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Yoshida J, Hayashi T, Munetsuna E, Khaledian B, Sueishi F, Mizuno M, Maeda M, Watanabe T, Ushida K, Sugihara E, Imaizumi K, Kawada K, Asai N, Shimono Y. Adipsin-dependent adipocyte maturation induces cancer cell invasion in breast cancer. Sci Rep 2024; 14:18494. [PMID: 39122742 PMCID: PMC11316094 DOI: 10.1038/s41598-024-69476-3] [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: 03/16/2024] [Accepted: 08/05/2024] [Indexed: 08/12/2024] Open
Abstract
Adipocyte-cancer cell interactions promote tumor development and progression. Previously, we identified adipsin (CFD) and its downstream effector, hepatocyte growth factor (HGF), as adipokines that enhance adipocyte-breast cancer stem cell interactions. Here, we show that adipsin-dependent adipocyte maturation and the subsequent upregulation of HGF promote tumor invasion in breast cancers. Mature adipocytes, but not their precursors, significantly induced breast tumor cell migration and invasion in an adipsin expression-dependent manner. Promoters of tumor invasion, galectin 7 and matrix metalloproteinases, were significantly upregulated in cancer cells cocultured with mature adipocytes; meanwhile, their expression levels in cancer cells cocultured with adipocytes were reduced by adipsin knockout (Cfd KO) or a competitive inhibitor of CFD. Tumor growth and distant metastasis of mammary cancer cells were significantly suppressed when syngeneic mammary cancer cells were transplanted into Cfd KO mice. Histological analyses revealed reductions in capsular formation and tumor invasion at the cancer-adipocyte interface in the mammary tumors formed in Cfd KO mice. These findings indicate that adipsin-dependent adipocyte maturation may play an important role in adipocyte-cancer cell interaction and breast cancer progression.
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Affiliation(s)
- Jumpei Yoshida
- Department of Biochemistry, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 4701192, Japan
- Department of Medical Oncology, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan
| | - Takanori Hayashi
- Department of Biochemistry, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 4701192, Japan
| | - Eiji Munetsuna
- Department of Biochemistry, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 4701192, Japan
| | - Behnoush Khaledian
- Department of Biochemistry, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 4701192, Japan
| | - Fujiko Sueishi
- Department of Biochemistry, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 4701192, Japan
| | - Masahiro Mizuno
- Department of Biochemistry, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 4701192, Japan
| | - Masao Maeda
- Department of Biochemistry, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 4701192, Japan
- Department of Pathology, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan
| | - Takashi Watanabe
- Division of Gene Regulation, Oncology Innovation Center, Fujita Health University, Toyoake, Aichi, 4701192, Japan
| | - Kaori Ushida
- Department of Pathology, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan
| | - Eiji Sugihara
- Division of Gene Regulation, Oncology Innovation Center, Fujita Health University, Toyoake, Aichi, 4701192, Japan
| | - Kazuyoshi Imaizumi
- Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan
| | - Kenji Kawada
- Department of Medical Oncology, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan
| | - Naoya Asai
- Department of Pathology, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan
| | - Yohei Shimono
- Department of Biochemistry, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 4701192, Japan.
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Ward AS, Hall CN, Tree MO, Kohtz DS. Spheroid architecture strongly enhances miR-221/222 expression and promotes oxidative phosphorylation in an ovarian cancer cell line through a mechanism that includes restriction of miR-9 expression. Mol Biol Rep 2024; 51:275. [PMID: 38310615 DOI: 10.1007/s11033-023-09168-9] [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: 09/30/2023] [Accepted: 12/15/2023] [Indexed: 02/06/2024]
Abstract
BACKGROUND Tumor cell spheroids are organized multicellular structures that form during the expansive growth of carcinoma cells. Spheroids formation is thought to contribute to metastasis by supporting growth and survival of mobile tumor cell populations. METHODS AND RESULTS We investigated how spheroid architecture affects OXPHOS activity, microRNA expression, and intraperitoneal survival of an ovarian carcinoma cell line using high resolution respirometry, quantitative RT-PCR, and a rodent intraperitoneal growth model. Rates of oxidative phosphorylation/respiration per cell of cells growing as spheroids were nearly double those of a variant of the same cell type growing in suspension as loosely aggregated cells. Further, inhibition of spheroid formation by treatment with CDH2 (N-cadherin) siRNA reduced the rate of OXPHOS to that of the non-spheroid forming variant. Cells growing as spheroids showed greatly enhanced expression of miR-221/222, an oncomiR that targets multiple tumor suppressor genes and promotes invasion, and reduced expression of miR-9, which targets mitochondrial tRNA-modification enzymes and inhibits OXPHOS. Consistent with greater efficiency of ATP generation, tumor cells growing as spheroids injected into the nutrient-poor murine peritoneum survived longer than cells growing in suspension as loosely associated aggregates. CONCLUSIONS The data indicate that growth in spheroid form enhances the OXPHOS activity of constituent tumor cells. In addition, spheroid architecture affects expression of microRNA genes involved in growth control and mitochondrial function. During the mobile phase of metastasis, when ovarian tumor cells disperse through nutrient-poor environments such as the peritoneum, enhanced OXPHOS activity afforded by spheroid architecture would enhance survival and metastatic potential.
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Affiliation(s)
- Avery S Ward
- Central Michigan University College of Medicine, Central Michigan University, Mt. Pleasant, MI, 48859, USA
| | - Cody N Hall
- Central Michigan University College of Medicine, Central Michigan University, Mt. Pleasant, MI, 48859, USA
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55901, USA
| | - Maya O Tree
- Central Michigan University College of Medicine, Central Michigan University, Mt. Pleasant, MI, 48859, USA
| | - D Stave Kohtz
- Central Michigan University College of Medicine, Central Michigan University, Mt. Pleasant, MI, 48859, USA.
