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1
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Nemours S, Solé C, Goicoechea I, Armesto M, Arestin M, Urruticoechea A, Rezola M, López IÁ, Schaapveld R, Schultz I, Zhang L, Lawrie CH. Use of Gain-of-Function Screening to Identify miRNAs Involved in Paclitaxel Resistance in Triple-Negative Breast Cancer. Int J Mol Sci 2024; 25:13630. [PMID: 39769392 PMCID: PMC11728027 DOI: 10.3390/ijms252413630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/11/2024] [Accepted: 12/18/2024] [Indexed: 01/30/2025] Open
Abstract
Paclitaxel is a widely used chemotherapeutic agent for the treatment of breast cancer (BC), including as a front-line treatment for triple-negative breast cancer (TNBC) patients. However, resistance to paclitaxel remains one of the major causes of death associated with treatment failure. Multiple studies have demonstrated that miRNAs play a role in paclitaxel resistance and are associated with both disease progression and metastasis. In the present study, we used a miRNA-encoding lentiviral library as a gain-of-function screen for paclitaxel resistance in the MDA-MB-231 TNBC cell line. We identified that miR-181b, miR-29a, miR-30c, miR-196 and miR-1295 conferred a resistant phenotype to cells. The expression of miR-29a also induced resistance to eribulin and vinorelbine, while miR-181b and miR-30c induced resistance to vinorelbine. We measured the levels of these miRNAs in breast cancer patients and observed higher levels of miR-29a in treatment-refractory patients. Taken together, we suggest that miR-29a and miR-181b may be good candidates for miRNA inhibition to overcome resistance to chemotherapy.
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Affiliation(s)
- Stéphane Nemours
- Molecular Oncology Group, Biogipuzkoa Health Research Institute, 20014 San Sebastian, Spain; (S.N.); (C.S.); (M.A.); (M.A.)
| | - Carla Solé
- Molecular Oncology Group, Biogipuzkoa Health Research Institute, 20014 San Sebastian, Spain; (S.N.); (C.S.); (M.A.); (M.A.)
| | - Ibai Goicoechea
- Department of Personalized Medicine, NASERTIC, Government of Navarra, 31011 Pamplona, Spain
| | - María Armesto
- Molecular Oncology Group, Biogipuzkoa Health Research Institute, 20014 San Sebastian, Spain; (S.N.); (C.S.); (M.A.); (M.A.)
| | - María Arestin
- Molecular Oncology Group, Biogipuzkoa Health Research Institute, 20014 San Sebastian, Spain; (S.N.); (C.S.); (M.A.); (M.A.)
| | - Ander Urruticoechea
- Breast Cancer Group, Biogipuzkoa Health Research Institute, 20014 San Sebastian, Spain; (A.U.); (I.Á.L.)
- Gipuzkoa Cancer Unit, OSI Donostialdea—Onkologikoa Foundation, Paseo Dr Begiristain 121, 20014 San Sebastian, Spain
| | - Marta Rezola
- Department of Pathology, Hospital Universitario Donostia Osakidetza, 20014 Donostia, Spain;
| | - Isabel Álvarez López
- Breast Cancer Group, Biogipuzkoa Health Research Institute, 20014 San Sebastian, Spain; (A.U.); (I.Á.L.)
- Gipuzkoa Cancer Unit, OSI Donostialdea—Onkologikoa Foundation, Paseo Dr Begiristain 121, 20014 San Sebastian, Spain
| | - Roel Schaapveld
- InteRNA Technologies, 3584 Utrecht, The Netherlands; (R.S.); (I.S.)
| | - Iman Schultz
- InteRNA Technologies, 3584 Utrecht, The Netherlands; (R.S.); (I.S.)
| | - Lei Zhang
- Sino-Swiss Institute of Advanced Technology (SSIAT), Shanghai University, Shanghai 201800, China;
| | - Charles H. Lawrie
- Molecular Oncology Group, Biogipuzkoa Health Research Institute, 20014 San Sebastian, Spain; (S.N.); (C.S.); (M.A.); (M.A.)
- Sino-Swiss Institute of Advanced Technology (SSIAT), Shanghai University, Shanghai 201800, China;
- IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
- Radcliffe Department of Medicine, University of Oxford, Oxford OX1 2JD, UK
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2
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Xu J, Zhao X, Liang X, Guo D, Wang J, Wang Q, Tang X. Development of miRNA-based PROTACs targeting Lin28 for breast cancer therapy. SCIENCE ADVANCES 2024; 10:eadp0334. [PMID: 39292784 PMCID: PMC11409961 DOI: 10.1126/sciadv.adp0334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 08/09/2024] [Indexed: 09/20/2024]
Abstract
Lin28, a highly conserved carcinogenic protein, plays an important role in the generation of cancer stem cells, contributing to the unfavorable prognosis of cancer patients. This RNA binding protein specifically binds to pri/pre-microRNA (miRNA) lethal-7 (let-7), impeding its miRNA maturation. The reduced expression of tumor suppressor miRNA let-7 fosters development and progression-related traits such as proliferation, invasion, metastasis, and drug resistance. We report a series of miRNA-based Lin28A-miRNA proteolysis-targeting chimeras (Lin28A-miRNA-PROTACs) designed to efficiently degrade Lin28A through a ubiquitin-proteasome-dependent mechanism, resulting in up-regulation of mature let-7 family. The augmented levels of matured let-7 miRNAs further exert inhibitory effects on cancer cell proliferation and migration, and increase its sensitivity to chemotherapy. In a mouse ectopic tumor model, Lin28A-miRNA-PROTAC demonstrates a substantial efficacy in inhibiting tumor growth. When combined with tamoxifen, the tumors exhibit gradual regression. This study displays an effective miRNA-based PROTACs to degrade Lin28A and inhibit tumor growth, providing a promising therapeutic avenue for cancer treatment with miRNA-based therapy.
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Affiliation(s)
- Jianfei Xu
- State Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center and School of Pharmaceutical Sciences, Peking University, Xueyuan Rd, Beijing 100191, China
| | - Xiaoran Zhao
- State Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center and School of Pharmaceutical Sciences, Peking University, Xueyuan Rd, Beijing 100191, China
| | - Xingxing Liang
- State Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center and School of Pharmaceutical Sciences, Peking University, Xueyuan Rd, Beijing 100191, China
| | - Dongyang Guo
- State Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center and School of Pharmaceutical Sciences, Peking University, Xueyuan Rd, Beijing 100191, China
| | - Jing Wang
- State Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center and School of Pharmaceutical Sciences, Peking University, Xueyuan Rd, Beijing 100191, China
| | - Qian Wang
- State Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center and School of Pharmaceutical Sciences, Peking University, Xueyuan Rd, Beijing 100191, China
| | - Xinjing Tang
- State Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center and School of Pharmaceutical Sciences, Peking University, Xueyuan Rd, Beijing 100191, China
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3
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Oyejobi GK, Yan X, Sliz P, Wang L. Regulating Protein-RNA Interactions: Advances in Targeting the LIN28/Let-7 Pathway. Int J Mol Sci 2024; 25:3585. [PMID: 38612395 PMCID: PMC11011352 DOI: 10.3390/ijms25073585] [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: 02/26/2024] [Revised: 03/19/2024] [Accepted: 03/20/2024] [Indexed: 04/14/2024] Open
Abstract
Originally discovered in C. elegans, LIN28 is an evolutionarily conserved zinc finger RNA-binding protein (RBP) that post-transcriptionally regulates genes involved in developmental timing, stem cell programming, and oncogenesis. LIN28 acts via two distinct mechanisms. It blocks the biogenesis of the lethal-7 (let-7) microRNA (miRNA) family, and also directly binds messenger RNA (mRNA) targets, such as IGF-2 mRNA, and alters downstream splicing and translation events. This review focuses on the molecular mechanism of LIN28 repression of let-7 and current strategies to overcome this blockade for the purpose of cancer therapy. We highlight the value of the LIN28/let-7 pathway as a drug target, as multiple oncogenic proteins that the pathway regulates are considered undruggable due to their inaccessible cellular location and lack of cavities for small molecule binding.
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Affiliation(s)
- Greater Kayode Oyejobi
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Ministry of Education), School of Pharmaceutical Sciences, Wuhan University, Wuhan 430072, China; (G.K.O.); (X.Y.)
| | - Xiaodan Yan
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Ministry of Education), School of Pharmaceutical Sciences, Wuhan University, Wuhan 430072, China; (G.K.O.); (X.Y.)
| | - Piotr Sliz
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Longfei Wang
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Ministry of Education), School of Pharmaceutical Sciences, Wuhan University, Wuhan 430072, China; (G.K.O.); (X.Y.)
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Vembuli H, Gor R, Ramalingam S, Perales S, Rajasingh J. RNA binding proteins in cancer chemotherapeutic drug resistance. Front Cell Dev Biol 2024; 12:1308102. [PMID: 38328550 PMCID: PMC10847363 DOI: 10.3389/fcell.2024.1308102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 01/12/2024] [Indexed: 02/09/2024] Open
Abstract
Drug resistance has been a major obstacle in the quest for a cancer cure. Many chemotherapeutic treatments fail to overcome chemoresistance, resulting in tumor remission. The exact process that leads to drug resistance in many cancers has not been fully explored or understood. However, the discovery of RNA binding proteins (RBPs) has provided insight into various pathways and post-transcriptional gene modifications involved in drug tolerance. RBPs are evolutionarily conserved proteins, and their abnormal gene expression has been associated with cancer progression. Additionally, RBPs are aberrantly expressed in numerous neoplasms. RBPs have also been implicated in maintaining cancer stemness, epithelial-to-mesenchymal transition, and other processes. In this review, we aim to provide an overview of RBP-mediated mechanisms of drug resistance and their implications in cancer malignancy. We discuss in detail the role of major RBPs and their correlation with noncoding RNAs (ncRNAs) that are associated with the inhibition of chemosensitivity. Understanding and exploring the pathways of RBP-mediated chemoresistance will contribute to the development of improved cancer diagnosis and treatment strategies.
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Affiliation(s)
- Hemanathan Vembuli
- Department of Genetic Engineering, School of Bio-Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
- Department of Bioscience Research, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Ravi Gor
- Department of Genetic Engineering, School of Bio-Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
| | - Satish Ramalingam
- Department of Genetic Engineering, School of Bio-Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
| | - Selene Perales
- Department of Bioscience Research, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Johnson Rajasingh
- Department of Genetic Engineering, School of Bio-Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
- Department of Bioscience Research, University of Tennessee Health Science Center, Memphis, TN, United States
- Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, United States
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5
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Li G, Wakao S, Kitada M, Dezawa M. Tumor suppressor let-7 acts as a key regulator for pluripotency gene expression in Muse cells. Cell Mol Life Sci 2024; 81:54. [PMID: 38261036 PMCID: PMC10805825 DOI: 10.1007/s00018-023-05089-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 12/01/2023] [Accepted: 12/12/2023] [Indexed: 01/24/2024]
Abstract
In embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), the expression of an RNA-binding pluripotency-relevant protein, LIN28, and the absence of its antagonist, the tumor-suppressor microRNA (miRNA) let-7, play a key role in maintaining pluripotency. Muse cells are non-tumorigenic pluripotent-like stem cells residing in the bone marrow, peripheral blood, and organ connective tissues as pluripotent surface marker SSEA-3(+). They express pluripotency genes, differentiate into triploblastic-lineage cells, and self-renew at the single cell level. Muse cells do not express LIN28 but do express let-7 at higher levels than in iPSCs. In Muse cells, we demonstrated that let-7 inhibited the PI3K-AKT pathway, leading to sustainable expression of the key pluripotency regulator KLF4 as well as its downstream genes, POU5F1, SOX2, and NANOG. Let-7 also suppressed proliferation and glycolysis by inhibiting the PI3K-AKT pathway, suggesting its involvement in non-tumorigenicity. Furthermore, the MEK/ERK pathway is not controlled by let-7 and may have a pivotal role in maintaining self-renewal and suppression of senescence. The system found in Muse cells, in which the tumor suppressor let-7, but not LIN28, tunes the expression of pluripotency genes, might be a rational cell system conferring both pluripotency-like properties and a low risk for tumorigenicity.
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Affiliation(s)
- Gen Li
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
| | - Shohei Wakao
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Masaaki Kitada
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
- Department of Anatomy, Kansai Medical University School of Medicine, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1191, Japan.
| | - Mari Dezawa
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
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6
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Singh S, Saini H, Sharma A, Gupta S, Huddar VG, Tripathi R. Breast cancer: miRNAs monitoring chemoresistance and systemic therapy. Front Oncol 2023; 13:1155254. [PMID: 37397377 PMCID: PMC10312137 DOI: 10.3389/fonc.2023.1155254] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 06/05/2023] [Indexed: 07/04/2023] Open
Abstract
With a high mortality rate that accounts for millions of cancer-related deaths each year, breast cancer is the second most common malignancy in women. Chemotherapy has significant potential in the prevention and spreading of breast cancer; however, drug resistance often hinders therapy in breast cancer patients. The identification and the use of novel molecular biomarkers, which can predict response to chemotherapy, might lead to tailoring breast cancer treatment. In this context, accumulating research has reported microRNAs (miRNAs) as potential biomarkers for early cancer detection, and are conducive to designing a more specific treatment plan by helping analyze drug resistance and sensitivity in breast cancer treatment. In this review, miRNAs are discussed in two alternative ways-as tumor suppressors to be used in miRNA replacement therapy to reduce oncogenesis and as oncomirs to lessen the translation of the target miRNA. Different miRNAs like miR-638, miR-17, miR-20b, miR-342, miR-484, miR-21, miR-24, miR-27, miR-23 and miR-200 are involved in the regulation of chemoresistance through diverse genetic targets. For instance, tumor-suppressing miRNAs like miR-342, miR-16, miR-214, and miR-128 and tumor-promoting miRNAs like miR101 and miR-106-25 cluster regulate the cell cycle, apoptosis, epithelial to mesenchymal transition and other pathways to impart breast cancer drug resistance. Hence, in this review, we have discussed the significance of miRNA biomarkers that could assist in providing novel therapeutic targets to overcome potential chemotherapy resistance to systemic therapy and further facilitate the design of tailored therapy for enhanced efficacy against breast cancer.
