Non-coding RNAs in Chemo- and Radioresistance of Colorectal Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 937:207-28. [DOI: 10.1007/978-3-319-42059-2_11] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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miR-222 confers the resistance of breast cancer cells to Adriamycin through suppression of p27(kip1) expression. Gene 2016; 590:44-50. [PMID: 27282281 DOI: 10.1016/j.gene.2016.06.013] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 05/26/2016] [Accepted: 06/04/2016] [Indexed: 01/24/2023]
Abstract
Adriamycin (Adr) is a potent chemotherapeutic agent for chemotherapy of breast cancer patients. Despite impressive initial clinical responses, some developed drug resistance to Adr-based therapy and the mechanisms underlying breast cancer cells resistance to Adr are not well known. In our previous study, in vitro, we verified that miR-222 was upregulated in Adr-resistant breast cancer cells (MCF-7/Adr) compared with the sensitive parental cells (MCF-7/S). Here, miR-222 inhibitors or mimics were transfected into MCF-7 cell lines. RT-qPCR and western blot were used to detect the expression of p27(kip1). Immunofluorescence showed that miR-222 altered the subcellular location of p27(kip1) in nucleus. MTT was employed to verify the sensitivity of breast cancer cell lines to Adr. Flow cytometry showed the apoptosis and cell cycles of the cells after adding Adr. The results showed that downregulation of miR-222 in MCF-7/Adr increased sensitivity to Adr and Adr-induced apoptosis, and arrested the cells in G1 phase, accompanied by more expressions of p27(kip1), especially in nucleus. Furthermore, overexpressed miR-222 in MCF-7/S had the inverse results. Taken together, the results found that miR-222 induced Adr-resistance at least in part via suppressing p27(kip1) expression and altering its subcellular localization, and miR-222 inhibitors could reverse Adr-resistance of breast cancer cells. These results disclosed that the future holds much promise for the targeted therapeutic in the treatment of Adr-resistant breast cancer.
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Thomas J, Ohtsuka M, Pichler M, Ling H. MicroRNAs: Clinical Relevance in Colorectal Cancer. Int J Mol Sci 2015; 16:28063-76. [PMID: 26602923 PMCID: PMC4691027 DOI: 10.3390/ijms161226080] [Citation(s) in RCA: 102] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Revised: 10/27/2015] [Accepted: 11/13/2015] [Indexed: 12/27/2022] Open
Abstract
Colorectal cancer is one of the most common cancer diagnoses and causes of mortality worldwide. MicroRNAs are a class of small, non-coding regulatory RNAs that have shown strong associations with colorectal cancer. Through the repression of target messenger RNAs, microRNAs modulate many cellular pathways, such as those involved in cell proliferation, apoptosis, and differentiation. The utilization of microRNAs has shown significant promise in the diagnosis and prognosis of colorectal cancer, owing to their unique expression profile associations with cancer types and malignancies. Moreover, microRNA therapeutics with mimics or antagonists show great promise in preclinical studies, which encourages further development of their clinical use for colorectal cancer patients. The unique ability of microRNAs to affect multiple downstream pathways represents a novel approach for cancer therapy. Although still early in its development, we believe that microRNAs can be used in the near future as biomarkers and therapeutic targets for colorectal cancer.
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Affiliation(s)
- Joe Thomas
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
| | - Masahisa Ohtsuka
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
| | - Martin Pichler
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
- Division of Oncology, Medical University of Graz, 8010 Graz, Austria.