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Zheng Y, Sukocheva O, Tse E, Neganova M, Aleksandrova Y, Zhao R, Chubarev V, Fan R, Liu J. MicroRNA-183 cluster: a promising biomarker and therapeutic target in gastrointestinal malignancies. Am J Cancer Res 2023; 13:6147-6175. [PMID: 38187051 PMCID: PMC10767355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 11/29/2023] [Indexed: 01/09/2024] Open
Abstract
Small non-coding RNAs (microRNA, miR), powerful epigenetic regulators, were found involved in the regulation of most biological functions via post-translational inhibition of protein expression. Increased expression of pro-oncogenic miRs (known as miR cancer biomarkers) and inhibition of pro-apoptotic miR expression have been demonstrated in different tumors. The recently identified miR-183 was found implicated in gastrointestinal tumor metabolism regulation. Elevated miR-183 expression and cancer-promoting effects were reported in esophageal and colorectal cancers, which was partially contradicted by controversial data observed in gastric cancers. Anti-cancer effect of miR-183 in gastric cancer cells was associated with the Bim-1 and Ezrin genes regulation. Many studies indicated that miR-183 can inhibit tumor suppressor genes in most cell lines, promoting tumor cell proliferation and migration. Increased miR-183 level results in the downregulation of FOXO1, PDCD4, and other tumor suppressor genes in gastrointestinal tumor cells. MiR-183 also influences the signaling of PI3K/AKT/mTOR, Wnt/β-catenin, and Bcl-2/p53 signaling pathways. Mir-183 inhibits apoptosis and autophagy, and promotes epithelial-to-mesenchymal transition, cancer cell proliferation, and migration. Accordingly, gastrointestinal cancer occurrence, development of chemoradiotherapy resistance, recurrence/metastasis, and prognosis were associated with miR-183 expression. The current study assessed reported miR-183 functions and signaling, providing new insights for the diagnosis and treatment of gastrointestinal malignancies.
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Affiliation(s)
- Yufei Zheng
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
| | - Olga Sukocheva
- Department of Hepatology, Royal Adelaide HospitalAdelaide, SA 5000, Australia
| | - Edmund Tse
- Department of Hepatology, Royal Adelaide HospitalAdelaide, SA 5000, Australia
| | - Margarita Neganova
- Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of SciencesSevernij Pr. 1, Chernogolovka 142432, Russia
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of SciencesAkad. Arbuzov St. 8, Kazan 420088, Russia
| | - Yulia Aleksandrova
- Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of SciencesSevernij Pr. 1, Chernogolovka 142432, Russia
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of SciencesAkad. Arbuzov St. 8, Kazan 420088, Russia
| | - Ruiwen Zhao
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
| | - Vladimir Chubarev
- Sechenov First Moscow State Medical University (Sechenov University)8-2 Trubetskaya St., Moscow 119991, Russia
| | - Ruitai Fan
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
| | - Junqi Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
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Khaledian B, Thibes L, Shimono Y. Adipocyte regulation of cancer stem cells. Cancer Sci 2023; 114:4134-4144. [PMID: 37622414 PMCID: PMC10637066 DOI: 10.1111/cas.15940] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/08/2023] [Accepted: 08/13/2023] [Indexed: 08/26/2023] Open
Abstract
Cancer stem cells (CSCs) are a highly tumorigenic subpopulation of the cancer cells within a tumor that drive tumor initiation, progression, and therapy resistance. In general, stem cell niche provides a specific microenvironment in which stem cells are present in an undifferentiated and self-renewable state. CSC niche is a specialized tumor microenvironment for CSCs which provides cues for their maintenance and propagation. However, molecular mechanisms for the CSC-niche interaction remain to be elucidated. We have revealed that adipsin (complement factor D) and its downstream effector hepatocyte growth factor are secreted from adipocytes and enhance the CSC properties in breast cancers in which tumor initiation and progression are constantly associated with the surrounding adipose tissue. Considering that obesity, characterized by excess adipose tissue, is associated with an increased risk of multiple cancers, it is reasonably speculated that adipocyte-CSC interaction is similarly involved in many types of cancers, such as pancreas, colorectal, and ovarian cancers. In this review, various molecular mechanisms by which adipocytes regulate CSCs, including secretion of adipokines, extracellular matrix production, biosynthesis of estrogen, metabolism, and exosome, are discussed. Uncovering the roles of adipocytes in the CSC niche will propose novel strategies to treat cancers, especially those whose progression is linked to obesity.
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Affiliation(s)
- Behnoush Khaledian
- Department of BiochemistryFujita Health University School of MedicineToyoakeAichiJapan
| | - Lisa Thibes
- Department of BiochemistryFujita Health University School of MedicineToyoakeAichiJapan
| | - Yohei Shimono
- Department of BiochemistryFujita Health University School of MedicineToyoakeAichiJapan
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Singla RK, Wang X, Gundamaraju R, Joon S, Tsagkaris C, Behzad S, Khan J, Gautam R, Goyal R, Rakmai J, Dubey AK, Simal-Gandara J, Shen B. Natural products derived from medicinal plants and microbes might act as a game-changer in breast cancer: a comprehensive review of preclinical and clinical studies. Crit Rev Food Sci Nutr 2023; 63:11880-11924. [PMID: 35838143 DOI: 10.1080/10408398.2022.2097196] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Breast cancer (BC) is the most prevalent neoplasm among women. Genetic and environmental factors lead to BC development and on this basis, several preventive - screening and therapeutic interventions have been developed. Hormones, both in the form of endogenous hormonal signaling or hormonal contraceptives, play an important role in BC pathogenesis and progression. On top of these, breast microbiota includes both species with an immunomodulatory activity enhancing the host's response against cancer cells and species producing proinflammatory cytokines associated with BC development. Identification of novel multitargeted therapeutic agents with poly-pharmacological potential is a dire need to combat advanced and metastatic BC. A growing body of research has emphasized the potential of natural compounds derived from medicinal plants and microbial species as complementary BC treatment regimens, including dietary supplements and probiotics. In particular, extracts from plants such as Artemisia monosperma Delile, Origanum dayi Post, Urtica membranacea Poir. ex Savigny, Krameria lappacea (Dombey) Burdet & B.B. Simpson and metabolites extracted from microbes such as Deinococcus radiodurans and Streptomycetes strains as well as probiotics like Bacillus coagulans and Lactobacillus brevis MK05 have exhibited antitumor effects in the form of antiproliferative and cytotoxic activity, increase in tumors' chemosensitivity, antioxidant activity and modulation of BC - associated molecular pathways. Further, bioactive compounds like 3,3'-diindolylmethane, epigallocatechin gallate, genistein, rutin, resveratrol, lycopene, sulforaphane, silibinin, rosmarinic acid, and shikonin are of special interest for the researchers and clinicians because these natural agents have multimodal action and act via multiple ways in managing the BC and most of these agents are regularly available in our food and fruit diets. Evidence from clinical trials suggests that such products had major potential in enhancing the effectiveness of conventional antitumor agents and decreasing their side effects. We here provide a comprehensive review of the therapeutic effects and mechanistic underpinnings of medicinal plants and microbial metabolites in BC management. The future perspectives on the translation of these findings to the personalized treatment of BC are provided and discussed.