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Affiliation(s)
- Shivam Singh
- Department of Radiation Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Heena Saini
- Integrated translational Molecular Biology laboratory, Department of Rog Nidan and Vikriti vigyan (Pathology), All India Institute of Ayurveda (AIIA), New Delhi, India
| | - Ashok Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Subhash Gupta
- Department of Radiation Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - V. G. Huddar
- Department of Kaya Chikitsa (Internal Medicine), All India Institute of Ayurveda (AIIA), New Delhi, India
| | - Richa Tripathi
- Integrated translational Molecular Biology laboratory, Department of Rog Nidan and Vikriti vigyan (Pathology), All India Institute of Ayurveda (AIIA), New Delhi, India
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Gao Y, Cao H, Huang D, Zheng L, Nie Z, Zhang S. RNA-Binding Proteins in Bladder Cancer. Cancers (Basel) 2023; 15:cancers15041150. [PMID: 36831493 PMCID: PMC9953953 DOI: 10.3390/cancers15041150] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 02/09/2023] [Accepted: 02/09/2023] [Indexed: 02/15/2023] Open
Abstract
RNA-binding proteins (RBPs) are key regulators of transcription and translation, with highly dynamic spatio-temporal regulation. They are usually involved in the regulation of RNA splicing, polyadenylation, and mRNA stability and mediate processes such as mRNA localization and translation, thereby affecting the RNA life cycle and causing the production of abnormal protein phenotypes that lead to tumorigenesis and development. Accumulating evidence supports that RBPs play critical roles in vital life processes, such as bladder cancer initiation, progression, metastasis, and drug resistance. Uncovering the regulatory mechanisms of RBPs in bladder cancer is aimed at addressing the occurrence and progression of bladder cancer and finding new therapies for cancer treatment. This article reviews the effects and mechanisms of several RBPs on bladder cancer and summarizes the different types of RBPs involved in the progression of bladder cancer and the potential molecular mechanisms by which they are regulated, with a view to providing information for basic and clinical researchers.
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8
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Targeting the "undruggable": RNA-binding proteins in the spotlight in cancer therapy. Semin Cancer Biol 2022; 86:69-83. [PMID: 35772609 DOI: 10.1016/j.semcancer.2022.06.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 05/19/2022] [Accepted: 06/24/2022] [Indexed: 01/27/2023]
Abstract
Tumors refractory to conventional therapy belong to specific subpopulations of cancer cells, which have acquired a higher number of mutations/epigenetic changes than the majority of cancer cells. This property provides them the ability to become resistant to therapy. Aberrant expression of certain RNA-binding proteins (RBPs) can regulate the sensitivity of tumor cells to chemotherapeutic drugs by binding to specific regions present in the 3´-UTR of certain mRNAs to promote or repress mRNA translation or by interacting with other proteins (including RBPs) and non-coding RNAs that are part of ribonucleoprotein complexes. In particular, an increasing interest in the RBPs involved in chemoresistance has recently emerged. In this review, we discuss how RBPs are not only affected by chemotherapeutic treatments, but also play an active role in therapeutic responses via the direct modulation of crucial cancer-related proteins. A special focus is being placed on the development of therapeutic strategies targeting these RBPs.
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Lin Z, Radaeva M, Cherkasov A, Dong X. Lin28 Regulates Cancer Cell Stemness for Tumour Progression. Cancers (Basel) 2022; 14:4640. [PMID: 36230562 PMCID: PMC9564245 DOI: 10.3390/cancers14194640] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/15/2022] [Accepted: 09/22/2022] [Indexed: 11/17/2022] Open
Abstract
Tumours develop therapy resistance through complex mechanisms, one of which is that cancer stem cell (CSC) populations within the tumours present self-renewable capability and phenotypical plasticity to endure therapy-induced stress conditions and allow tumour progression to the therapy-resistant state. Developing therapeutic strategies to cope with CSCs requires a thorough understanding of the critical drivers and molecular mechanisms underlying the aforementioned processes. One such hub regulator of stemness is Lin28, an RNA-binding protein. Lin28 blocks the synthesis of let-7, a tumour-suppressor microRNA, and acts as a global regulator of cell differentiation and proliferation. Lin28also targets messenger RNAs and regulates protein translation. In this review, we explain the role of the Lin28/let-7 axis in establishing stemness, epithelial-to-mesenchymal transition, and glucose metabolism reprogramming. We also highlight the role of Lin28 in therapy-resistant prostate cancer progression and discuss the emergence of Lin28-targeted therapeutics and screening methods.
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Affiliation(s)
- Zhuohui Lin
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
- Faculty of Food and Land Systems, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Mariia Radaeva
- The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
| | - Artem Cherkasov
- The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
| | - Xuesen Dong
- The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
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10
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Neurospora crassa is a potential source of anti-cancer agents against breast cancer. Breast Cancer 2022; 29:1032-1041. [PMID: 35881300 DOI: 10.1007/s12282-022-01383-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 06/23/2022] [Indexed: 11/02/2022]
Abstract
Fungi are an excellent source of pharmaceuticals including anti-tumor agents. Neurospora crassa generates metabolites with diverse structural classes, however, its potential as an anti-tumor agent source has not been explored. The purpose of this study aimed to investigate the potential of Neurospora crassa mixture against breast cancer. The in vitro T-47D and MDA-MB-231 experiments showed that N. crassa mixture at the concentrations of both 1.7 and 0.85 µg/ml significantly inhibited tumor cell proliferation, migration and invasion, and 3D spheroid formation. However, the inhibition rates of MCF-10A ranged 10-20% at concentrations of 0.85 and 1.7 µg/ml. The mixture at the concentration of 0.85 µg/ml could significantly downregulate the expressions of transcription factors of E2F1 and E2F3, cancer stem cell-related genes of LIN28, HIWI, and CD133, and onco-lncRNA HOTAIR, and increase CASP3 activity in either T-47D or MDA-MD-231 breast cancer cell lines. In vivo breast cancer C3H mouse model results showed that N. crassa mixture significantly inhibited tumor growth. These findings suggest that N. crassa contains an antitumor component(s) against breast cancer invasiveness, which may inhibit the self-renewal and differentiation of breast cancer stem cells possibly by downregulating cancer stem cell-associated and/or transcription factor genes and oncogenes, and promoting apoptosis.
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11
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LIN28 Family in Testis: Control of Cell Renewal, Maturation, Fertility and Aging. Int J Mol Sci 2022; 23:ijms23137245. [PMID: 35806250 PMCID: PMC9266904 DOI: 10.3390/ijms23137245] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/20/2022] [Accepted: 06/25/2022] [Indexed: 12/12/2022] Open
Abstract
Male reproductive development starts early in the embryogenesis with somatic and germ cell differentiation in the testis. The LIN28 family of RNA-binding proteins promoting pluripotency has two members—LIN28A and LIN28B. Their function in the testis has been investigated but many questions about their exact role based on the expression patterns remain unclear. LIN28 expression is detected in the gonocytes and the migrating, mitotically active germ cells of the fetal testis. Postnatal expression of LIN28 A and B showed differential expression, with LIN28A expressed in the undifferentiated spermatogonia and LIN28B in the elongating spermatids and Leydig cells. LIN28 interferes with many signaling pathways, leading to cell proliferation, and it is involved in important testicular physiological processes, such as cell renewal, maturation, fertility, and aging. In addition, aberrant LIN28 expression is associated with testicular cancer and testicular disorders, such as hypogonadotropic hypogonadism and Klinefelter’s syndrome. This comprehensive review encompasses current knowledge of the function of LIN28 paralogs in testis and other tissues and cells because many studies suggest LIN28AB as a promising target for developing novel therapeutic agents.
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12
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Zhang W, Liu L, Zhao S, Chen L, Wei Y, Chen W, Ge F. Research progress on RNA‑binding proteins in breast cancer (Review). Oncol Lett 2022; 23:121. [PMID: 35261635 PMCID: PMC8867207 DOI: 10.3892/ol.2022.13241] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 02/03/2022] [Indexed: 11/28/2022] Open
Abstract
Breast cancer is the most common malignancy among women, and the abnormal regulation of gene expression serves an important role in its occurrence and development. However, the molecular mechanisms underlying gene expression are highly complex and heterogeneous, and RNA-binding proteins (RBPs) are among the key regulatory factors. RBPs bind targets in an environment-dependent or environment-independent manner to influence mRNA stability and the translation of genes involved in the formation, progression, metastasis and treatment of breast cancer. Due to the growing interest in these regulators, the present review summarizes the most influential studies concerning RBPs associated with breast cancer to elucidate the role of RBPs in breast cancer and to assess how they interact with other key pathways to provide new molecular targets for the diagnosis and treatment of breast cancer.
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Affiliation(s)
- Wenzhu Zhang
- Department of Breast Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Linlin Liu
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Shengdi Zhao
- Department of Breast Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Liang Chen
- Department of Breast Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Yuxian Wei
- Department of Endocrine Breast Surgery, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Wenlin Chen
- Third Department of Breast Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Fei Ge
- Department of Breast Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
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13
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Tian JH, Liu SH, Yu CY, Wu LG, Wang LB. The Role of Non-Coding RNAs in Breast Cancer Drug Resistance. Front Oncol 2021; 11:702082. [PMID: 34589423 PMCID: PMC8473733 DOI: 10.3389/fonc.2021.702082] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 08/17/2021] [Indexed: 12/21/2022] Open
Abstract
Breast cancer (BC) is one of the commonly occurring malignancies in females worldwide. Despite significant advances in therapeutics, the mortality and morbidity of BC still lead to low survival and poor prognosis due to the drug resistance. There are certain chemotherapeutic, endocrine, and target medicines often used for BC patients, including anthracyclines, taxanes, docetaxel, cisplatin, and fluorouracil. The drug resistance mechanisms of these medicines are complicated and have not been fully elucidated. It was reported that non-coding RNAs (ncRNAs), such as micro RNAs (miRNA), long-chain non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) performed key roles in regulating tumor development and mediating therapy resistance. However, the mechanism of these ncRNAs in BC chemotherapeutic, endocrine, and targeted drug resistance was different. This review aims to reveal the mechanism and potential functions of ncRNAs in BC drug resistance and to highlight the ncRNAs as a novel target for achieving improved treatment outcomes for BC patients.
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Affiliation(s)
- Jin-Hai Tian
- The Biochip Research Center, General Hospital of Ningxia Medical University, Yinchuan, China, Yinchuan, China.,The Clinical Medicine College of Ningxia Medical University, Yinchuan, China
| | - Shi-Hai Liu
- Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Chuan-Yang Yu
- The Biochip Research Center, General Hospital of Ningxia Medical University, Yinchuan, China, Yinchuan, China.,The Clinical Medicine College of Ningxia Medical University, Yinchuan, China
| | - Li-Gang Wu
- Department of Oncology, General Hospital of Ningxia Medical University, Yingchuan, China
| | - Li-Bin Wang
- The Biochip Research Center, General Hospital of Ningxia Medical University, Yinchuan, China, Yinchuan, China.,The Clinical Medicine College of Ningxia Medical University, Yinchuan, China
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14
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Wu Y, Liu Z, Wei X, Feng H, Hu B, Liu B, Luan Y, Ruan Y, Liu X, Liu Z, Wang S, Liu J, Wang T. Identification of the Functions and Prognostic Values of RNA Binding Proteins in Bladder Cancer. Front Genet 2021; 12:574196. [PMID: 34239534 PMCID: PMC8258248 DOI: 10.3389/fgene.2021.574196] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 05/19/2021] [Indexed: 12/01/2022] Open
Abstract
Post-transcriptional regulation plays a leading role in gene regulation and RNA binding proteins (RBPs) are the most important posttranscriptional regulatory protein. RBPs had been found to be abnormally expressed in a variety of tumors and is closely related to its occurrence and progression. However, the exact mechanism of RBPs in bladder cancer (BC) is unknown. We downloaded transcriptomic data of BC from the Cancer Genome Atlas (TCGA) database and used bioinformatics techniques for subsequent analysis. A total of 116 differentially expressed RBPs were selected, among which 61 were up-regulated and 55 were down-regulated. We then identified 12 prognostic RBPs including CTIF, CTU1, DARS2, ENOX1, IGF2BP2, LIN28A, MTG1, NOVA1, PPARGC1B, RBMS3, TDRD1, and ZNF106, and constructed a prognostic risk score model. Based on this model we found that patients in the high-risk group had poorer overall survival (P < 0.001), and the area under the receiver operator characteristic curve for this model was 0.677 for 1 year, 0.697 for 3 years, and 0.709 for 5 years. Next, we drew a nomogram based on the risk score and other clinical variables, which showed better predictive performance. Our findings contribute to a better understanding of the pathogenesis, progression and metastasis of BC. The model of these 12 genes has good predictive value and may have good prospects for improving clinical treatment regimens and patient prognosis.