| | - Hui Ling
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
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Lin G, Xu K. [Advances in tumor chemo-resistance regulated by MicroRNA]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2015; 17:741-9. [PMID: 25342041 PMCID: PMC6000396 DOI: 10.3779/j.issn.1009-3419.2014.10.06] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Chemotherapy is one of the primary treatment for malignant tumors. Tumor multidrug resistance (MDR) is a major cause of clinical failure of chemotherapy; however the mechanisms of chemo-resistance have not been fully elucidated. Recently, microRNA is one of the new hotspots in life science. MicroRNA regulates the expression of genes and plays roles a series of life events by post-transcriptional regulations, including cell proliferation, apoptosis, fat metabolism, nervous development, hormone secretion, tumor vessels generation, stem cell differentiation, tumor cell invasion and metastasis, and other physiological and pathological processes. Recent studies show that microRNA regulates the expression of multiple genes with high efficiency and specificity. The abnormal regulation of target genes by microRNA is responsible for tumor chemo-resistance, this may be an important component of the complexity of the regulation of chemo-resistance. Therefore, the study of microRNA and tumor drug resistance has profound practical significance. In this review, recent studies of tumor drug resistance, regulation of tumor drug resistance by microRNA, and microRNA as a potential target for tumor drug resistance therapy are reviewed.
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Affiliation(s)
- Gaoyang Lin
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute,
Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Ke Xu
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute,
Tianjin Medical University General Hospital, Tianjin 300052, China
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40
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Weng W, Feng J, Qin H, Ma Y, Goel A. An update on miRNAs as biological and clinical determinants in colorectal cancer: a bench-to-bedside approach. Future Oncol 2015; 11:1791-808. [PMID: 26075447 PMCID: PMC4489702 DOI: 10.2217/fon.15.83] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Colorectal carcinogenesis represents a sequential progression of normal colonic mucosa from adenoma to carcinoma. It has become apparent that miRNA deregulation contributes to the initiation and progression of colorectal cancer (CRC). These oncogenic or tumor-suppressive miRNAs interact with intracellular signaling networks and lead to alteration of cell proliferation, apoptosis, metastasis and even response to chemotherapeutic treatments. This article aims to review the cutting edge progress in the discovery of the role of novel mechanisms for miRNAs in the development of CRC. We will also discuss the potential use of miRNAs as biomarkers for early diagnosis and prognosis of CRC. Furthermore, with advancements in RNA delivery technology, it is anticipated that manipulation of miRNAs may offer an alternative therapy for CRC treatment.
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Affiliation(s)
- Wenhao Weng
- Department of Clinical Laboratory, Shanghai Tenth People’s Hospital Affiliated with Tongji University, Shanghai 200072, China
| | - Junlan Feng
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
| | - Huanlong Qin
- Department of GI Surgery, Shanghai Tenth People’s Hospital Affiliated with Tongji University, 301 Yanchang Road, Shanghai 200072, China
| | - Yanlei Ma
- Department of GI Surgery, Shanghai Tenth People’s Hospital Affiliated with Tongji University, 301 Yanchang Road, Shanghai 200072, China
| | - Ajay Goel
- Center for Gastrointestinal Research & Center for Epigenetics, Cancer Prevention & Cancer Genomics, Baylor Research Institute & Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
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41
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GNAI3 inhibits tumor cell migration and invasion and is post-transcriptionally regulated by miR-222 in hepatocellular carcinoma. Cancer Lett 2015; 356:978-84. [DOI: 10.1016/j.canlet.2014.11.013] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Revised: 11/04/2014] [Accepted: 11/06/2014] [Indexed: 12/11/2022]
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42
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Liu MZ, McLeod HL, He FZ, Chen XP, Zhou HH, Shu Y, Zhang W. Epigenetic perspectives on cancer chemotherapy response. Pharmacogenomics 2014; 15:699-715. [PMID: 24798726 DOI: 10.2217/pgs.14.41] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Epigenetic programs are now widely recognized as being critical to the biological processes of cancer genesis. However, it has not been comprehensively understood how and to what degree they can influence anticancer drugs responses. The development of drugs targeting epigenetic regulation has generated great enthusiasm, with a growing number in clinical development. We highlight here that epigenetic modifications can be involved in the regulation of genes responsible for the absorption, distribution, metabolism and excretion of drugs and for the pathological progression of cancer, thereby affecting anticancer drug responses. The major epigenetic regulatory mechanisms are reviewed, including DNA methylation, miRNA regulation and histone modification, with the aim of promoting rational use of anticancer drugs in the clinic and epigenetic drug development.