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Affiliation(s)
- Rajeev K Singla
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- iGlobal Research and Publishing Foundation, New Delhi, India
| | - Xiaoyan Wang
- Department of Pathology, Clinical Medical College and the First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Rohit Gundamaraju
- ER Stress and Mucosal Immunology Lab, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Tasmania, Australia
| | - Shikha Joon
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- iGlobal Research and Publishing Foundation, New Delhi, India
| | | | - Sahar Behzad
- Evidence-based Phytotherapy and Complementary Medicine Research Center, Alborz University of Medical Sciences, Karaj, Iran
- Department of Pharmacognosy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Johra Khan
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al Majmaah, Saudi Arabia
- Health and Basic Sciences Research Center, Majmaah University, Majmaah, Saudi Arabia
| | - Rupesh Gautam
- Department of Pharmacology, MM School of Pharmacy, MM University, Sadopur, Haryana, India
| | - Rajat Goyal
- Department of Pharmacology, MM School of Pharmacy, MM University, Sadopur, Haryana, India
| | - Jaruporn Rakmai
- Kasetsart Agricultural and Agro-Industrial Product Improvement Institute (KAPI), Kasetsart University, Bangkok, Thailand
| | | | - Jesus Simal-Gandara
- Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Science, Universidade de Vigo, Ourense, Spain
| | - Bairong Shen
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Hao H, Wang B, Yang L, Sang Y, Xu W, Liu W, Zhang L, Jiang D. miRNA-186-5p inhibits migration, invasion and proliferation of breast cancer cells by targeting SBEM. Aging (Albany NY) 2023; 15:6993-7007. [PMID: 37477531 PMCID: PMC10415540 DOI: 10.18632/aging.204887] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 06/22/2023] [Indexed: 07/22/2023]
Abstract
The paper aimed to investigate the effect of miR186-5p on invasion and migration of breast cancer cells and its molecular mechanism. MicroRNA-186-5p was found to be low expressed in breast cancer and highly expressed in SBEM by bioinformatics analysis. After transfecting MDA-MB-231 cells with miR-186-5p inhibitor NC, miR-186-5p inhibitor, miR-186-5p mimic NC and miR-186-5p mimic, respectively. The migration and invasive ability of breast cancer cells were detected by cell scratch test and Transwell test. Moreover, after adding 740 Y-P to the miR-186-5p mimic NC group and miR-186-5p mimic group cells, SBEM and PI3K pathway-related proteins were detected by Western blotting and proliferation of the cancer cells was evaluated by monoclonal cell experiment. Meanwhile, exogenous miR-186-5p mimic in MDA-MB-231 cells significantly inhibited the expression of SBEM, p-PI3K, p-AKT and their downstream pathways, MMP1, MMP3, MMP9, CyclinD1, PCNA and CyclinB1 proteins and reduced proliferation of breast cancer cells. Furthermore, the expression of SBEM protein in the miR-186-5p mimic + 740Y-P group was significantly lower than the miR-186-5p mimic NC + 740Y-P group after adding 740 Y-P. However, there were no significant changes in the protein's levels associated with PI3K pathway and the cancer cells proliferation. These results suggest that low expression of miR-186-5p in breast cancer results in an abnormally high expression of SBEM, activation of PI3K/AKT signaling pathway, promoting migration and invasion of human breast cancer cells.
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Affiliation(s)
- Hui Hao
- Department of Medical Oncology, The Forth Hospital of Hebei Medical University, Shijiazhuang 050000, China
| | - Bingsheng Wang
- Department of Medical Oncology, Hebei Cangzhou People’s Hospital, Cangzhou 061001, China
| | - Lin Yang
- Graduate School, Chengde Medical University and Cangzhou People’s Hospital, Cangzhou 061001, China
| | - Yinzhou Sang
- Department of Pathology, Hebei Cangzhou People’s Hospital, Cangzhou 061001, China
| | - Wei Xu
- Department of Medical Oncology, Hebei Cangzhou People’s Hospital, Cangzhou 061001, China
| | - Wei Liu
- Department of Medical Oncology, Hebei Cangzhou People’s Hospital, Cangzhou 061001, China
| | - Lili Zhang
- Department of Medicine, Cangzhou Medical College, Cangzhou 061011, China
| | - Da Jiang
- Department of Medical Oncology, The Forth Hospital of Hebei Medical University, Shijiazhuang 050000, China
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Shao Z, Wang X, Li Y, Hu Y, Li K. The role of long noncoding RNAs as regulators of the epithelial–Mesenchymal transition process in oral squamous cell carcinoma cells. Front Mol Biosci 2022; 9:942636. [PMID: 36106022 PMCID: PMC9465078 DOI: 10.3389/fmolb.2022.942636] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 08/01/2022] [Indexed: 11/30/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) is a highly invasive and relatively prevalent cancer, accounting for around 3% of all cancers diagnosed. OSCC is associated with bad outcomes, with only 50% overall survival (OS) after five years. The ability of OSCC to invade local and distant tissues relies on the induction of the epithelial–mesenchymal transition (EMT), wherein epithelial cells shed their polarity and cell-to-cell contacts and acquire mesenchymal characteristics. Consequently, a comprehensive understanding of how tumor cell EMT induction is regulated has the potential of direct attempts to prevent tumor progression and metastasis, resulting in better patient outcomes. Several recent studies have established the significance of particular long noncoding RNAs (lncRNAs) in the context of EMT induction. Moreover, lncRNAs regulate a vast array of oncogenic pathways. With a focus on the mechanisms by which the underlined lncRNAs shape the metastatic process and a discussion of their potential utility as clinical biomarkers or targets for therapeutic intervention in patients with OSCC, the present review thus provides an overview of the EMT-related lncRNAs that are dysregulated in OSCC.