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Affiliation(s)
- Yue Wu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zheng Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xian Wei
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huan Feng
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bintao Hu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bo Liu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Luan
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yajun Ruan
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaming Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhuo Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shaogang Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jihong Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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15
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Lovnicki J, Gan Y, Feng T, Li Y, Xie N, Ho CH, Lee AR, Chen X, Nappi L, Han B, Fazli L, Huang J, Gleave ME, Dong X. LIN28B promotes the development of neuroendocrine prostate cancer. J Clin Invest 2021; 130:5338-5348. [PMID: 32634132 DOI: 10.1172/jci135373] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 06/25/2020] [Indexed: 12/13/2022] Open
Abstract
Therapy-induced neuroendocrine prostate cancer (t-NEPC) is a highly aggressive subtype of prostate cancer with poor patient survival. Emerging evidence indicates that t-NEPC can develop when prostate adenocarcinoma cells acquire cancer stem-like cell signaling in the presence of androgen receptor inhibition, followed by redifferentiation toward neuroendocrine lineage and subsequent t-NEPC progression. Whether the stem-like signaling is controlled by the core pluripotency stem cell genes (e.g., LIN28 and SOX2) remains unknown. Here, we report that the transcription of the LIN28B isoform and SOX2 were co-upregulated in t-NEPC patient tumors, patient-derived xenografts, transgenic mice, and cell models. Immunohistochemistry validated that LIN28B and SOX2 protein expression were elevated in t-NEPC patient biopsies. Using prostate adenocarcinoma and t-NEPC cell models, we demonstrated that LIN28B induced a stem-like gene network, neuroendocrine biomarkers, and neuroendocrine cell morphology. LIN28B depletion by CRISPR inhibited t-NEPC tumorigenesis and xenograft growth. These LIN28B functions were mediated mainly through the suppression of let-7 miRNA expression, resulting in de-repression of the transcription factor HMGA2 and HMGA2-mediated SOX2 expression. This study revealed a mechanism by which t-NEPC can develop through the LIN28B/let-7/SOX2 axis that regulates a cancer cell stem-like gene network, highlighting LIN28B as a potential therapeutic target in t-NEPC.
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Affiliation(s)
- Jessica Lovnicki
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Yu Gan
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Urology, Xiangya Hospital, Central South University, Changsha, China
| | - Tingting Feng
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.,Key Laboratory of Experimental Teratology, Ministry of Education, and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Yinan Li
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Ning Xie
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Chia-Hao Ho
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Ahn R Lee
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Xufeng Chen
- Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Lucia Nappi
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Bo Han
- Key Laboratory of Experimental Teratology, Ministry of Education, and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Ladan Fazli
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Jiaoti Huang
- Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Martin E Gleave
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Xuesen Dong
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
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16
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Akbarpoor V, Karimabad MN, Mahmoodi M, Mirzaei MR. The saffron effects on expression pattern of critical self-renewal genes in adenocarcinoma tumor cell line (AGS). GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100629] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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17
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Mizushima E, Tsukahara T, Emori M, Murata K, Akamatsu A, Shibayama Y, Hamada S, Watanabe Y, Kaya M, Hirohashi Y, Kanaseki T, Nakatsugawa M, Kubo T, Yamashita T, Sato N, Torigoe T. Osteosarcoma-initiating cells show high aerobic glycolysis and attenuation of oxidative phosphorylation mediated by LIN28B. Cancer Sci 2019; 111:36-46. [PMID: 31705593 PMCID: PMC6942429 DOI: 10.1111/cas.14229] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 10/23/2019] [Accepted: 11/04/2019] [Indexed: 02/06/2023] Open
Abstract
Osteosarcoma (OS) is a highly malignant bone tumor and the prognosis for non‐responders to chemotherapy remains poor. Previous studies have shown that human sarcomas contain sarcoma‐initiating cells (SIC), which have the characteristics of high tumorigenesis and resistance to chemotherapy. In the present study, we characterized SIC of a novel OS cell line, screened for SIC‐related genes, and tried to regulate the proliferation of OS by metabolic interference. Initially, we established a new human OS cell line (OS13) and isolated clones showing higher tumorigenesis as SIC (OSHIGH) and counterpart clones. OSHIGH cells showed chemoresistance and their metabolism highly depended on aerobic glycolysis and suppressed oxidative phosphorylation. Using RNA‐sequencing, we identified LIN28B as a SIC‐related gene highly expressed in OSHIGH cells. mRNA of LIN28B was expressed in sarcoma cell lines including OS13, but its expression was not detectable in normal organs other than the testis and placenta. LIN28B protein was also detected in various sarcoma tissues. Knockdown of LIN28B in OS13 cells reduced tumorigenesis, decreased chemoresistance, and reversed oxidative phosphorylation function. Combination therapy consisting of a glycolysis inhibitor and low‐dose chemotherapy had antitumor effects. In conclusion, manipulation of glycolysis combined with chemotherapy might be a good adjuvant treatment for OS. Development of immunotherapy targeting LIN28B, a so‐called cancer/testis antigen, might be a good approach.
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Affiliation(s)
- Emi Mizushima
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tomohide Tsukahara
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Makoto Emori
- Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kenji Murata
- Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Asuka Akamatsu
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yuji Shibayama
- Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Shuto Hamada
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yuto Watanabe
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | | | - Yoshihiko Hirohashi
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takayuki Kanaseki
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Munehide Nakatsugawa
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Terufumi Kubo
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Toshihiko Yamashita
- Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Noriyuki Sato
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Toshihiko Torigoe
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
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18
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Abu Samaan TM, Samec M, Liskova A, Kubatka P, Büsselberg D. Paclitaxel's Mechanistic and Clinical Effects on Breast Cancer. Biomolecules 2019; 9:biom9120789. [PMID: 31783552 PMCID: PMC6995578 DOI: 10.3390/biom9120789] [Citation(s) in RCA: 334] [Impact Index Per Article: 55.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 11/23/2019] [Accepted: 11/25/2019] [Indexed: 02/07/2023] Open
Abstract
Paclitaxel (PTX), the most widely used anticancer drug, is applied for the treatment of various types of malignant diseases. Mechanisms of PTX action represent several ways in which PTX affects cellular processes resulting in programmed cell death. PTX is frequently used as the first-line treatment drug in breast cancer (BC). Unfortunately, the resistance of BC to PTX treatment is a great obstacle in clinical applications and one of the major causes of death associated with treatment failure. Factors contributing to PTX resistance, such as ABC transporters, microRNAs (miRNAs), or mutations in certain genes, along with side effects of PTX including peripheral neuropathy or hypersensitivity associated with the vehicle used to overcome its poor solubility, are responsible for intensive research concerning the use of PTX in preclinical and clinical studies. Novelties such as albumin-bound PTX (nab-PTX) demonstrate a progressive approach leading to higher efficiency and decreased risk of side effects after drug administration. Moreover, PTX nanoparticles for targeted treatment of BC promise a stable and efficient therapeutic intervention. Here, we summarize current research focused on PTX, its evaluations in preclinical research and application clinical practice as well as the perspective of the drug for future implication in BC therapy.
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Affiliation(s)
- Tala M. Abu Samaan
- Department of Pre-Medical Education, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar
- Correspondence: (T.M.A.S.); (D.B.); Tel.: +974-4492-8334 (D.B.); Fax: +974-4492-8333 (D.B.)
| | - Marek Samec
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia; (M.S.)
| | - Alena Liskova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia; (M.S.)
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia;
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar
- Correspondence: (T.M.A.S.); (D.B.); Tel.: +974-4492-8334 (D.B.); Fax: +974-4492-8333 (D.B.)
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19
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Ritter A, Hirschfeld M, Berner K, Rücker G, Jäger M, Weiss D, Medl M, Nöthling C, Gassner S, Asberger J, Erbes T. Circulating non‑coding RNA‑biomarker potential in neoadjuvant chemotherapy of triple negative breast cancer? Int J Oncol 2019; 56:47-68. [PMID: 31789396 PMCID: PMC6910196 DOI: 10.3892/ijo.2019.4920] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 09/26/2019] [Indexed: 12/11/2022] Open
Abstract
Due to the positive association between neoadjuvant chemotherapy (NACT) and the promising early response rates of patients with triple negative breast cancer (TNBC), including probabilities of pathological complete response, NACT is increasingly used in TNBC management. Liquid biopsy-based biomarkers with the power to diagnose the early response to NACT may support established monitoring tools, which are to a certain extent imprecise and costly. Simple serum- or urine-based analyses of non-coding RNA (ncRNA) expression may allow for fast, minimally-invasive testing and timely adjustment of the therapy regimen. The present study investigated breast cancer-related ncRNAs [microRNA (miR)-7, -9, -15a, -17, -18a, -19b, -21, -30b, -222 and -320c, PIWI-interacting RNA-36743 and GlyCCC2] in triple positive BT-474 cells and three TNBC cell lines (BT-20, HS-578T and MDA-MB-231) treated with various chemotherapeutic agents using reverse transcription-quantitative PCR. Intracellular and secreted microvesicular ncRNA expression levels were analysed using a multivariable statistical regression analysis. Chemotherapy-driven effects were investigated by analysing cell cycle determinants at the mRNA and protein levels. Serum and urine specimens from 8 patients with TNBC were compared with 10 healthy females using two-sample t-tests. Samples from the patients with TNBC were compared at two time points. Chemotherapeutic treatments induced distinct changes in ncRNA expression in TNBC cell lines and the BT-474 cell line in intra- and extracellular compartments. Serum and urine-based ncRNA expression analysis was able to discriminate between patients with TNBC and controls. Time point comparisons in the urine samples of patients with TNBC revealed a general rise in the level of ncRNA. Serum data suggested a potential association between piR-36743, miR-17, -19b and -30b expression levels and an NACT-driven complete clinical response. The present study highlighted the potential of ncRNAs as liquid biopsy-based biomarkers in TNBC chemotherapy treatment. The ncRNAs tested in the present study have been previously investigated for their involvement in BC or TNBC chemotherapy responses; however, these previous studies were restricted to patient tissue or in vitro models. The data from the present study offer novel insight into ncRNA expression in liquid samples from patients with TNBC, and the study serves as an initial step in the evaluation of ncRNAs as diagnostic biomarkers in the monitoring of TNBC therapy.
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Affiliation(s)
- Andrea Ritter
- Department of Obstetrics and Gynecology, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79106 Freiburg, Germany
| | - Marc Hirschfeld
- Department of Obstetrics and Gynecology, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79106 Freiburg, Germany
| | - Kai Berner
- Department of Obstetrics and Gynecology, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79106 Freiburg, Germany
| | - Gerta Rücker
- Institute of Medical Biometry and Statistics, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79104 Freiburg, Germany
| | - Markus Jäger
- Department of Obstetrics and Gynecology, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79106 Freiburg, Germany
| | - Daniela Weiss
- Department of Obstetrics and Gynecology, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79106 Freiburg, Germany
| | - Markus Medl
- Department of Obstetrics and Gynecology, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79106 Freiburg, Germany
| | - Claudia Nöthling
- Department of Obstetrics and Gynecology, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79106 Freiburg, Germany
| | - Sandra Gassner
- Department of Obstetrics and Gynecology, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79106 Freiburg, Germany
| | - Jasmin Asberger
- Department of Obstetrics and Gynecology, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79106 Freiburg, Germany
| | - Thalia Erbes
- Department of Obstetrics and Gynecology, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79106 Freiburg, Germany
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20
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Clinical Theragnostic Relationship between Drug-Resistance Specific miRNA Expressions, Chemotherapeutic Resistance, and Sensitivity in Breast Cancer: A Systematic Review and Meta-Analysis. Cells 2019; 8:cells8101250. [PMID: 31615089 PMCID: PMC6830093 DOI: 10.3390/cells8101250] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 09/20/2019] [Accepted: 09/21/2019] [Indexed: 12/12/2022] Open
Abstract
Awareness of breast cancer has been increasing due to early detection, but the advanced disease has limited treatment options. There has been growing evidence on the role of miRNAs involved in regulating the resistance in several cancers. We performed a comprehensive systematic review and meta-analysis on the role of miRNAs in influencing the chemoresistance and sensitivity of breast cancer. A bibliographic search was performed in PubMed and Science Direct based on the search strategy, and studies published until December 2018 were retrieved. The eligible studies were included based on the selection criteria, and a detailed systematic review and meta-analysis were performed based on PRISMA guidelines. A random-effects model was utilised to evaluate the combined effect size of the obtained hazard ratio and 95% confidence intervals from the eligible studies. Publication bias was assessed with Cochran’s Q test, I2 statistic, Orwin and Classic fail-safe N test, Begg and Mazumdar rank correlation test, Duval and Tweedie trim and fill calculation and the Egger’s bias indicator. A total of 4584 potential studies were screened. Of these, 85 articles were eligible for our systematic review and meta-analysis. In the 85 studies, 188 different miRNAs were studied, of which 96 were upregulated, 87 were downregulated and 5 were not involved in regulation. Overall, 24 drugs were used for treatment, with doxorubicin being prominently reported in 15 studies followed by Paclitaxel in 11 studies, and 5 drugs were used in combinations. We found only two significant HR values from the studies (miR-125b and miR-4443) and our meta-analysis results yielded a combined HR value of 0.748 with a 95% confidence interval of 0.508–1.100; p-value of 0.140. In conclusion, our results suggest there are different miRNAs involved in the regulation of chemoresistance through diverse drug genetic targets. These biomarkers play a crucial role in guiding the effective diagnostic and prognostic efficiency of breast cancer. The screening of miRNAs as a theragnostic biomarker must be brought into regular practice for all diseases. We anticipate that our study serves as a reference in framing future studies and clinical trials for utilising miRNAs and their respective drug targets.