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Affiliation(s)
- Mou-Ze Liu
- Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha, Hunan, 410078, PR China
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Muhammad S, Kaur K, Huang R, Zhang Q, Kaur P, Yazdani HO, Bilal MU, Zheng J, Zheng L, Wang XS. MicroRNAs in colorectal cancer: Role in metastasis and clinical perspectives. World J Gastroenterol 2014; 20:17011-17019. [PMID: 25493013 PMCID: PMC4258569 DOI: 10.3748/wjg.v20.i45.17011] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Revised: 06/19/2014] [Accepted: 07/30/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common malignancy and the third leading cause of cancer related deaths in the United States. Almost 90% of the patients diagnosed with CRC die due to metastases. MicroRNAs (miRNAs) are evolutionarily conserved molecules that modulate the expression of their target genes post-transcriptionally, and they may participate in various physiological and pathological processes including CRC metastasis by influencing various factors in the human body. Recently, the role miRNAs play throughout the CRC metastatic cascade has gain attention. Many studies have been published to link them with CRC metastasis. In this review, we will briefly discuss metastatic steps in the light of miRNAs, along with their target genes. We will discuss how the aberration in the expression of miRNAs leads to the formation of CRC by effecting the regulation of their target genes. As miRNAs are being exploited for diagnosis, prognosis, and monitoring of cancer and other diseases, their high tissue specificity and critical role in oncogenesis make them new biomarkers for the diagnosis and classification of cancer as well as for predicting patients’ outcome. MiRNA signatures have been identified for many human tumors including CRC, and miRNA-based therapies to treat cancer have been emphasized lately. These will also be discussed in this review.
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44
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Liu K, Liu S, Zhang W, Ji B, Wang Y, Liu Y. miR‑222 regulates sorafenib resistance and enhance tumorigenicity in hepatocellular carcinoma. Int J Oncol 2014; 45:1537-1546. [PMID: 25096647 DOI: 10.3892/ijo.2014.2577] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Accepted: 07/24/2014] [Indexed: 11/06/2022] Open
Abstract
The miR‑222 cluster has been demonstrated to function as oncomiR in human hepatocellular carcinoma (HCC). miR‑222 confers chemotherapy drug resistance in various cancers, including HCC. However, the effects and mechanisms by which miR‑222 regulates liver tumorigenicity and confers sorafenib (SOR) resistance remain unclear. Here we first investigated the miR‑222 effect on proliferation, cell cycle, apoptosis, migration and invasion of HCC. Our results demonstrated that miRNA inhibitors specially targeting miR‑222 significantly suppressed cellular proliferation, migration, invasion and G1/S transition of the cell cycle, and induced cell apoptosis in HepG2 cells. In addition, we investigated whether miR‑222 confers SOR resistance in HepG2 cells to explore it roles in acquisition of drug resistance. The results showed that miR‑222 inhibitors induced sensitivity to the antitumor effect of sorafenib in human HepG2 cells. Importantly, our study also showed that miR‑222 could regulate the expression of phosphorylation PI3K and AKT, which might contribute to miR‑222 conferred SOR resistance in HepG2 cells. In conclusion, this study demonstrates that miR‑222 can promote cell proliferation, migration and invasion, and decrease cell apoptosis, as well as enhance the resistance of HCC cells to sorafenib miR‑222 through activating the PI3K/AKT signaling pathway.