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Affiliation(s)
- Zifei Shao
- Xiangya School of Stomatology, Central South University, Changsha, Hunan, China
| | - Xiang Wang
- Xiangya School of Stomatology, Central South University, Changsha, Hunan, China
| | - Yiyang Li
- Xiangya School of Stomatology, Central South University, Changsha, Hunan, China
| | - Yanjia Hu
- Xiangya School of Stomatology, Central South University, Changsha, Hunan, China
- Hunan Clinical Research Center of Oral Major Diseases and Oral Health and Xiangya Stomatological Hospital, Changsha, China
- *Correspondence: Yanjia Hu, ; Kun Li,
| | - Kun Li
- Xiangya School of Stomatology, Central South University, Changsha, Hunan, China
- Hunan Clinical Research Center of Oral Major Diseases and Oral Health and Xiangya Stomatological Hospital, Changsha, China
- *Correspondence: Yanjia Hu, ; Kun Li,
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Wang L, Jin Z, Master RP, Maharjan CK, Carelock ME, Reccoppa TBA, Kim MC, Kolb R, Zhang W. Breast Cancer Stem Cells: Signaling Pathways, Cellular Interactions, and Therapeutic Implications. Cancers (Basel) 2022; 14:3287. [PMID: 35805056 PMCID: PMC9265870 DOI: 10.3390/cancers14133287] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/02/2022] [Accepted: 07/02/2022] [Indexed: 02/01/2023] Open
Abstract
Breast cancer stem cells (BCSCs) constitute a small population of cells within breast cancer and are characterized by their ability to self-renew, differentiate, and recapitulate the heterogeneity of the tumor. Clinically, BCSCs have been correlated with cancer progression, metastasis, relapse, and drug resistance. The tumorigenic roles of BCSCs have been extensively reviewed and will not be the major focus of the current review. Here, we aim to highlight how the crucial intrinsic signaling pathways regulate the fate of BCSCs, including the Wnt, Notch, Hedgehog, and NF-κB signaling pathways, as well as how different cell populations crosstalk with BCSCs within the TME, including adipocytes, endothelial cells, fibroblasts, and immune cells. Based on the molecular and cellular activities of BCSCs, we will also summarize the targeting strategies for BCSCs and related clinical trials. This review will highlight that BCSC development in breast cancer is impacted by both BCSC endogenous signaling and external factors in the TME, which provides an insight into how to establish a comprehensively therapeutic strategy to target BCSCs for breast cancer treatments.
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Affiliation(s)
- Lei Wang
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
- Immunology Concentration, Biomedical Graduate Program, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Zeng Jin
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
- Cancer Biology Concentration, Biomedical Graduate Program, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Rohan P. Master
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
| | - Chandra K. Maharjan
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
| | - Madison E. Carelock
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
- Cancer Biology Concentration, Biomedical Graduate Program, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Tiffany B. A. Reccoppa
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
- Department of Biology, College of Liberal Arts & Sciences, University of Florida, Gainesville, FL 32610, USA
| | - Myung-Chul Kim
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
| | - Ryan Kolb
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
- UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA
| | - Weizhou Zhang
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
- UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA
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Sukocheva OA, Lukina E, Friedemann M, Menschikowski M, Hagelgans A, Aliev G. The crucial role of epigenetic regulation in breast cancer anti-estrogen resistance: Current findings and future perspectives. Semin Cancer Biol 2022; 82:35-59. [PMID: 33301860 DOI: 10.1016/j.semcancer.2020.12.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 10/22/2020] [Accepted: 12/03/2020] [Indexed: 02/07/2023]
Abstract
Breast cancer (BC) cell de-sensitization to Tamoxifen (TAM) or other selective estrogen receptor (ER) modulators (SERM) is a complex process associated with BC heterogeneity and the transformation of ER signalling. The most influential resistance-related mechanisms include modifications in ER expression and gene regulation patterns. During TAM/SERM treatment, epigenetic mechanisms can effectively silence ER expression and facilitate the development of endocrine resistance. ER status is efficiently regulated by specific epigenetic tools including hypermethylation of CpG islands within ER promoters, increased histone deacetylase activity in the ER promoter, and/or translational repression by miRNAs. Over-methylation of the ER α gene (ESR1) promoter by DNA methyltransferases was associated with poor prognosis and indicated the development of resistance. Moreover, BC progression and spreading were marked by transformed chromatin remodelling, post-translational histone modifications, and expression of specific miRNAs and/or long non-coding RNAs. Therefore, targeted inhibition of histone acetyltransferases (e.g. MYST3), deacetylases (e.g. HDAC1), and/or demethylases (e.g. lysine-specific demethylase LSD1) was shown to recover and increase BC sensitivity to anti-estrogens. Indicated as a powerful molecular instrument, the administration of epigenetic drugs can regain ER expression along with the activation of tumour suppressor genes, which can in turn prevent selection of resistant cells and cancer stem cell survival. This review examines recent advances in the epigenetic regulation of endocrine drug resistance and evaluates novel anti-resistance strategies. Underlying molecular mechanisms of epigenetic regulation will be discussed, emphasising the utilization of epigenetic enzymes and their inhibitors to re-program irresponsive BCs.
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Affiliation(s)
- Olga A Sukocheva
- Discipline of Health Sciences, College of Nursing and Health Sciences, Flinders University, Bedford Park, South Australia, 5042, Australia.
| | - Elena Lukina
- Discipline of Biology, College of Sciences, Flinders University, Bedford Park, South Australia, 5042, Australia
| | - Markus Friedemann
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital `Carl Gustav Carus`, Technical University of Dresden, Dresden 01307, Germany
| | - Mario Menschikowski
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital `Carl Gustav Carus`, Technical University of Dresden, Dresden 01307, Germany
| | - Albert Hagelgans
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital `Carl Gustav Carus`, Technical University of Dresden, Dresden 01307, Germany
| | - Gjumrakch Aliev
- Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Russia; Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, 142432, Russia; Federal State Budgetary Institution «Research Institute of Human Morphology», 3, Tsyurupy Str., Moscow, 117418, Russian Federation; GALLY International Research Institute, San Antonio, TX, 78229, USA.
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10
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Karami Fath M, Azargoonjahromi A, Kiani A, Jalalifar F, Osati P, Akbari Oryani M, Shakeri F, Nasirzadeh F, Khalesi B, Nabi-Afjadi M, Zalpoor H, Mard-Soltani M, Payandeh Z. The role of epigenetic modifications in drug resistance and treatment of breast cancer. Cell Mol Biol Lett 2022; 27:52. [PMID: 35764927 PMCID: PMC9238060 DOI: 10.1186/s11658-022-00344-6] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 05/24/2022] [Indexed: 02/08/2023] Open
Abstract
Background Breast cancer is defined as a biological and molecular heterogeneous disorder that originates from breast cells. Genetic predisposition is the most important factor giving rise to this malignancy. The most notable mutations in breast cancer occur in the BRCA1 and BRCA2 genes. Owing to disease heterogeneity, lack of therapeutic target, anti-cancer drug resistance, residual disease, and recurrence, researchers are faced with challenges in developing strategies to treat patients with breast cancer. Results It has recently been reported that epigenetic processes such as DNA methylation and histone modification, as well as microRNAs (miRNAs), have potently contributed to the pathophysiology, diagnosis, and treatment of breast cancer. These observations have persuaded researchers to move their therapeutic approaches beyond the genetic framework toward the epigenetic concept. Conclusion Herein we discuss the molecular and epigenetic mechanisms underlying breast cancer progression and resistance as well as various aspects of epigenetic-based therapies as monotherapy and combined with immunotherapy.