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21
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Rezai M, Saravani R, Sargazi S, Moudi M, Jafari Shahroudi M, Saravani R. Achillea Wilhelmsii C. KochHydroalcoholic Extract Induces Apoptosis and Alters LIN28B and p53 Gene Expression in Hela Cervical Cancer Cells. Rep Biochem Mol Biol 2019; 8:318-325. [PMID: 32274404 PMCID: PMC7103081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 06/03/2019] [Indexed: 06/11/2023]
Abstract
BACKGROUND Inappropriate activation of the proto-oncogene LIN28B and inactivation of the p53 tumor suppressor, have been shown to have a critical role in tumorigenesis. Previous research has shown therapeutic potential for the use of herbal plants as an alternative strategy for cancer treatment. Achillae wilhelmsii C. Koch is a plant that has been traditionally used for its medicinal properties. The aim of this study was to investigate the cytotoxic and apoptosis-inducing effect of Achillea wilhelmsii C. Koch hydroalcoholic extract (AWHE) on HeLa cervical cancer cells and its effect on LIN28B and p53 expression. METHODS The cytotoxic activity of AWHE was evaluated on HeLa cells using a trypan blue exclusion assay. The Annexin V/PI double staining assay was used to evaluate the apoptosis-inducing effect of the extract. The expression of LIN28B and p53 mRNA was measured using the real-time-PCR method. RESULTS Treatment with AWHE was shown to induce cytotoxicity in both time and concentration-dependent manners (P<0.05). The proposition of HeLa cells undergoing apoptosis increased with increasing concentrations of AWHE (P<0.05). The mRNA levels of p53 increased following 12, 24, and 48 hours of AWHE treatment whereas the mRNA levels of LIN28B were significantly decreased after 4 to 12 hours of AWHE treatment (p<0.05). CONCLUSION Our findings confirmed the pro-apoptotic function of AWHE on the cervical cancer HeLa cell line. This indicates that targeting the LIN28B signaling cascade may be a promising therapeutic strategy for cervical cancer. Further research is required to understand the therapeutic effects of AWHE in primary human cervical cancer cells and a pre-clinical cervical cancer model.
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Affiliation(s)
- Mehdi Rezai
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran.
| | - Ramin Saravani
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran.
- Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran.
| | - Saman Sargazi
- Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran.
| | - Mahdiyeh Moudi
- Genetics of Non-Communicable Disease Research Center, Zahedan University of Medical Sciences, Zahedan, Iran.
| | - Mahdieh Jafari Shahroudi
- Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran.
| | - Roya Saravani
- Department of Chemistry, Iran University of Science and Technology; Tehran, Iran.
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22
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Hu XB, Ouyang LZ, He Y, Xia MZ. Numb confers to inhibit epithelial mesenchymal transition via β-catenin/Lin28 signaling pathway in breast cancer. Exp Mol Pathol 2019; 109:104262. [PMID: 31095937 DOI: 10.1016/j.yexmp.2019.104262] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 04/13/2019] [Accepted: 05/10/2019] [Indexed: 12/21/2022]
Abstract
OBJECTIVES This study aimed to investigate role of Numb in the epithelial mesenchymal transition (EMT) of breast cancer. METHODS Numb and β-catenin were inhibited in MCF-7 cells using sh-RNA and overexpressed in T47D cells by pcDNA3.0-Numb, pcDNA3.0-β-catenin. Cell proliferation, invasion and migration were evaluated using MTT and Transwell assay, respectively. β-catenin, Lin28, and EMT related markers were determined using qRT-PCR and Western Blotting. RESULTS Knockdown of Numb significantly promoted the proliferation, invasion and migration of MCF-7 cells, further increased the expression of β-catenin, Lin28, Snail-1, and N-cadherin, as well as decreased E-cadherin. In T47D cells transfected with pcDNA3.0-Numb, the results were quite the reverse. CONCLUSIONS Knockdown of Numb could promote the EMT of breast cancer cells via β-cateni/Lin28 signaling pathway.
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Affiliation(s)
- Xiao-Bo Hu
- Breast Surgery Department I, Hunan Cancer Hospital, Changsha, Hunan 410013, PR China; Department of Mammary Gland of Hunan Tumor Hospital, Changsha 410013, PR China.
| | - Li-Zhi Ouyang
- Department of Mammary Gland of Hunan Tumor Hospital, Changsha 410013, PR China
| | - Yue He
- Department of Mammary Gland of Hunan Tumor Hospital, Changsha 410013, PR China
| | - Ming-Zhi Xia
- Breast Surgery Department I, Hunan Cancer Hospital, Changsha, Hunan 410013, PR China; Department of Mammary Gland of Hunan Tumor Hospital, Changsha 410013, PR China.
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23
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Huang J, Lin H, Zhong M, Huang J, Sun S, Lin L, Chen Y. Role of Lin28A/let-7a/c-Myc Pathway in Growth and Malignant Behavior of Papillary Thyroid Carcinoma. Med Sci Monit 2018; 24:8899-8909. [PMID: 30531691 PMCID: PMC6296344 DOI: 10.12659/msm.908628] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Lin28 is a gene involved in many biological processes, including development, glucose metabolism, and tumorigenesis. Let-7 miRNA is a tumor-suppressor gene that is frequently inactivated in cancer cells. The role of c-Myc (a target gene of let-7) and the Lin28-let-7-c-Myc pathway in the growth and malignancy of thyroid cancer is unclear. The purpose of the present study was to evaluate the expression of Lin28A, let-7a, and c-Myc in human papillary thyroid carcinoma (PTC) and to investigate their potential mechanisms in the progression of PTC. MATERIAL AND METHODS Lin28A and c-Myc expression were assessed in PTC tissues and PTC cell lines using immunohistochemistry, Western blotting, and real-time PCR. CCK-8 and Transwell assays were performed to evaluate PTC cell proliferation, migration, and invasion in cells in which the expression of Lin28A was downregulated by RNA interference or in which let-7a was overexpressed after transfection with let-7a mimics. RESULTS The expression of Lin28A and c-Myc was upregulated in PTC tissues and cell lines, whereas the expression of let-7a was downregulated in PTC cell lines. Clinically, Lin28A was linked to a higher tumor/node/metastasis stage and the presence of lymph node metastases. Moreover, knockdown of Lin28A activated let-7a processing and inhibited the expression of the downstream gene c-Myc, suppressing cell proliferation, migration, and invasion. Similar results were obtained after let-7a overexpression. CONCLUSIONS The Lin28A/let-7a/c-Myc pathway is involved in cancer growth and malignant behavior in PTC and is a potential target for therapeutic intervention in this disease.
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Affiliation(s)
- Jiaqi Huang
- Department of Endocrinology, The First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong, P.R. China
| | - Haishan Lin
- Department of Endocrinology, The First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong, P.R. China
| | - Muxun Zhong
- Department of Endocrinology, The First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong, P.R. China
| | - Jiexiong Huang
- Department of Pathology, The First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong, P.R. China
| | - Shuming Sun
- Breast Surgery, The First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong, P.R. China
| | - Ling Lin
- Department of Rheumatology, The First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong, P.R. China
| | - Yongsong Chen
- Department of Endocrinology, The First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong, P.R. China
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24
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The Molecular Basis and Therapeutic Potential of Let-7 MicroRNAs against Colorectal Cancer. Can J Gastroenterol Hepatol 2018; 2018:5769591. [PMID: 30018946 PMCID: PMC6029494 DOI: 10.1155/2018/5769591] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 06/06/2018] [Indexed: 12/12/2022] Open
Abstract
Although a number of studies have revealed the underlying mechanisms which regulate the development of colorectal cancer (CRC), we have not completely overcome this disease yet. Accumulating evidence has shown that the posttranscriptional regulation by the noncoding RNAs such as microRNAs plays an important role in the development or progression of CRC. Among a number of microRNAs, the let-7 microRNA family that was first discovered in C. elegans and conserved from worms to humans has been linked with the development of many types of cancers including CRC. The expression level of let-7 microRNAs is temporally low during the normal developmental processes, while elevated in the differentiated tissues. The let-7 microRNAs regulate the cell proliferation, cell cycle, apoptosis, metabolism, and stemness. In CRC, expressions of let-7 microRNAs have been reported to be reduced, and so let-7 microRNAs are considered to be a tumor suppressor. In this review, we discuss the mechanisms regulating the let-7 microRNA expression and the downstream targets of let-7 in the context of intestinal tumorigenesis. The application of let-7 mimics is also highlighted as a novel therapeutic agent.
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25
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Oncogene Lin28B increases chemosensitivity of colon cancer cells in a let-7-independent manner. Oncol Lett 2018; 15:6975-6981. [PMID: 29725425 PMCID: PMC5920276 DOI: 10.3892/ol.2018.8250] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Accepted: 05/18/2017] [Indexed: 02/06/2023] Open
Abstract
Lin-28 homolog B (Lin28B) is a RNA binding protein conserved between Caenorhabditis elegans and humans, and it has important roles in regulating development. The overexpression of Lin28B has been observed in various human malignant tumors and the upregulation of Lin28B predicts tumor progression and/or poor prognosis. The majority of studies suggested that Lin28B is an oncogene that promotes the proliferation and metastasis of cancer cells. However, few studies have focused on the function of Lin28B in chemotherapy. In the present study, the role of Lin28B in the chemosensitivity of colon cancer cells to 5-fluorouracil (5-FU) was detected by establishing a Lin28B over-expressing HCT116 (EGFP-Lin28B-HCT116) cell line. In accordance with the immunohistochemistry results, Lin28B-GFP expression was predominantly distributed in the cytoplasm, and the overexpression of Lin28B was confirmed using quantitative polymerase chain reaction and western blot analysis. The control EGFP-HCT116 and Lin28B over-expressing EGFP-Lin28B-HCT116 cells were then exposed to various concentrations of 5-FU for 48 h. A luminescence-based cell viability assay was used to detect the effect of Lin28B on the chemotherapeutic sensitivity of colon cancer cells. It was demonstrated that overexpression of Lin28B improved the chemotherapeutic sensitivity of colon cancer cells to 5-FU. Additional investigation revealed that Lin28B enhanced the chemosensitivity of colon cancer cells by promoting cell apoptosis induced by 5-FU; however, this effect was independent of Lin28B inhibiting the biogenesis of let-7, the well-known target of Lin28B. The mechanism of this effect of Lin28B on the chemosensitivity of cells requires additional investigation. The present study suggested that Lin28B may act as a biomarker for predicting chemotherapy sensitivity in patients with colon cancer.
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26
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Xiong H, Zhao W, Wang J, Seifer BJ, Ye C, Chen Y, Jia Y, Chen C, Shen J, Wang L, Sui X, Zhou J. Oncogenic mechanisms of Lin28 in breast cancer: new functions and therapeutic opportunities. Oncotarget 2018; 8:25721-25735. [PMID: 28147339 PMCID: PMC5421965 DOI: 10.18632/oncotarget.14891] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 01/11/2017] [Indexed: 12/25/2022] Open
Abstract
The RNA binding protein Lin28 is best known for the critical role in cell development, recent researches also have implied its oncogenic function in various human cancers, including breast cancer. Specifically, aberrant Lin28 participates in multiple pathological processes, such as proliferation, metastasis, radiotherapy and chemotherapy resistance, metabolism, immunity and inflammation as well as stemness. In this review, we summarize the let-7-dependent and let-7-independent mechanism regulated by Lin28, focusing on its relation with tumor hallmarks in breast cancer, and subsequently discuss our present knowledge of Lin28 to develop a molecular-based therapeutic strategy against breast cancer.