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Affiliation(s)
- Kai Liu
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin Province, P.R. China
| | - Songyang Liu
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin Province, P.R. China
| | - Wei Zhang
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin Province, P.R. China
| | - Bai Ji
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin Province, P.R. China
| | - Yingchao Wang
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin Province, P.R. China
| | - Yahui Liu
- Department of Hepatopancreatobiliary Surgery, The First Hospital, Jilin University, Changchun, Jilin Province, P.R. China
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45
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Orang AV, Barzegari A. MicroRNAs in Colorectal Cancer: from Diagnosis to Targeted Therapy. Asian Pac J Cancer Prev 2014; 15:6989-99. [DOI: 10.7314/apjcp.2014.15.17.6989] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Zhang DQ, Zhou CK, Jiang XW, Chen J, Shi BK. Increased expression of miR-222 is associated with poor prognosis in bladder cancer. World J Surg Oncol 2014; 12:241. [PMID: 25078265 PMCID: PMC4132207 DOI: 10.1186/1477-7819-12-241] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 07/04/2014] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND MicroRNA-222 (miR-222) has been shown to play a potential oncogenic role in bladder cancer. The aim of this study was to evaluate the expression of miR-222 in bladder cancer and its potential relevance to clinicopathological characteristics and patient survival. METHODS Surgical specimens of cancer tissue and adjacent normal tissue were obtained from 97 patients with bladder cancer. The relative expression levels of miR-222 in the cancer and the normal adjacent tissue were measured by quantitative reverse-transcriptase PCR. We analyzed their correlation with clinicopathological parameters and prognostic value. RESULTS The expression level of miR-222 was significantly higher in tumor tissues than in corresponding non-cancerous tissues (5.46 ± 1.45 versus 1.92 ± 0.65, P < 0.0001), and a high expression of miR-222 was found to be significantly associated with tumor grade (P = 0.003) and tumor stage (P = 0.005). The miR-222 expression level was classified as high or low in relation to the median value (cutoff value = 5.15). Kaplan-Meier analysis showed that patients with higher levels of miR-222 had significantly poorer survival than those with lower expression of this miRNA in patients, with a 5-year overall survival of 29.53% and 52.75%, respectively (P = 0.0034). In the multivariate Cox proportional hazards analysis, which included miR-222 level, tumor grade, tumor stage, and tumor number, high miR-222 expression was independently associated with poor survival (P < 0.001; hazard ratio 6.17; 95% CI 2.33 to 10.39). CONCLUSION miR-222 overexpression is involved in the poor prognosis of bladder cancer and can be used as a biomarker for selection of cases requiring special attention.
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Affiliation(s)
- Dong-qing Zhang
- Department of Urology, Qilu Hospital of Shandong University, Jinan 250012, People's Republic of China.
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Pulito C, Donzelli S, Muti P, Puzzo L, Strano S, Blandino G. microRNAs and cancer metabolism reprogramming: the paradigm of metformin. ANNALS OF TRANSLATIONAL MEDICINE 2014; 2:58. [PMID: 25333033 PMCID: PMC4200659 DOI: 10.3978/j.issn.2305-5839.2014.06.03] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Accepted: 05/26/2014] [Indexed: 12/13/2022]
Abstract
Increasing evidence witnesses that cancer metabolism alterations represent a critical hallmark for many types of human tumors. There is a strong need to understand and dissect the molecular mechanisms underlying cancer metabolism to envisage specific biomarkers and underpin critical molecular components that might represent novel therapeutic targets. One challenge, that is the focus of this review, is the reprogramming of the altered metabolism of a cancer cell toward that of un-transformed cell. The anti-hyperglicemic agent, metformin has proven to be effective in reprogramming the metabolism of cancer cells even from those subpopulations endowed with cancer stem like features and very high chemoresistenace to conventional anticancer treatments. A functional interplay involving selective modulation of microRNAs (miRNAs) takes place along the anticancer metabolic effects exerted by metformin. The implications of this interplay will be also discussed in this review.
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Chen Z, Zhu X, Xie T, Xie J, Quo K, Liu X. Drug resistance reversed by silencing LIM domain-containing protein 1 expression in colorectal carcinoma. Oncol Lett 2014; 8:795-798. [PMID: 25013501 PMCID: PMC4081406 DOI: 10.3892/ol.2014.2155] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2013] [Accepted: 03/20/2014] [Indexed: 12/12/2022] Open
Abstract
The role of LIM domain-containing protein 1 (LIMD1) in the multidrug resistance of colorectal carcinoma (CRC) has not yet been established. The aim of the current study was to investigate the chemosensitivity of CRC multidrug-resistant (MDR) cells following the silencing of LIMD1. The MDR phenotypic Colo205 and HCT-8 cell lines were examined, which were established by exposure to increasing doses of 5-fluorouracil (5-FU) over a period of one year. LIMD1 siRNA constructs were transfected into CRC MDR cells and the phenotypic effects were determined comprehensively. The Colo205 and HCT-8 cell lines were more resistant to 5-FU compared with their respective parental cell lines. In addition, the two MDR cell types expressed significantly more LIMD1 compared with their parental lines. The stably transfected cells showed various degrees of reversal of the MDR phenotype, and 5-FU-induced apoptosis was increased in the transfected cells compared with the controls. In conclusion, RNA interference targeting LIMD1 may present a novel therapeutic option for CRC.