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Affiliation(s)
- Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | | | - Arash Kiani
- Student Research Committee, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Fateme Jalalifar
- School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Parisa Osati
- Chemical Engineering Department, Fouman Faculty of Engineering, College of Engineering, University of Tehran, Fouman, Iran
| | - Mahsa Akbari Oryani
- Department of Pathology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fateh Shakeri
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Farhad Nasirzadeh
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Behman Khalesi
- Department of Research and Production of Poultry Viral Vaccine, Razi Vaccine and Serum Research Institute, Agricultural Research Education and Extension Organization, Karaj, Iran
| | - Mohsen Nabi-Afjadi
- Department of Biochemistry, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran
| | - Hamidreza Zalpoor
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Maysam Mard-Soltani
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Dezful University of Medical Sciences, Dezful, Iran.
| | - Zahra Payandeh
- Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden.
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11
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Non-Coding RNAs in the Crosstalk between Breast Cancer Cells and Tumor-Associated Macrophages. Noncoding RNA 2022; 8:ncrna8010016. [PMID: 35202089 PMCID: PMC8874851 DOI: 10.3390/ncrna8010016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/19/2022] [Accepted: 02/01/2022] [Indexed: 11/17/2022] Open
Abstract
Non-coding RNAs (ncRNAs) play a pivotal role in regulating the tumor microenvironment (TME) by controlling gene expression at multiple levels. In tumors, ncRNAs can mediate the crosstalk between cancer cells and other cells in the TME, such as immune cells, stromal cells, and endothelial cells, influencing tumor development and progression. Tumor-associated macrophages (TAMs) are among the most abundant inflammatory cells infiltrating solid cancers that promote tumorigenesis, and their infiltration correlates with a poor prognosis in many tumors. Cancer cells produce different ncRNAs that orchestrate TAM recruitment and polarization toward a tumor-promoting phenotype. Tumor-reprogrammed macrophages shape the TME by promoting angiogenesis and tissue remodeling, and suppressing the anti-tumor activity of adaptive immune cells. TAMs can also produce ncRNA molecules that boost cancer cell proliferation and direct their phenotype and metabolic changes facilitating cancer progression and metastasis. This review will focus on the crosstalk between cancer cells and TAMs mediated by microRNAs and long non-coding RNAs during breast cancer (BC) initiation and progression.
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12
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Watson KL, Yi R, Moorehead RA. Transgenic overexpression of the miR-200b/200a/429 cluster inhibits mammary tumor initiation. Transl Oncol 2021; 14:101228. [PMID: 34562686 PMCID: PMC8473771 DOI: 10.1016/j.tranon.2021.101228] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 09/15/2021] [Indexed: 12/24/2022] Open
Abstract
The miR-200 family consists of five members expressed as two clusters: miR-200c/141 cluster and miR-200b/200a/429 cluster. In the mammary gland, miR-200s maintain epithelial identity by decreasing the expression of mesenchymal markers leading to high expression of epithelial markers. While the loss of miR-200s is associated with breast cancer growth and metastasis the impact of miR-200 expression on mammary tumor initiation has not been investigated. Using mammary specific expression of the miR-200b/200a/429 cluster in transgenic mice, we found that elevated expression miR-200s could almost completely prevent mammary tumor development. Only 1 of 16 MTB-IGFIRba429 transgenic mice (expressing both the IGF-IR and miR-200b/200a/429 transgenes) developed a mammary tumor while 100% of MTB-IGFIR transgenic mice (expressing only the IGF-IR transgene) developed mammary tumors. RNA sequencing, qRT-PCR, and immunohistochemistry of mammary tissue from 55-day old mice found Spp1, Saa1, and Saa2 to be elevated in mammary tumors and inhibited by miR-200b/200a/429 overexpression. This study suggests that miR-200s could be used as a preventative strategy to protect women from developing breast cancer. One concern with this approach is the potential negative impact miR-200 overexpression may have on mammary function. However, transgenic overexpression of miR-200s, on their own, did not significantly impact mammary ductal development indicating the miR-200 overexpression should not significantly impact mammary function. Thus, this study provides the initial foundation for using miR-200s for breast cancer prevention and additional studies should be performed to identify strategies for increasing mammary miR-200 expression and determine whether miR-200s can prevent mammary tumor initiation by other genetic alterations.
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Affiliation(s)
- Katrina L Watson
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
| | - Rui Yi
- Department of Pathology, Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Roger A Moorehead
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada.
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13
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Stojiljković A, Gaschen V, Forterre F, Rytz U, Stoffel MH, Bluteau J. Novel immortalization approach defers senescence of cultured canine adipose-derived mesenchymal stromal cells. GeroScience 2021; 44:1301-1323. [PMID: 34806133 DOI: 10.1007/s11357-021-00488-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 11/08/2021] [Indexed: 01/10/2023] Open
Abstract
In the last decades, the scientific community spared no effort to elucidate the therapeutic potential of mesenchymal stromal cells (MSCs). Unfortunately, in vitro cellular senescence occurring along with a loss of proliferative capacity is a major drawback in view of future therapeutic applications of these cells in the field of regenerative medicine. Even though insight into the mechanisms of replicative senescence in human medicine has evolved dramatically, knowledge about replicative senescence of canine MSCs is still scarce. Thus, we developed a high-content analysis workflow to simultaneously investigate three important characteristics of senescence in canine adipose-derived MSCs (cAD-MSCs): morphological changes, activation of the cell cycle arrest machinery, and increased activity of the senescence-associated β-galactosidase. We took advantage of this tool to demonstrate that passaging of cAD-MSCs results in the appearance of a senescence phenotype and proliferation arrest. This was partially prevented upon immortalization of these cells using a newly designed PiggyBac™ Transposon System, which allows for the expression of the human polycomb ring finger proto-oncogene BMI1 and the human telomerase reverse transcriptase under the same promotor. Our results indicate that cAD-MSCs immortalized with this new vector maintain their proliferation capacity and differentiation potential for a longer time than untreated cAD-MSCs. This study not only offers a workflow to investigate replicative senescence in eukaryotic cells with a high-content analysis approach but also paves the way for a rapid and effective generation of immortalized MSC lines. This promotes a better understanding of these cells in view of future applications in regenerative medicine.