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Affiliation(s)
- Hanchu Xiong
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Wenhe Zhao
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Ji Wang
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | | | - Chenyang Ye
- Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education), Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yongxia Chen
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yunlu Jia
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Cong Chen
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Jianguo Shen
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Linbo Wang
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Xinbing Sui
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China.,Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jichun Zhou
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China
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27
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Mizuno R, Chatterji P, Andres S, Hamilton K, Simon L, Foley SW, Jeganathan A, Gregory BD, Madison B, Rustgi AK. Differential Regulation of LET-7 by LIN28B Isoform-Specific Functions. Mol Cancer Res 2018; 16:403-416. [PMID: 29330293 DOI: 10.1158/1541-7786.mcr-17-0514] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Revised: 11/07/2017] [Accepted: 11/29/2017] [Indexed: 12/30/2022]
Abstract
The RNA-binding protein LIN28B plays an important role in development, stem cell biology, and tumorigenesis. LIN28B has two isoforms: the LIN28B-long and -short isoforms. Although studies have revealed the functions of the LIN28B-long isoform in tumorigenesis, the role of the LIN28B-short isoform remains unclear and represents a major gap in the field. The LIN28B-long and -short isoforms are expressed in a subset of human colorectal cancers and adjacent normal colonic mucosa, respectively. To elucidate the functional and mechanistic aspects of these isoforms, colorectal cancer cells (Caco-2 and LoVo) were generated to either express no LIN28B or the -short or -long isoform. Interestingly, the long isoform suppressed LET-7 expression and activated canonical RAS/ERK signaling, whereas the short isoform did not. The LIN28B-long isoform-expressing cells demonstrated increased drug resistance to 5-fluorouracil and cisplatin through the upregulation of ERCC1, a DNA repair gene, in a LET-7-dependent manner. The LIN28B-short isoform preserved its ability to bind pre-let-7, without inhibiting the maturation of LET-7, and competed with the LIN28B-long isoform for binding to pre-let-7 Coexpression of the short isoform in the LIN28B-long isoform-expressing cells rescued the phenotypes induced by the LIN28B-long isoform.Implications: This study demonstrates the differential antagonistic functions of the LIN28B-short isoform against the LIN28B-long isoform through an inability to degrade LET-7, which leads to the novel premise that the short isoform may serve to counterbalance the long isoform during normal colonic epithelial homeostasis, but its downregulation during colonic carcinogenesis may reveal the protumorigenic effects of the long isoform. Mol Cancer Res; 16(3); 403-16. ©2018 AACR.
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Affiliation(s)
- Rei Mizuno
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Priya Chatterji
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Sarah Andres
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kathryn Hamilton
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Lauren Simon
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Shawn W Foley
- Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Arjun Jeganathan
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Brian D Gregory
- Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Blair Madison
- Division of Gastroenterology, Department of Medicine, Washington University, St. Louis, Missouri
| | - Anil K Rustgi
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. .,Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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28
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Xu Q, Lin G, Xu H, Hu L, Wang Y, Du S, Deng W, Hu W, Cheng W, Jiang K. MLN4924 neddylation inhibitor promotes cell death in paclitaxel-resistant human lung adenocarcinoma cells. Oncol Lett 2017; 15:515-521. [PMID: 29387232 DOI: 10.3892/ol.2017.7314] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 03/30/2017] [Indexed: 12/21/2022] Open
Abstract
Acquired resistance to first-line chemotherapeutics, including paclitaxel (PTX), is a primary factor contributing to chemotherapy failure in non-small cell lung cancer (NSCLC) patients. Previous studies have identified that targeting NEDD8-activating enzyme (NAE) with MLN4924 effectively overcomes platinum resistance in preclinical models of ovarian cancer. However, the underlying mechanisms are yet to be fully elucidated. The present study demonstrates that the inhibition of the neddylation pathway with MLN4924 an NAE inhibitor inhibited protein neddylation, inactivated cullin-RING E3 ligase and exhibited a potent antiproliferative effect on PTX-resistant A549 and H460 cells (A549/PTX and H460/PTX). The application of MLN4924 promotes apoptosis and DNA damage in A549/PTX and H460/PTX cells. Additionally, MLN4924 abrogated the 3-dimensional growth potential of these cells and inhibited the formation of the A549/PTX and H460/PTX spheroids. Notably, combining MLN4924 with PTX did not exhibit synergy in PTX-resistant NSCLC cells. Taken together, the results of the current study suggest that MLN4924 may be utilized as an effective strategy for the treatment of PTX-resistant NSCLC.
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Affiliation(s)
- Qiang Xu
- Department of Orthopedics, The Affiliated Yuhuangding Hospital of Qingdao University Medical College, Yantai, Shandong 264000, P.R. China
| | - Guibin Lin
- Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, Liaoning 116044, P.R. China
| | - Huizhe Xu
- Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, Liaoning 116044, P.R. China
| | - Lulu Hu
- Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, Liaoning 116044, P.R. China
| | - Yupeng Wang
- Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, Liaoning 116044, P.R. China
| | - Sha Du
- Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, Liaoning 116044, P.R. China
| | - Wuguo Deng
- Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, Liaoning 116044, P.R. China
| | - Wenxian Hu
- Key Laboratory of Biotherapy of Zhejiang Province, Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310020, P.R. China
| | - Wei Cheng
- Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, Liaoning 116044, P.R. China
| | - Ke Jiang
- Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, Liaoning 116044, P.R. China
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29
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Shuang W, Hou L, Zhu Y, Li Q, Hu W. Mcl-1 stabilization confers resistance to taxol in human gastric cancer. Oncotarget 2017; 8:82981-82990. [PMID: 29137317 PMCID: PMC5669943 DOI: 10.18632/oncotarget.20222] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Accepted: 07/26/2017] [Indexed: 12/11/2022] Open
Abstract
Taxol has been extensively used as an antineoplastic drug to treat human gastric cancer. However, the acquired drug resistance invariably develops and greatly limits the therapeutic efficacy of Taxol. Identification of the underlying resistance mechanisms may inform the development of new therapies of gastric cancers to Taxol treatment. Here we report that upregulation of Mcl-1 (Myeloid cell leukemia-1) confers acquired resistance to Taxol in human gastric cancer. Mcl-1 is shown to be stabilized in Taxol -resistant gastric cancer cells because of the hyper-activation of the PI3K/Akt signaling pathway. The increased Mcl-1 prevents of the permeabilization of the outer mitochondrial membrane, thereby blocking the Taxol-induced apoptosis. Furthermore, inhibition of Mcl-1 or PI3K/Akt pathway significantly reversed the resistant phenotype of Taxol-resistant human gastric cancer cells. Taken together, our findings broaden the view of PI3K/Akt pathway as an important regulator in Taxol acquired resistance, and implicate Mcl-1 as a specific therapeutic target for the treatment of Taxol-resistant human gastric cancer.
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Affiliation(s)
- Wu Shuang
- Department of Immunology, Anhui Medical University, Hefei, China
| | - Lili Hou
- Department of Clinical Nutriology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yan Zhu
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qun Li
- Department of Immunology, Anhui Medical University, Hefei, China
| | - Wanglai Hu
- Department of Immunology, Anhui Medical University, Hefei, China
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30
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Campos-Parra AD, Mitznahuatl GC, Pedroza-Torres A, Romo RV, Reyes FIP, López-Urrutia E, Pérez-Plasencia C. Micro-RNAs as Potential Predictors of Response to Breast Cancer Systemic Therapy: Future Clinical Implications. Int J Mol Sci 2017; 18:E1182. [PMID: 28574440 PMCID: PMC5486005 DOI: 10.3390/ijms18061182] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 05/24/2017] [Accepted: 05/27/2017] [Indexed: 12/11/2022] Open
Abstract
Despite advances in diagnosis and new treatments such as targeted therapies, breast cancer (BC) is still the most prevalent tumor in women worldwide and the leading cause of death. The principal obstacle for successful BC treatment is the acquired or de novo resistance of the tumors to the systemic therapy (chemotherapy, endocrine, and targeted therapies) that patients receive. In the era of personalized treatment, several studies have focused on the search for biomarkers capable of predicting the response to this therapy; microRNAs (miRNAs) stand out among these markers due to their broad spectrum or potential clinical applications. miRNAs are conserved small non-coding RNAs that act as negative regulators of gene expression playing an important role in several cellular processes, such as cell proliferation, autophagy, genomic stability, and apoptosis. We reviewed recent data that describe the role of miRNAs as potential predictors of response to systemic treatments in BC. Furthermore, upon analyzing the collected published information, we noticed that the overexpression of miR-155, miR-222, miR-125b, and miR-21 predicts the resistance to the most common systemic treatments; nonetheless, the function of these particular miRNAs must be carefully studied and further analyses are still necessary to increase knowledge about their role and future potential clinical uses in BC.
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Affiliation(s)
- Alma D Campos-Parra
- Laboratorio de Genomica, Instituto Nacional de Cancerología (INCan), Av. San Fernando 22, Col. Sección XVI, C.P. 14080 Tlalpan, Ciudad de México, Mexico.
| | - Gerardo Cuamani Mitznahuatl
- Laboratorio de Genomica, Instituto Nacional de Cancerología (INCan), Av. San Fernando 22, Col. Sección XVI, C.P. 14080 Tlalpan, Ciudad de México, Mexico.
| | - Abraham Pedroza-Torres
- Laboratorio de Genomica, Instituto Nacional de Cancerología (INCan), Av. San Fernando 22, Col. Sección XVI, C.P. 14080 Tlalpan, Ciudad de México, Mexico.
- CATEDRA-CONACyT, Av. De los Insurgente Sur 1582, Col. Crédito Constructor., C.P. 03940 Benito Juárez, Ciudad de México, Mexico.
| | - Rafael Vázquez Romo
- Departamento de Cirugia de Tumores mamarios, Instituto Nacional de Cancerología (INCan), Av. San Fernando 22, Col. Sección XVI, C.P. 14080 Tlalpan, Ciudad de México, Mexico.
| | - Fany Iris Porras Reyes
- Servicio de Anatomia Patologica, Instituto Nacional de Cancerología (INCan), Av. San Fernando 22, Col. Sección XVI, C.P. 14080 Tlalpan, Ciudad de México, Mexico.
| | - Eduardo López-Urrutia
- Unidad de Biomedicina, FES-IZTACALA, Universidad Nacional Autónoma de Mexico (UNAM), Av. De Los Barrios 1, Los Reyes Ixtacala, Hab Los Reyes Ixtacala Barrio de los Árboles/Barrio de los Héroes, C.P. 54090 Tlalnepantla, México, Mexico.
| | - Carlos Pérez-Plasencia
- Unidad de Biomedicina, FES-IZTACALA, Universidad Nacional Autónoma de Mexico (UNAM), Av. De Los Barrios 1, Los Reyes Ixtacala, Hab Los Reyes Ixtacala Barrio de los Árboles/Barrio de los Héroes, C.P. 54090 Tlalnepantla, México, Mexico.
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31
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Xiao M, Cai J, Cai L, Jia J, Xie L, Zhu Y, Huang B, Jin D, Wang Z. Let-7e sensitizes epithelial ovarian cancer to cisplatin through repressing DNA double strand break repair. J Ovarian Res 2017; 10:24. [PMID: 28376831 PMCID: PMC5379542 DOI: 10.1186/s13048-017-0321-8] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 03/28/2017] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Resistance to platinum-based chemotherapy remains a great challenge for ovarian cancer treatment. The human let-7 family contains 13 members located on nine different chromosomes, and most members have been implicated in the modulation of drug sensitivity in cancers. Our previous study showed that deregulation of let-7e in epithelial ovarian cancer (EOC) promoted the development of resistance to cisplatin. In the present study, we aimed to investigate the underlying mechanism and further evaluate the clinical value of let-7e in predicting chemo-response and prognosis in EOC. RESULTS In situ hybridization assays revealed a significantly decreased expression of let-7e in chemo-resistant EOC tissues compared with chemo-sensitive cases. Transfection with let-7e agomir sensitized EOC cells to cisplatin, down-regulated BRCA1 and Rad51 expression, and repressed the repair of cisplatin-induced DNA double strand break, while let-7e inhibitor exerted the opposite effects. In human EOC tissues, BRCA1 and Rad51 levels were increased in the chemo-resistant group compared with the sensitive group and were negatively correlated with let-7e. Low let-7e and high Rad51 were significantly associated with poor progression-free survival and overall survival and multivariate regression analyses showed that let-7e was an independent predictor for overall survival and chemotherapy response in EOC. Receiver operating characteristic analysis indicated that let-7e level was highly predictive of resistance to platinum-taxane chemotherapy with an area under the curve of 0.826. CONCLUSIONS In EOC, low let-7e leads to activation of BRCA1 and Rad51 expression and subsequent enhancement of DSB repair, which in turn results in cisplatin-resistance. Let-7e is a potential predictor for survival and chemo-response in EOC and re-expression of let-7e might be an effective strategy for overcoming chemo-resistance.
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Affiliation(s)
- Man Xiao
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Jing Cai
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Liqiong Cai
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Jinghui Jia
- Department of Obstetrics and Gynecology, Air Force General Hospital, PLA, Beijing, 100142, China
| | - Lisha Xie
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Ying Zhu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Bangxing Huang
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Dongdong Jin
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Zehua Wang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China.