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Affiliation(s)
- Zhangxing Chen
- Department of Gastroenterology, The 174th Hospital of the PLA, Xiamen University, Xiamen, Fujian 361003, USA
| | - Xiaosan Zhu
- Department of Gastroenterology, The 174th Hospital of the PLA, Xiamen University, Xiamen, Fujian 361003, USA ; Department of Gastroenterology, Chenggong Hospital, Xiamen University, Xiamen, Fujian 361003, USA
| | - Tao Xie
- Department of Gastroenterology, The 174th Hospital of the PLA, Xiamen University, Xiamen, Fujian 361003, USA
| | - Junpei Xie
- Department of Gastroenterology, The 174th Hospital of the PLA, Xiamen University, Xiamen, Fujian 361003, USA
| | - Kong Quo
- Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE 68178, USA
| | - Xiang Liu
- Department of Gastroenterology, The 174th Hospital of the PLA, Xiamen University, Xiamen, Fujian 361003, USA
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Ye JJ, Cao J. MicroRNAs in colorectal cancer as markers and targets: Recent advances. World J Gastroenterol 2014; 20:4288-4299. [PMID: 24764666 PMCID: PMC3989964 DOI: 10.3748/wjg.v20.i15.4288] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 01/02/2014] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs are evolutionarily conserved small non-coding RNA molecules encoded by eukaryotic genomic DNA, and function in post-transcriptional regulation of gene expression via base-pairing with complementary sequences in target mRNAs, resulting in translational repression or degradation of target mRNAs. They represent one of the major types of epigenetic modification and play important roles in all aspects of cellular activities. Altered expression of microRNAs has been found in various human diseases including cancer. Many efforts have been made to discover the characteristic microRNA expression profiles, to understand the roles of aberrantly expressed microRNAs and underlying mechanisms in different cancers. With the application of DNA microarray, real-time quantitative polymerase chain reaction and other molecular biology techniques, increasing evidence has been accumulated which reveal that aberrant microRNAs can be detected not only intracellularly within the cancer cells, but also extracellularly in plasma of patients, postulating the potential of aberrant microRNAs as promising diagnostic/prognostic markers and attracting therapeutic targets. This review is intended to provide the most recent advances in microRNA studies in one of the most common cancers, colorectal cancer, especially the identification of those specifically altered microRNAs in colorectal cancer, validation for their relevance to clinical pathological parameters of patients, functional analyses and potential applications of these microRNAs.
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50
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MicroRNA-222 expression and its prognostic potential in non-small cell lung cancer. ScientificWorldJournal 2014; 2014:908326. [PMID: 24955421 PMCID: PMC4009118 DOI: 10.1155/2014/908326] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 03/17/2014] [Indexed: 11/18/2022] Open
Abstract
Overexpression of miR-222 has been found in several types of cancers; however, the expression of miR-222 in non-small cell lung cancer (NSCLC) and its prognostic values are unclear. This study aimed to investigate whether the miR-222 expression level is related to clinicopathological factors and prognosis of NSCLC. Through a prospective study, 100 pairs of NSCLC tissues and adjacent normal tissues were examined by quantitative reverse-transcription polymerase chain reaction. The correlation between miR-222 expression and clinicopathological features was analyzed, and the significance of miR-222 as a prognostic factor and its relationship with survival were determined. Results showed that the expression levels of miR-222 were significantly elevated in the NSCLC tissue compared with that in adjacent normal tissue. In addition, Cox's proportional hazards model analysis confirmed that miR-222 high expression level was an independent predictor of poor prognosis. In conclusion, miR-222 overexpression is involved in the poor prognosis of NSCLC and can be used as a biomarker for selection of cases requiring especial attention.
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