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Affiliation(s)
- Ana Stojiljković
- Division of Veterinary Anatomy, Vetsuisse Faculty, University of Bern, Bern, Switzerland. .,Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
| | - Véronique Gaschen
- Division of Veterinary Anatomy, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Franck Forterre
- Division of Small Animal Surgery and Orthopaedics, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Ulrich Rytz
- Division of Small Animal Surgery and Orthopaedics, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Michael H Stoffel
- Division of Veterinary Anatomy, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Jasmin Bluteau
- Division of Veterinary Anatomy, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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14
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Huang WC, Chi HC, Tung SL, Chen PM, Shih YC, Huang YC, Chu PY. Identification of the Novel Tumor Suppressor Role of FOCAD/miR-491-5p to Inhibit Cancer Stemness, Drug Resistance and Metastasis via Regulating RABIF/MMP Signaling in Triple Negative Breast Cancer. Cells 2021; 10:2524. [PMID: 34685504 PMCID: PMC8534268 DOI: 10.3390/cells10102524] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 09/19/2021] [Accepted: 09/19/2021] [Indexed: 12/11/2022] Open
Abstract
Triple negative breast cancer (TNBC) possesses poor prognosis mainly due to development of chemoresistance and lack of effective endocrine or targeted therapies. MiR-491-5p has been found to play a tumor suppressor role in many cancers including breast cancer. However, the precise role of miR-491-5p in TNBC has never been elucidated. In this study, we reported the novel tumor suppressor function of FOCAD/miR-491-5p in TNBC. High expression of miR-491-5p was found to be associated with better overall survival in breast cancer patients. We found that miR-491-5p could be an intronic microRNA processed form FOCAD gene. We are the first to demonstrate that both miR-491-5p and FOCAD function as tumor suppressors to inhibit cancer stemness, epithelial-mesenchymal transition, drug resistance, cell migration/invasion, and pulmonary metastasis etc. in TNBC. MiR-491-5p was first reported to directly target Rab interacting factor (RABIF) to downregulate RABIF-mediated TNBC cancer stemness, drug resistance, cell invasion, and pulmonary metastasis via matrix metalloproteinase (MMP) signaling. High expression of RABIF was found to be correlated with poor clinical outcomes of breast cancer and TNBC patients. Our data indicated that miR-491-5p and RABIF are potential prognostic biomarkers and targeting the novel FOCAD/miR-491-5p/RABIF/MMP signaling pathway could serve as a promising strategy in TNBC treatment.
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Affiliation(s)
- Wei-Chieh Huang
- Graduate Institute of Integrated Medicine, China Medical University, NO91, Hsueh-Shih Road, Taichung 40402, Taiwan; (W.-C.H.); (H.-C.C.); (P.-M.C.); (Y.-C.S.); (Y.-C.H.)
- Chinese Medicine Research Center, China Medical University, NO91, Hsueh-Shih Road, Taichung 40402, Taiwan
| | - Hsiang-Cheng Chi
- Graduate Institute of Integrated Medicine, China Medical University, NO91, Hsueh-Shih Road, Taichung 40402, Taiwan; (W.-C.H.); (H.-C.C.); (P.-M.C.); (Y.-C.S.); (Y.-C.H.)
- Chinese Medicine Research Center, China Medical University, NO91, Hsueh-Shih Road, Taichung 40402, Taiwan
| | - Shiao-Lin Tung
- Department of Hematology and Oncology, Ton-Yen General Hospital, Hsinchu County 30210, Taiwan;
- Department of Nursing, Hsin Sheng Junior College of Medical Care and Management, Taoyuan 33858, Taiwan
| | - Po-Ming Chen
- Graduate Institute of Integrated Medicine, China Medical University, NO91, Hsueh-Shih Road, Taichung 40402, Taiwan; (W.-C.H.); (H.-C.C.); (P.-M.C.); (Y.-C.S.); (Y.-C.H.)
| | - Ya-Chi Shih
- Graduate Institute of Integrated Medicine, China Medical University, NO91, Hsueh-Shih Road, Taichung 40402, Taiwan; (W.-C.H.); (H.-C.C.); (P.-M.C.); (Y.-C.S.); (Y.-C.H.)
| | - Yi-Ching Huang
- Graduate Institute of Integrated Medicine, China Medical University, NO91, Hsueh-Shih Road, Taichung 40402, Taiwan; (W.-C.H.); (H.-C.C.); (P.-M.C.); (Y.-C.S.); (Y.-C.H.)
| | - Pei-Yi Chu
- Graduate Institute of Biomedical Engineering, National Chung Hsing University, Taichung 40402, Taiwan
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei 242, Taiwan
- Department of Pathology, Show Chwan Memorial Hospital, Changhua 500, Taiwan
- Department of Health Food, Chung Chou University of Science and Technology, Changhua 510, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan
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15
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Resistin Induces LIN28A-Mediated Let-7a Repression in Breast Cancer Cells Leading to IL-6 and STAT3 Upregulation. Cancers (Basel) 2021; 13:cancers13184498. [PMID: 34572725 PMCID: PMC8470467 DOI: 10.3390/cancers13184498] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/31/2021] [Accepted: 09/03/2021] [Indexed: 01/20/2023] Open
Abstract
Simple Summary Breast cancer is the second leading cause of cancer-related death in women in the United States and exhibits significant racial disparities in clinical outcomes. Earlier, we reported that the levels of resistin and IL-6 were significantly more elevated in the serum of African American women with breast cancer than in their Caucasian American counterparts. Here, we uncover its mechanistic significance by characterizing a novel resistin/LIN28A/Let-7a/IL-6/STAT3 signaling axis supporting the growth and stemness of breast cancer cells. Abstract Downregulation of the Let-7 family of microRNAs (miRNAs) has been reported in several cancers, including breast malignancy; however, underlying mechanisms are not completely understood. Resistin is an important component of the tumor microenvironment, having a functional impact on the tumor cell phenotypes. Here, we examined the role of resistin in the regulation of Let-7 miRNAs and studied its downstream consequences. We found that resistin treatment led to the reduced expression of Let-7 family miRNAs in breast cancer (BC) cells, with the highest downregulation reported for Let-7a. Furthermore, resistin induced the expression of LIN28A, and its silencing abrogated resistin-mediated Let-7a suppression. Let-7a restoration or LIN28A silencing abolished the resistin-induced growth, clonogenicity, and sphere-forming ability of BC cells. Restoration of Let-7a also suppressed the resistin-induced expression of genes associated with growth, survival, and stemness. Pathway analysis suggested STAT3 as a putative central node associated with Let-7a-mediated gene regulation. In silico analysis identified STAT3 and its upstream modifier, IL-6, as putative Let-7a gene targets, which were later confirmed by 3′UTR-reporter assays. Together, our findings demonstrate a novel resistin/LIN28A/Let-7a/IL-6/STAT3 signaling axis supporting the growth and stemness of BC cells.