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CD44 + cancer cell-induced metastasis: A feasible neck metastasis model. Eur J Pharm Sci 2017; 101:243-250. [DOI: 10.1016/j.ejps.2017.02.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 02/09/2017] [Accepted: 02/09/2017] [Indexed: 01/27/2023]
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Balzeau J, Menezes MR, Cao S, Hagan JP. The LIN28/let-7 Pathway in Cancer. Front Genet 2017; 8:31. [PMID: 28400788 PMCID: PMC5368188 DOI: 10.3389/fgene.2017.00031] [Citation(s) in RCA: 344] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Accepted: 02/27/2017] [Indexed: 01/12/2023] Open
Abstract
Among all tumor suppressor microRNAs, reduced let-7 expression occurs most frequently in cancer and typically correlates with poor prognosis. Activation of either LIN28A or LIN28B, two highly related RNA binding proteins (RBPs) and proto-oncogenes, is responsible for the global post-transcriptional downregulation of the let-7 microRNA family observed in many cancers. Specifically, LIN28A binds the terminal loop of precursor let-7 and recruits the Terminal Uridylyl Transferase (TUTase) ZCCHC11 that polyuridylates pre-let-7, thereby blocking microRNA biogenesis and tumor suppressor function. For LIN28B, the precise mechanism responsible for let-7 inhibition remains controversial. Functionally, the decrease in let-7 microRNAs leads to overexpression of their oncogenic targets such as MYC, RAS, HMGA2, BLIMP1, among others. Furthermore, mouse models demonstrate that ectopic LIN28 expression is sufficient to drive and/or accelerate tumorigenesis via a let-7 dependent mechanism. In this review, the LIN28/let-7 pathway is discussed, emphasizing its role in tumorigenesis, cancer stem cell biology, metabolomics, metastasis, and resistance to ionizing radiation and several chemotherapies. Also, emerging evidence will be presented suggesting that molecular targeting of this pathway may provide therapeutic benefit in cancer.
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Affiliation(s)
- Julien Balzeau
- Department of Neurosurgery, University of Texas Health Science Center at Houston Houston, TX, USA
| | - Miriam R Menezes
- Department of Neurosurgery, University of Texas Health Science Center at Houston Houston, TX, USA
| | - Siyu Cao
- Department of Neurosurgery, University of Texas Health Science Center at Houston Houston, TX, USA
| | - John P Hagan
- Department of Neurosurgery, University of Texas Health Science Center at Houston Houston, TX, USA
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Němcová-Fürstová V, Kopperová D, Balušíková K, Ehrlichová M, Brynychová V, Václavíková R, Daniel P, Souček P, Kovář J. Characterization of acquired paclitaxel resistance of breast cancer cells and involvement of ABC transporters. Toxicol Appl Pharmacol 2016; 310:215-228. [PMID: 27664577 DOI: 10.1016/j.taap.2016.09.020] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 09/02/2016] [Accepted: 09/20/2016] [Indexed: 12/12/2022]
Abstract
Development of taxane resistance has become clinically very important issue. The molecular mechanisms underlying the resistance are still unclear. To address this issue, we established paclitaxel-resistant sublines of the SK-BR-3 and MCF-7 breast cancer cell lines that are capable of long-term proliferation in 100nM and 300nM paclitaxel, respectively. Application of these concentrations leads to cell death in the original counterpart cells. Both sublines are cross-resistant to doxorubicin, indicating the presence of the MDR phenotype. Interestingly, resistance in both paclitaxel-resistant sublines is circumvented by the second-generation taxane SB-T-1216. Moreover, we demonstrated that it was not possible to establish sublines of SK-BR-3 and MCF-7 cells resistant to this taxane. It means that at least the tested breast cancer cells are unable to develop resistance to some taxanes. Employing mRNA expression profiling of all known human ABC transporters and subsequent Western blot analysis of the expression of selected transporters, we demonstrated that only the ABCB1/PgP and ABCC3/MRP3 proteins were up-regulated in both paclitaxel-resistant sublines. We found up-regulation of ABCG2/BCRP and ABCC4 proteins only in paclitaxel-resistant SK-BR-3 cells. In paclitaxel-resistant MCF-7 cells, ABCB4/MDR3 and ABCC2/MRP2 proteins were up-regulated. Silencing of ABCB1 expression using specific siRNA increased significantly, but did not completely restore full sensitivity to both paclitaxel and doxorubicin. Thus we showed a key, but not exclusive, role for ABCB1 in mechanisms of paclitaxel resistance. It suggests the involvement of multiple mechanisms in paclitaxel resistance in tested breast cancer cells.
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Affiliation(s)
- Vlasta Němcová-Fürstová
- Division of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
| | - Dana Kopperová
- Division of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Kamila Balušíková
- Division of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Marie Ehrlichová
- Toxicogenomics Unit, National Institute of Public Health, Prague, Czech Republic
| | - Veronika Brynychová
- Toxicogenomics Unit, National Institute of Public Health, Prague, Czech Republic
| | - Radka Václavíková
- Toxicogenomics Unit, National Institute of Public Health, Prague, Czech Republic
| | - Petr Daniel
- Division of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Pavel Souček
- Toxicogenomics Unit, National Institute of Public Health, Prague, Czech Republic
| | - Jan Kovář
- Division of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
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Park CH, Lee JH, Lee NK, Lee YC, Lee SK. Clinicopathological Characteristics of Patients with Gastric Cancer according to the Expression of LIN28A. Gut Liver 2016; 10:714-718. [PMID: 26893371 PMCID: PMC5003193 DOI: 10.5009/gnl15283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 09/05/2015] [Accepted: 09/08/2015] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS Although LIN28A is known to potentially play a role in the oncogenesis of various cancers, whether LIN28A expression is a predictor of poor prognosis in patients with gastric cancer has not been fully explored. We sought to evaluate clinicopathological characteristics according to the expression of LIN28A in numerous gastric cancer tissue samples. METHODS LIN28A expression was evaluated by immunohistochemical (IHC) analysis of a tissue microarray comprising 288 gastric cancer tissues and 288 adjacent normal tissues. Clinicopathological characteristics, including overall survival, were compared according to LIN28A expression. RESULTS The IHC staining score was lower for the cancer tissues than the normal tissues (p<0.001). However, no significant differences were observed in the clinicopathological characteristics between the low and high LIN28A expression groups. In addition, the 5-year overall survival rate did not differ between the two groups: 75.3% (95% confidence interval [CI], 69.3% to 81.7%) versus 71.6% (95% CI, 63.3% to 80.9%) for low versus high expression, respectively. CONCLUSIONS The expression of LIN28A did not appear to play a distinct role in predicting the clinicopathological characteristics of patients with gastric cancer. In addition, LIN28A expression was not an independently associated factor for overall survival in patients with gastric cancer.
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Affiliation(s)
- Chan Hyuk Park
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri,
Korea
| | - Jung Hwa Lee
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
| | - Na Keum Lee
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
| | - Yong Chan Lee
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
| | - Sang Kil Lee
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
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Stagner AM, Jakobiec FA. Updates on the Molecular Pathology of Selected Ocular and Ocular Adnexal Tumors: Potential Targets for Future Therapy. Semin Ophthalmol 2016; 31:188-96. [PMID: 26959146 DOI: 10.3109/08820538.2015.1115257] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Ophthalmic pathologic studies of retinoblastoma first definitively elucidated a genetic etiology for cancer three decades ago. Advances in DNA sequencing, protein expression profiling, and the exploration of epigenetics have since led to categorization of tumors and clinical prognostication based on genetic aberrancy. There are now many neoplasms that are defined by a characteristic genetic signature. In the past several years alone, much has been discovered in regard to the original tumor-suppressor gene initially defined in retinoblastoma as well as in other intraocular tumors such as medulloepithelioma. Our further understanding of ocular adnexal tumors that result in substantial morbidity and mortality, such as sebaceous carcinoma, has also benefited from a genetic approach. In this article, we review the clinicopathologic features of the foregoing three entities--retinoblastoma, medulloepithelioma, and sebaceous carcinoma--in order to highlight discoveries in their underlying abnormal molecular genetic functioning.
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Affiliation(s)
- Anna M Stagner
- a David G. Cogan Ophthalmic Pathology Laboratory, Massachusetts Eye and Ear Infirmary, and Department of Ophthalmology, Harvard Medical School , Boston , Massachusetts , USA
| | - Frederick A Jakobiec
- a David G. Cogan Ophthalmic Pathology Laboratory, Massachusetts Eye and Ear Infirmary, and Department of Ophthalmology, Harvard Medical School , Boston , Massachusetts , USA
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37
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Jiang S, Baltimore D. RNA-binding protein Lin28 in cancer and immunity. Cancer Lett 2016; 375:108-113. [PMID: 26945970 DOI: 10.1016/j.canlet.2016.02.050] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2015] [Revised: 02/24/2016] [Accepted: 02/24/2016] [Indexed: 01/10/2023]
Abstract
The highly conserved RNA-binding protein, Lin28, is involved in many biological processes, including development, reprogramming, pluripotency, and metabolism. Importantly, Lin28 functions as an oncogene, promoting tumor progression and metastasis in various human cancers. Lin28 can regulate gene expression either by directly binding to mRNAs or by blocking microRNA biogenesis, and the underlying mechanisms include Let-7-dependent and Let-7-independent modes of action. Recent evidence shows that Lin28 also plays a fundamental role in immunity. The roles of Lin28 in disease are complex and require characterization of its physiological functions in cancer and immunological contexts. Here we review emerging information on the role of Lin28 in cancer and immunity and the molecular mechanisms it uses. We discuss our present knowledge of the system and highlight remaining mysteries related to the functions of this small RNA-binding protein. This knowledge may lead to Lin28 becoming a diagnostic marker for cancer or immune-related diseases and a possible therapeutic target.
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Affiliation(s)
- Shuai Jiang
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | - David Baltimore
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
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38
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Wang H, Zhao Q, Deng K, Guo X, Xia J. Lin28: an emerging important oncogene connecting several aspects of cancer. Tumour Biol 2016; 37:2841-8. [PMID: 26762415 DOI: 10.1007/s13277-015-4759-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 12/29/2015] [Indexed: 12/29/2022] Open
Abstract
RNA-binding protein Lin28 was originally found as a heterochronic gene which played a significant role in the development of Caenorhabditis elegans. The tumor suppressor let-7 is a downstream target of Lin28, which has a wide variety of target genes which are involved in many aspects of cellular activities. By inhibition of let-7 and directly binding the target RNAs, Lin28 plays an important role in different biological and pathological processes including differentiation, metabolism, proliferation, pluripotency, and tumorigenesis. Overexpression of Lin28 has been reported in several kinds of cancers and is correlated with poor outcomes. It has been shown that Lin28 could affect the progression of cancers in several ways, such as promoting proliferation, increasing glucose metabolism, and inducing epithelial-mesenchymal transition (EMT) and cancer stem cells. Decrease of Lin28 expression or reactivation of let-7 in cancer cells could induce a reverse effect, indicating their therapeutic values in developing novel strategies for cancer treatment. Here, we will overview the regulatory mechanisms and functions of Lin28 in cancers.
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Affiliation(s)
- Hao Wang
- Department of General Surgery and Translational Medicine Center, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, 214002, Jiangsu, China
| | - Qin Zhao
- Department of General Surgery and Translational Medicine Center, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, 214002, Jiangsu, China
| | - Kaiyuan Deng
- Department of General Surgery and Translational Medicine Center, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, 214002, Jiangsu, China
| | - Xiaoqiang Guo
- Department of General Surgery and Translational Medicine Center, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, 214002, Jiangsu, China
| | - Jiazeng Xia
- Department of General Surgery and Translational Medicine Center, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, 214002, Jiangsu, China.
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Wang T, Han P, He Y, Zhao C, Wang G, Yang W, Shan M, Zhu Y, Yang C, Weng M, Wu D, Gao L, Jin X, Wei Y, Cui B, Shen G, Li X. Lin28A enhances chemosensitivity of colon cancer cells to 5-FU by promoting apoptosis in a let-7 independent manner. Tumour Biol 2015; 37:7657-65. [PMID: 26687759 DOI: 10.1007/s13277-015-4559-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 12/01/2015] [Indexed: 02/04/2023] Open
Abstract
RNA-binding protein Lin28A is frequently over-expressed in human malignant tumors and is associated with tumor advance and poor prognosis. However, the expression pattern and functions of Lin28A in colon cancer are unknown. In this study, we detected the expression of Lin28A in colon cancer patients and tested the effect of Lin28A on the chemotherapeutic sensitivity of colon cancer cells to 5-fluorouracil (5-FU). As expected, we showed that Lin28A is up-regulated in 73.3 % of colon cancer patients. However, to our surprise, we found that oncogenic protein Lin28A-enforced expression in colon cancer cells enhanced the chemosensitivity of cancer cells to 5-FU via promoting the cell apoptosis. Further mechanisms study revealed that the effect of Lin28A increasing chemosensitivity of cancer cells is in a let-7 independent manner, but which is associated with decreasing the expression of DNA damage repair protein H2AX. Conclusively, here we reported an unexpected function of Lin28A, which may shed lights on fully understanding the physiological and pathological roles of this oncogene.
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Affiliation(s)
- Tianzhen Wang
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Peng Han
- Department of Colorectal Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Yan He
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Ci Zhao
- Department of Gastrointestinal Medical Oncology, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Guangyu Wang
- Department of Gastrointestinal Medical Oncology, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Weiwei Yang
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Ming Shan
- Department of Breast Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Yuanyuan Zhu
- Department of Gastrointestinal Medical Oncology, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Chao Yang
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Mingjiao Weng
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Di Wu
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Lin Gao
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, China
| | - Xiaoming Jin
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Yunwei Wei
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - BinBin Cui
- Department of Colorectal Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China.
| | - Guomin Shen
- Department of Medical Genetics, Medical College, Henan University of Science and Technology, Luoyang, China.
| | - Xiaobo Li
- Department of Pathology, Harbin Medical University, Harbin, China.
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Teng R, Hu Y, Zhou J, Seifer B, Chen Y, Shen J, Wang L. Overexpression of Lin28 Decreases the Chemosensitivity of Gastric Cancer Cells to Oxaliplatin, Paclitaxel, Doxorubicin, and Fluorouracil in Part via microRNA-107. PLoS One 2015; 10:e0143716. [PMID: 26636340 PMCID: PMC4670127 DOI: 10.1371/journal.pone.0143716] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 11/08/2015] [Indexed: 02/07/2023] Open
Abstract
Higher Lin28 expression is associated with worse pathologic tumor responses in locally advanced gastric cancer patients undergoing neoadjuvant chemotherapy. However, the characteristics of Lin28 and its mechanism of action in chemotherapy resistance is still unclear. In this study, we found that transfection of Lin28 into gastric cancer cells (MKN45 and MKN28) increased their resistance to the chemo-drugs oxaliplatin (OXA), paclitaxel (PTX), doxorubicin (ADM), and fluorouracil (5-Fu) compared with gastric cancer cells transfected with a control vector. When knockdown Lin28 expression by Lin28 small interfering RNA (siRNA) was evaluated in vitro, we found that the resistance to chemo-drugs was reduced. Furthermore, we found that Lin28 up-regulates C-myc and P-gp and down-regulates Cylin D1. Finally, we found that miR-107 is a target microRNA of Lin28 and that it participates in the mechanism of chemotherapy resistance. Our results suggest that the Lin28/miR-107 pathway could be one of many signaling pathways regulated by Lin28 and associated with gastric cancer chemo-resistance.
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Affiliation(s)
- Rongyue Teng
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Hangzhou, Zhejiang Province, People’s Republic of China
| | - Yan Hu
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Hangzhou, Zhejiang Province, People’s Republic of China
- Zhejiang University, Hangzhou, Zhejiang province, People’s Republic of China
| | - Jichun Zhou
- Zhejiang University, Hangzhou, Zhejiang province, People’s Republic of China
| | - Benjamin Seifer
- Postgraduate Research Associate Yale School of Medicine, Department of Ob/Gyn & Reproductive Sciences, New Haven, Connecticut, United States of America
| | - Yongxia Chen
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Hangzhou, Zhejiang Province, People’s Republic of China
| | - Jianguo Shen
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Hangzhou, Zhejiang Province, People’s Republic of China
- * E-mail: (JS); (LW)
| | - Linbo Wang
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Hangzhou, Zhejiang Province, People’s Republic of China
- * E-mail: (JS); (LW)
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Kim Y, Kim H, Jeoung D. Tubulin Beta3 Serves as a Target of HDAC3 and Mediates Resistance to Microtubule-Targeting Drugs. Mol Cells 2015; 38:705-14. [PMID: 26126538 PMCID: PMC4546942 DOI: 10.14348/molcells.2015.0086] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Revised: 05/22/2015] [Accepted: 06/03/2015] [Indexed: 12/22/2022] Open
Abstract
We investigated the role of HDAC3 in anti-cancer drug-resistance. The expression of HDAC3 was decreased in cancer cell lines resistant to anti-cancer drugs such as celastrol and taxol. HDAC3 conferred sensitivity to these anti-cancer drugs. HDAC3 activity was necessary for conferring sensitivity to these anti-cancer drugs. The down-regulation of HDAC3 increased the expression of MDR1 and conferred resistance to anti-cancer drugs. The expression of tubulin β3 was increased in drug-resistant cancer cell lines. ChIP assays showed the binding of HDAC3 to the promoter sequences of tubulin β3 and HDAC6. HDAC6 showed an interaction with tubulin β3. HDAC3 had a negative regulatory role in the expression of tubulin β3 and HDAC6. The down-regulation of HDAC6 decreased the expression of MDR1 and tubulin β3, but did not affect HDAC3 expression. The down-regulation of HDAC6 conferred sensitivity to taxol. The down-regulation of tubulin β3 did not affect the expression of HDAC6 or MDR1. The down-regulation of tubulin β3 conferred sensitivity to anti-cancer drugs. Our results showed that tubulin β3 serves as a downstream target of HDAC3 and mediates resistance to microtubule-targeting drugs. Thus, the HDAC3-HDAC6-Tubulin β axis can be employed for the development of anti-cancer drugs.
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Affiliation(s)
- Youngmi Kim
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 200-701,
Korea
| | - Hyuna Kim
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 200-701,
Korea
| | - Dooil Jeoung
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 200-701,
Korea
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LIN28A Modulates Splicing and Gene Expression Programs in Breast Cancer Cells. Mol Cell Biol 2015; 35:3225-43. [PMID: 26149387 DOI: 10.1128/mcb.00426-15] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Accepted: 06/26/2015] [Indexed: 12/22/2022] Open
Abstract
LIN28 is an evolutionarily conserved RNA-binding protein with critical functions in developmental timing and cancer. However, the molecular mechanisms underlying LIN28's oncogenic properties are yet to be described. RNA-protein immunoprecipitation coupled with genome-wide sequencing (RIP-Seq) analysis revealed significant LIN28 binding within 843 mRNAs in breast cancer cells. Many of the LIN28-bound mRNAs are implicated in the regulation of RNA and cell metabolism. We identify heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), a protein with multiple roles in mRNA metabolism, as a LIN28-interacting partner. Subsequently, we used a custom computational method to identify differentially spliced gene isoforms in LIN28 and hnRNP A1 small interfering RNA (siRNA)-treated cells. The results reveal that these proteins regulate alternative splicing and steady-state mRNA expression of genes implicated in aspects of breast cancer biology. Notably, cells lacking LIN28 undergo significant isoform switching of the ENAH gene, resulting in a decrease in the expression of the ENAH exon 11a isoform. The expression of ENAH isoform 11a has been shown to be elevated in breast cancers that express HER2. Intriguingly, analysis of publicly available array data from the Cancer Genome Atlas (TCGA) reveals that LIN28 expression in the HER2 subtype is significantly different from that in other breast cancer subtypes. Collectively, our data suggest that LIN28 may regulate splicing and gene expression programs that drive breast cancer subtype phenotypes.
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43
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Zhou M, Li Z, Han Z, Tian N. Paclitaxel-sensitization enhanced by curcumin involves down-regulation of nuclear factor-κB and Lin28 in Hep3B cells. J Recept Signal Transduct Res 2015; 35:618-25. [PMID: 26108226 DOI: 10.3109/10799893.2015.1041644] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Although paclitaxel is an effective chemotherapeutic drug used in the treatment of many tumors, hepatoma cells, in particular, are known to be highly resistant to it. Previously, we discovered that Lin28 was closely associated with resistance to paclitaxel in Hep3B cells. The nuclear factor-kappa B (NF-κB) transcription factor, which plays an important role in tumor survival, directly activates Lin28 expression through a binding site on the first intron. Curcumin, a non-toxic anti-inflammatory agent, inhibits NF-κB activity in vitro. In this study, we reported that a combination of curcumin and paclitaxel exhibited synergistic anti-proliferative and pro-apoptosis effects on Hep3B cells, and curcumin down-regulated paclitaxel-induced enhanced expression of Lin28 and NF-κB activation. Furthermore, our results revealed that curcumin reduced Lin28 levels via mechanisms directly mediated by inhibition of NF-κB activity. These mechanism-based observations evidence that curcumin enhances the sensitivity of hepatoma cells to paclitaxe, and strongly support the notion that paclitaxel in combination with curcumin may provide a superior therapeutic index for HCC chemotherapy.
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Affiliation(s)
- Mingjie Zhou
- a College of Life Science, Zhejiang Chinese Medical University , Zhejiang , China and
| | - Zhaohui Li
- b Department of neurosurgery , China-Japan Union Hospital, Jilin University , Jilin , China
| | - Ziwu Han
- a College of Life Science, Zhejiang Chinese Medical University , Zhejiang , China and
| | - Nan Tian
- a College of Life Science, Zhejiang Chinese Medical University , Zhejiang , China and
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Jakobiec FA, Kool M, Stagner AM, Pfister SM, Eagle RC, Proia AD, Korshunov A. Intraocular Medulloepitheliomas and Embryonal Tumors With Multilayered Rosettes of the Brain: Comparative Roles of LIN28A and C19MC. Am J Ophthalmol 2015; 159:1065-1074.e1. [PMID: 25748578 DOI: 10.1016/j.ajo.2015.03.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Revised: 02/26/2015] [Accepted: 03/02/2015] [Indexed: 11/16/2022]
Abstract
PURPOSE To compare immunohistochemical and genetic overlaps and differences between intraocular medulloepitheliomas and embryonal tumors with multilayered rosettes of the brain. DESIGN Retrospective histopathologic, immunohistochemical, and genetic analysis of 20 intraocular medulloepitheliomas. METHODS (1) Review of clinical data and hematoxylin-eosin-stained sections with (2) immunohistochemical staining of paraffin sections using a polyclonal antibody against the protein LIN28A, and (3) fluorescence in situ hybridization (FISH) testing for the amplification of the genetic locus 19q13.42 involving the C19MC cluster of miRNA. Ten retinoblastomas served as controls and to determine the specificity of these biomarkers for intraocular medulloepitheliomas. RESULTS Nineteen of the 20 intraocular medulloepitheliomas were either diffusely or focally LIN28A positive (weak, moderate, or strong). The most intense positivity correlated with aggressive behavior such as intraocular tissue invasion or extraocular extension. None of the cases studied by FISH harbored an amplicon for C19MC. The 10 retinoblastomas were LIN28A and C19MC negative. CONCLUSION LIN28A has a putative role in oncogenesis and is found only in embryonic cells and malignancies. Intraocular medulloepitheliomas and embryonal tumors with multilayered rosettes of the brain both display LIN28A positivity. Only the latter, however, display amplification of the 19q13.42 locus involving C19MC, implying that other causative factors are at play in intraocular medulloepitheliomas. More aggressive tumor behavior within the eye can be partially predicted by LIN28A staining intensity.
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MESH Headings
- Adolescent
- Adult
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Child
- Child, Preschool
- Chromosomes, Human, Pair 19/genetics
- Ciliary Body/pathology
- Diagnosis, Differential
- Female
- Gene Amplification
- Humans
- Immunoenzyme Techniques
- In Situ Hybridization, Fluorescence
- Infant
- Male
- MicroRNAs/genetics
- Middle Aged
- Neoplasms, Germ Cell and Embryonal/diagnosis
- Neoplasms, Germ Cell and Embryonal/genetics
- Neoplasms, Germ Cell and Embryonal/metabolism
- Neuroectodermal Tumors, Primitive/diagnosis
- Neuroectodermal Tumors, Primitive/genetics
- Neuroectodermal Tumors, Primitive/metabolism
- RNA-Binding Proteins/metabolism
- Retrospective Studies
- Uveal Neoplasms/diagnosis
- Uveal Neoplasms/genetics
- Uveal Neoplasms/metabolism
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Affiliation(s)
- Frederick A Jakobiec
- David G. Cogan Ophthalmic Pathology Laboratory, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, Massachusetts.
| | - Marcel Kool
- Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Anna M Stagner
- David G. Cogan Ophthalmic Pathology Laboratory, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, Massachusetts
| | - Stefan M Pfister
- Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Ralph C Eagle
- Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Alan D Proia
- Duke University Department of Pathology, Durham, North Carolina
| | - Andrey Korshunov
- Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), and Department of Neuropathology, University Hospital, Heidelberg, Germany
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Lv J, Fu Z, Shi M, Xia K, Ji C, Xu P, Lv M, Pan B, Dai L, Xie H. Systematic analysis of gene expression pattern in has-miR-760 overexpressed resistance of the MCF-7 human breast cancer cell to doxorubicin. Biomed Pharmacother 2014; 69:162-9. [PMID: 25661353 DOI: 10.1016/j.biopha.2014.11.028] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 11/12/2014] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND/AIMS Chemoresistance of breast cancer is a growing problem and still a major clinical obstacle to successful treatment in clinical patients. miR-760 was significantly downregulated in chemoresistance breast cancer tissues compared to chemo-sensitive tissues in our previous study. However, the role of miR-760 in modulating drug resistance remains largely unexplored. In this study, we sought to determine the expression pattern of miR-760 targeted mRNAs, and explore their potential functions and participated-pathways in breast cancer drug resistance cells. RESULTS Compared to parental cell line MCF-7, miR-760 was downregulated by 6.15 folds in MCF-7/Adr cells. The qRT-PCR result showed that compared to miR-760 negative control cells group, miR-760 was up-regulated 15.817 folds after miR-760 lentiviral transfection in miR-760 mimics group. The microarray data showed that 270 genes were dysregulated over 2-fold change in MCF-7/Adr cells after miR-760 overexpressed, including 241 up-regulated and 29 downregulated genes. GO analysis result appeared that the predicted target genes of miR-760 mainly regulated DNA binding, protein binding, molecular function, nucleic acid binding, and so on; the pathway analysis data demonstrated that these target genes mainly involved in cell cycle, TGF-beta signaling pathway, mRNA processing reactome, G protein signaling, apoptosis, Wnt signaling pathway, and other signaling pathways. There were 3 predicted target genes (RHOB, ANGOTL4, ABCA1) of miR-760 were selected at a P value<0.05 and the fold enrichment was>40. CONCLUSION Our study explored the genes expression pattern after miR-760 overexpresssed, and confirmed 3 dominantly dysregulated genes, which could expand the insights into the miR-760 function and molecular mechanisms in drug resistance of breast cancer. This study might afford a comprehensive understanding of miR-760 as prognostic biomarkers during clinical treatment, and we supposed that the miR-760 expression levels in drug resistance carcinoma tissues could be pursued to develop new strategies for targeted therapies in chemoresistant breast cancer patients.