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16
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Mizuno M, Khaledian B, Maeda M, Hayashi T, Mizuno S, Munetsuna E, Watanabe T, Kono S, Okada S, Suzuki M, Takao S, Minami H, Asai N, Sugiyama F, Takahashi S, Shimono Y. Adipsin-Dependent Secretion of Hepatocyte Growth Factor Regulates the Adipocyte-Cancer Stem Cell Interaction. Cancers (Basel) 2021; 13:cancers13164238. [PMID: 34439392 PMCID: PMC8393397 DOI: 10.3390/cancers13164238] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/18/2021] [Accepted: 08/19/2021] [Indexed: 01/18/2023] Open
Abstract
Simple Summary Obesity, which is characterized by the excess of adipose tissue, is associated with an increased risk of multiple cancers. We have previously reported that adipsin, a secreted factor from adipocytes, enhances cancer cell proliferation and stem cell properties. In this study, we found that adipsin affected adipocytes themselves and enhanced their secretion of hepatocyte growth factor (HGF). We found that HGF enhanced the adipocyte-cancer cell interactions as a downstream effector of adipsin. Understanding the adipocyte-cancer cell interaction will provide a novel strategy to treat cancers whose initiation, invasion, and metastatic progression are associated with adipose tissues. Abstract Adipose tissue is a component of the tumor microenvironment and is involved in tumor progression. We have previously shown that adipokine adipsin (CFD) functions as an enhancer of tumor proliferation and cancer stem cell (CSC) properties in breast cancers. We established the Cfd-knockout (KO) mice and the mammary adipose tissue-derived stem cells (mADSCs) from them. Cfd-KO in mADSCs significantly reduced their ability to enhance tumorsphere formation of breast cancer patient-derived xenograft (PDX) cells, which was restored by the addition of Cfd in the culture medium. Hepatocyte growth factor (HGF) was expressed and secreted from mADSCs in a Cfd-dependent manner. HGF rescued the reduced ability of Cfd-KO mADSCs to promote tumorsphere formation in vitro and tumor formation in vivo by breast cancer PDX cells. These results suggest that HGF is a downstream effector of Cfd in mADSCs that enhances the CSC properties in breast cancers.
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Affiliation(s)
- Masahiro Mizuno
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake 4701192, Japan or (M.M.); (B.K.); (M.M.); (T.H.); (E.M.); (T.W.)
| | - Behnoush Khaledian
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake 4701192, Japan or (M.M.); (B.K.); (M.M.); (T.H.); (E.M.); (T.W.)
| | - Masao Maeda
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake 4701192, Japan or (M.M.); (B.K.); (M.M.); (T.H.); (E.M.); (T.W.)
- Department of Pathology, Fujita Health University School of Medicine, Toyoake 4701192, Japan;
| | - Takanori Hayashi
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake 4701192, Japan or (M.M.); (B.K.); (M.M.); (T.H.); (E.M.); (T.W.)
| | - Seiya Mizuno
- Laboratory Animal Resource Center, Transborder Medical Research Center, Faculty of Medicine, University of Tsukuba, Tsukuba 3058575, Japan; (S.M.); (F.S.); (S.T.)
| | - Eiji Munetsuna
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake 4701192, Japan or (M.M.); (B.K.); (M.M.); (T.H.); (E.M.); (T.W.)
| | - Takashi Watanabe
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake 4701192, Japan or (M.M.); (B.K.); (M.M.); (T.H.); (E.M.); (T.W.)
| | - Seishi Kono
- Division of Breast and Endocrine Surgery, Kobe University Graduate School of Medicine, Kobe 6500017, Japan; (S.K.); (S.T.)
| | - Seiji Okada
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 8600811, Japan;
| | - Motoshi Suzuki
- Department of Molecular Oncology, Fujita Health University School of Medicine, Toyoake 4701192, Japan;
| | - Shintaro Takao
- Division of Breast and Endocrine Surgery, Kobe University Graduate School of Medicine, Kobe 6500017, Japan; (S.K.); (S.T.)
| | - Hironobu Minami
- Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe 6500017, Japan;
| | - Naoya Asai
- Department of Pathology, Fujita Health University School of Medicine, Toyoake 4701192, Japan;
| | - Fumihiro Sugiyama
- Laboratory Animal Resource Center, Transborder Medical Research Center, Faculty of Medicine, University of Tsukuba, Tsukuba 3058575, Japan; (S.M.); (F.S.); (S.T.)
| | - Satoru Takahashi
- Laboratory Animal Resource Center, Transborder Medical Research Center, Faculty of Medicine, University of Tsukuba, Tsukuba 3058575, Japan; (S.M.); (F.S.); (S.T.)
| | - Yohei Shimono
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake 4701192, Japan or (M.M.); (B.K.); (M.M.); (T.H.); (E.M.); (T.W.)
- Correspondence: ; Tel.: +81-562-932-450
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17
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González-Martínez S, Pérez-Mies B, Pizarro D, Caniego-Casas T, Cortés J, Palacios J. Epithelial Mesenchymal Transition and Immune Response in Metaplastic Breast Carcinoma. Int J Mol Sci 2021; 22:ijms22147398. [PMID: 34299016 PMCID: PMC8306902 DOI: 10.3390/ijms22147398] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/04/2021] [Accepted: 07/07/2021] [Indexed: 01/08/2023] Open
Abstract
Metaplastic breast carcinoma (MBC) is a heterogeneous group of infrequent triple negative (TN) invasive carcinomas with poor prognosis. MBCs have a different clinical behavior from other types of triple negative breast cancer (TNBC), being more resistant to standard chemotherapy. MBCs are an example of tumors with activation of epithelial–mesenchymal transition (EMT). The mechanisms involved in EMT could be responsible for the increase in the infiltrative and metastatic capacity of MBCs and resistance to treatments. In addition, a relationship between EMT and the immune response has been seen in these tumors. In this sense, MBC differ from other TN tumors showing a lower number of tumor-infiltrating lymphocytes (TILS) and a higher percentage of tumor cells expressing programmed death-ligand 1 (PD-L1). A better understanding of the relationship between the immune system and EMT could provide new therapeutic approaches in MBC.