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Affiliation(s)
- Jianxin Lv
- Yangzhou Maternal and Child Health Hospital, Affiliated with Yangzhou Medical University, Yangzhou 225002, China
| | - Ziyi Fu
- Nanjing Maternal and Child Health Medical Institute, Affiliated Nanjing Maternal and Child Health Hospital, Nanjing Medical University, Nanjing 210004, China
| | - Min Shi
- Yangzhou Maternal and Child Health Hospital, Affiliated with Yangzhou Medical University, Yangzhou 225002, China
| | - Kai Xia
- The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin 214400, China
| | - Chenbo Ji
- Nanjing Maternal and Child Health Medical Institute, Affiliated Nanjing Maternal and Child Health Hospital, Nanjing Medical University, Nanjing 210004, China
| | - Pengfei Xu
- Nanjing Maternal and Child Health Medical Institute, Affiliated Nanjing Maternal and Child Health Hospital, Nanjing Medical University, Nanjing 210004, China
| | - Mingming Lv
- Nanjing Maternal and Child Health Medical Institute, Affiliated Nanjing Maternal and Child Health Hospital, Nanjing Medical University, Nanjing 210004, China
| | - Bo Pan
- Yangzhou Maternal and Child Health Hospital, Affiliated with Yangzhou Medical University, Yangzhou 225002, China
| | - Luxian Dai
- Yangzhou Maternal and Child Health Hospital, Affiliated with Yangzhou Medical University, Yangzhou 225002, China
| | - Hui Xie
- Nanjing Maternal and Child Health Medical Institute, Affiliated Nanjing Maternal and Child Health Hospital, Nanjing Medical University, Nanjing 210004, China; The People's Hospital of Jiangsu Province/The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
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The mystery of let-7d - a small RNA with great power. Contemp Oncol (Pozn) 2014; 18:293-301. [PMID: 25477749 PMCID: PMC4248056 DOI: 10.5114/wo.2014.44467] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Revised: 05/16/2014] [Accepted: 06/18/2014] [Indexed: 12/21/2022] Open
Abstract
miRNAs belong to a class of small non-coding RNAs which can modulate gene expression. Disturbances in their expression and function may cause cancer formation, progression and cell response to various types of stress. The let-7 family is one of the most studied groups of miRNAs. The family contains 13 members with similar sequences and a wide spectrum of target genes. In this paper, we mostly focus on one member of the family – let-7d. This miRNA is dysregulated in many types of cancers. It can be over- or down-expressed, and it acts as a tumor suppressor or oncogene. It regulates various genes such as LIN28, C-MYC, K-RAS, HMGA2 and IMP-1. Moreover, let-7d has a significant impact on epithelial-to-mesenchymal transition (EMT) and formation of cancer initiating cells which are resistant to irradiation and chemical exposure and responsible for cancer metastasis. Let-7d can serve as a prognostic and predictive marker for personalization of the treatment. Let-7d is a small RNA with great power, but in different cell genetic backgrounds it acts in different ways, which makes this molecule still mysterious.
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Tulsyan S, Agarwal G, Lal P, Mittal B. Significant association of combination of OCT4, NANOG, and SOX2 gene polymorphisms in susceptibility and response to treatment in North Indian breast cancer patients. Cancer Chemother Pharmacol 2014; 74:1065-1078. [PMID: 25223935 DOI: 10.1007/s00280-014-2588-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Accepted: 09/07/2014] [Indexed: 10/24/2022]
Abstract
PURPOSE Dysregulations of regulatory genes in embryonic stem cells (ESCs) gene polymorphisms may lead to breast cancer cell growth, differentiation, and tumor metastasis. METHODS Polymorphisms in OCT4 (rs3130932), NANOG (rs11055786), LIN28 (rs4274112), and SOX2 (rs11915160) genes were evaluated for susceptibility in 297 breast cancer females and 273 healthy controls from north Indian population. Response to neo-adjuvant chemotherapy was followed in 128 locally advanced breast cancer patients along with clinicopathological features. Genotyping was done using TaqMan allelic discrimination assays. Statistical analysis was performed using SPSS and multifactor dimensionality reduction (MDR). RESULTS For OCT4 gene polymorphism, protective effect of genotypes AC [P corr = 0.031, OR = 0.63 (0.44-0.91)] and AC+CC [P corr = 0.031, OR = 0.68 (0.48-0.95)] was seen in patients. However, no association of NANOG, LIN28, and SOX2 gene polymorphisms was found with overall breast cancer susceptibility. Further, significant association of AG+GG genotype [P corr = 0.021, OR = 6.08 (1.83-20.15)] and G allele [P corr = 0.021, OR = 3.07 (1.21-7.77)] of rs4274112 polymorphism was seen with positive lymph node. For OCT4, significant association of allele C was seen with patients having negative hormone receptor [P corr = 0.021, OR = 0.51 (0.29-0.90)], but no association of any of the studied polymorphisms individually was found with response to NACT. On MDR analysis, we found combination of SNPs SOX2 rs11915160, OCT4 rs3130932, and NANOG rs11055786 to be the best interaction model for predicting breast cancer risk [p for permutation test <10(-3), OR = 2.04 (1.43-2.910] and response to NACT [p for permutation test = 0.005, OR = 2.09 (1.24-3.52)]. CONCLUSION Combination of genetic variants of ESCs gene may have a profound effect in breast cancer risk and response to NACT.
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Affiliation(s)
- Sonam Tulsyan
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli road, Lucknow, 226 014, India
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Wang Q, Zhou J, Guo J, Teng R, Shen J, Huang Y, Xie S, Wei Q, Zhao W, Chen W, Yuan X, Chen Y, Wang L. Lin28 promotes Her2 expression and Lin28/Her2 predicts poorer survival in gastric cancer. Tumour Biol 2014; 35:11513-21. [PMID: 25128063 DOI: 10.1007/s13277-014-2481-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Accepted: 08/08/2014] [Indexed: 12/13/2022] Open
Abstract
The main purpose of this study is to investigate the interactions between Lin28 and Her2 in gastric cancer. Lin28 and Her2 expression were evaluated in surgically resected samples of 298 gastric cancer patients using immunohistochemical staining. The correlations between Lin28/Her2 expression and clinical variables were retrospectively analyzed. The mRNA level of LIN28 and HER2 was detected by reverse-transcriptase polymerase chain reaction. Among all gastric cancer patients, 33.9% (101/298) were determined as Her2-positive, and 43.0% (128/298) were defined as Lin28-positive. Lin28 was significantly associated with Her2, advanced tumor stage, lesion size, and Ki67 level (p<0.05 for each). Kaplan-Meier analysis illustrated that both Lin28 and Her2 are poor prognostic factors in gastric cancer; Lin28(+)/Her2(+) patients have the poorest survival (median survival = 17 months, p<0.01). Multivariate Cox analysis showed that Lin28 is a significant prognostic factor (hazard ratio (HR) = 1.79, 95% confidence interval (CI) 1.23-2.62). Further stratification analysis indicated that Lin28 may be a prognostic factor in chemotherapy. In vitro data on MKN-28 and MKN-45 cells showed that Lin28 can upregulate Her2 expression at translational level. Both Lin28 and Her2 are poor prognostic factors in gastric cancer. Lin28 may regulate Her2 post-transcriptionally in gastric cancer cells, which indicates it might be a potential target in the treatment of gastric cancer.
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Affiliation(s)
- Qinchuan Wang
- Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, 310008, China
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Moyret-Lalle C, Ruiz E, Puisieux A. Epithelial-mesenchymal transition transcription factors and miRNAs: “Plastic surgeons” of breast cancer. World J Clin Oncol 2014; 5:311-322. [PMID: 25114847 PMCID: PMC4127603 DOI: 10.5306/wjco.v5.i3.311] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 03/18/2014] [Accepted: 06/27/2014] [Indexed: 02/06/2023] Open
Abstract
Growing evidence suggests that breast cancer cell plasticity arises due to a partial reactivation of epithelial-mesenchymal transition (EMT) programs in order to give cells pluripotency, leading to a stemness-like phenotype. A complete EMT would be a dead end program that would render cells unable to fully metastasize to distant organs. Evoking the EMT-mesenchymal-to-epithelial transition (MET) cascade promotes successful colonization of distal target tissues. It is unlikely that direct reprogramming or trans-differentiation without passing through a pluripotent stage would be the preferred mechanism during tumor progression. This review focuses on key EMT transcriptional regulators, EMT-transcription factors involved in EMT (TFs) and the miRNA pathway, which are deregulated in breast cancer, and discusses their implications in cancer cell plasticity. Cross-regulation between EMT-TFs and miRNAs, where miRNAs act as co-repressors or co-activators, appears to be a pivotal mechanism for breast cancer cells to acquire a stem cell-like state, which is implicated both in breast metastases and tumor recurrence. As a master regulator of miRNA biogenesis, the ribonuclease type III endonuclease Dicer plays a central role in EMT-TFs/miRNAs regulating networks. All these EMT-MET key regulators represent valuable new prognostic and predictive markers for breast cancer as well as promising new targets for drug-resistant breast cancers.
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50
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Hu Q, Peng J, Liu W, He X, Cui L, Chen X, Yang M, Liu H, Liu S, Wang H. Lin28B is a novel prognostic marker in gastric adenocarcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2014; 7:5083-5092. [PMID: 25197381 PMCID: PMC4152071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Accepted: 07/12/2014] [Indexed: 06/03/2023]
Abstract
Lin28B, a homologue of Lin28, represses biogenesis of let-7 microRNAs with a role in tumorigenesis and is considered a potential therapeutic target for various human cancers. The aim of the study was to identify the clinical significance of Lin28B in gastric adenocarcinoma (GAC). We examined the expression of Lin28B in 97 human gastric cancer samples with 32 samples of non-dysplastic tissues by immunohistochemistry. In the 97 GAC cases, 42 were with high Lin28B expression. The expression levels of Lin28B proteins in GAC were higher than in corresponding adjacent normal tissues (P=0.001). Significant correlations were noted between Lin28B expression and lymph node status (P=0.005), TNM stage (P < 0.001), tumor invasion (P=0.036), and differentiation (P=0.001) of GAC patients. The Kaplan-Meier estimates showed a negative correlation of overall 5-year survival rate with Lin28B expression where higher expression resulted in poorer prognosis in GAC. In univariate analysis, lymph node metastasis, TNM stage, serosal invasion, Lin28B expression as well as differentiation grade could predict the prognosis of GAC patients (P=0.002, P < 0.001, P=0.003, P < 0.001, P=0.001, respectively). Multivariate analysis revealed that the expression level of Lin28B (P < 0.001), TNM stage (P < 0.001) as well as differentiation grade (P < 0.001) were the three potential independent prognostic factors in our study [Hazard ratio (HR)=2.108 and P=0.017, HR=1.994 and P=0.018, HR=1.939 and P=0.046, respectively]. Our findings point to the prognostic role of Lin28B in GAC, and indicate Lin28B as a potential therapeutic target of GAC patients.
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Affiliation(s)
- Qian Hu
- Laboratory of Genetics, West China Institute of Women and Children’s Health, West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Laboratory of Cell and Gene Therapy, West China Institute of Women and Children’s Health, West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Department of Obstetric and Gynecologic, West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of EducationChengdu 610041, China
| | - Jing Peng
- Laboratory of Genetics, West China Institute of Women and Children’s Health, West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Laboratory of Cell and Gene Therapy, West China Institute of Women and Children’s Health, West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Department of Obstetric and Gynecologic, West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of EducationChengdu 610041, China
| | - Weiping Liu
- Department of Pathology, West China Hospital of Sichuan University37 Guoxue Street, Chengdu, Sichuan 610041, China
| | - Xiaoli He
- Department of Obstetric and Gynecologic, Henan Provincial People’s HospitalZhengzhou, Henan 450003, China
| | - Ling Cui
- Department of Gynecological Oncology, Second People’s Hospital of Sichuan (Sichuan Cancer Hospital)Chengdu, Sichuan 610041, China
| | - Xinlian Chen
- Laboratory of Genetics, West China Institute of Women and Children’s Health, West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Laboratory of Cell and Gene Therapy, West China Institute of Women and Children’s Health, West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Department of Obstetric and Gynecologic, West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of EducationChengdu 610041, China
| | - Mei Yang
- Laboratory of Genetics, West China Institute of Women and Children’s Health, West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Laboratory of Cell and Gene Therapy, West China Institute of Women and Children’s Health, West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Department of Obstetric and Gynecologic, West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of EducationChengdu 610041, China
| | - Hongqian Liu
- Laboratory of Genetics, West China Institute of Women and Children’s Health, West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Laboratory of Cell and Gene Therapy, West China Institute of Women and Children’s Health, West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Department of Obstetric and Gynecologic, West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of EducationChengdu 610041, China
| | - Shanling Liu
- Laboratory of Cell and Gene Therapy, West China Institute of Women and Children’s Health, West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Department of Obstetric and Gynecologic, West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of EducationChengdu 610041, China
| | - He Wang
- Laboratory of Genetics, West China Institute of Women and Children’s Health, West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Department of Obstetric and Gynecologic, West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of EducationChengdu 610041, China
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