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Affiliation(s)
| | - Belén Pérez-Mies
- Department of Pathology, Hospital Ramón y Cajal, 28034 Madrid, Spain;
- Institute Ramón y Cajal for Health Research (IRYCIS), 28034 Madrid, Spain; (D.P.); (T.C.-C.)
- CIBER-ONC, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Faculty of Medicine, University of Alcalá de Henares, Alcalá de Henares, 28801 Madrid, Spain
| | - David Pizarro
- Institute Ramón y Cajal for Health Research (IRYCIS), 28034 Madrid, Spain; (D.P.); (T.C.-C.)
| | - Tamara Caniego-Casas
- Institute Ramón y Cajal for Health Research (IRYCIS), 28034 Madrid, Spain; (D.P.); (T.C.-C.)
| | - Javier Cortés
- CIBER-ONC, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Faculty of Biomedical and Health Sciences, Department of Medicine, Universidad Europea de Madrid, 28670 Madrid, Spain
- International Breast Cancer Center (IBCC), Quironsalud Group, 08017 Barcelona, Spain
- Medica Scientia Innovation Research, 08007 Barcelona, Spain
- Medica Scientia Innovation Research, Ridgewood, NJ 07450, USA
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain
- Correspondence: (J.C.); (J.P.)
| | - José Palacios
- Department of Pathology, Hospital Ramón y Cajal, 28034 Madrid, Spain;
- Institute Ramón y Cajal for Health Research (IRYCIS), 28034 Madrid, Spain; (D.P.); (T.C.-C.)
- CIBER-ONC, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Faculty of Medicine, University of Alcalá de Henares, Alcalá de Henares, 28801 Madrid, Spain
- Correspondence: (J.C.); (J.P.)
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18
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Wu TY, Leng Q, Tian LQ. The microRNA-210/Casp8ap2 Axis Alleviates Hypoxia-Induced Myocardial Injury by Regulating Apoptosis and Autophagy. Cytogenet Genome Res 2021; 161:132-142. [PMID: 33882492 DOI: 10.1159/000512254] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 10/13/2020] [Indexed: 11/19/2022] Open
Abstract
Coronary heart disease (CHD) is a serious condition comprising atherosclerosis-mediated ischaemic and hypoxic myocardial injury. This study aimed to investigate the mechanism of the miR-210/Casp8ap2 signalling pathway in hypoxic myocardial cells. mRNA and protein expression levels were determined by quantitative real-time PCR and western blotting, respectively. MTT was used to evaluate cell survival, and flow cytometry was used to assess apoptosis and the cell cycle distribution. The interaction between miR-210 and -Casp8ap2 was detected by dual-luciferase reporter assay. As a result, overexpression of miR-210 significantly inhibited apoptosis and reduced the proportion of cells in G1 phase. Moreover, miR-210 suppressed autophagy by upregulating p62 levels and reducing the LC3-II/I ratio in hypoxic cardiomyocytes. miR-210 regulated apoptosis and autophagy by directly targeting Casp8ap2. Furthermore, the expression levels of Casp8ap2, Cleaved caspase 8, Cleaved caspase 3and Beclin-1 were all decreased in response to miR-210. In short, our results suggest that miR-210 exerts anti-apoptotic and anti-autophagic effects in hypoxic cardiomyocytes, which alleviates myocardial injury in response to hypoxia.
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Affiliation(s)
- Ting-Yu Wu
- Department of Geriatrics, Wuhan No.1 Hospital, Wuhan, China
| | - Qin Leng
- Department of Cardiovascular Medicine, Wuhan No.1 Hospital, Wuhan, China
| | - Li-Qun Tian
- Department of Cardiovascular Medicine, Wuhan No.1 Hospital, Wuhan, China
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19
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Song K, Farzaneh M. Signaling pathways governing breast cancer stem cells behavior. Stem Cell Res Ther 2021; 12:245. [PMID: 33863385 PMCID: PMC8052733 DOI: 10.1186/s13287-021-02321-w] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 03/31/2021] [Indexed: 02/06/2023] Open
Abstract
Breast cancer is the second common cancer and the leading cause of malignancy among females overall. Breast cancer stem cells (BCSCs) are a small population of breast cancer cells that play a critical role in the metastasis of breast cancer to other organs in the body. BCSCs have both self-renewal and differentiation capacities, which are thought to contribute to the aggressiveness of metastatic lesions. Therefore, targeting BCSCs can be a suitable approach for the treatment and metastasis of breast cancer. Growing evidence has indicated that the Wnt, NFκB, Notch, BMP2, STAT3, and hedgehog (Hh) signaling pathways govern epithelial-to-mesenchymal transition (EMT) activation, growth, and tumorigenesis of BCSCs in the primary regions. miRNAs as the central regulatory molecules also play critical roles in BCSC self-renewal, metastasis, and drug resistance. Hence, targeting these pathways might be a novel therapeutic approach for breast cancer diagnosis and therapy. This review discusses known signaling mechanisms involved in the stimulation or prevention of BCSC self-renewal, metastasis, and tumorigenesis.
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Affiliation(s)
- Kai Song
- Xuzhou Vocational College of Bioengineering, Xuzhou, 221006, Jiangsu, China.
| | - Maryam Farzaneh
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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20
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Salem S, Mosaad R. Crosstalk between miR-203 and PKCθ regulates breast cancer stem cell markers. Ann Hum Genet 2021; 85:105-114. [PMID: 33576006 DOI: 10.1111/ahg.12415] [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: 06/27/2020] [Revised: 09/25/2020] [Accepted: 01/20/2021] [Indexed: 10/22/2022]
Abstract
INTRODUCTION Protein kinase C theta (PKCθ) is expressed in ER-negative breast cancer and promotes cancer stem cells (CSCs) phenotype. PKCθ gene (PRKCQ) is predicted to be a target for tumor suppressor miR-203. Herein, we aim to validate this prediction and evaluate the ability of miR-203 to inhibit migration of breast cancer cell line enriched with CSCs, MDA-MB-231, via PRKCQ targeting. METHODS Cells were transfected with miR-203 mimic, PRKCQ siRNA and negative control; then real-time PCR, migration assay, western blotting, reporter assay, and chromatin accessibility assay were performed. RESULTS Our findings displayed significant decrease in PRKCQ mRNA level and luciferase signals in cells with restored miR-203 expression, therefore, validated PRKCQ as a direct target of miR-203. Additionally, inhibiting PRKCQ by siRNA led to significant inhibition of miR-203 expression and significant decrease of chromatin accessibility at miR-203 promoter region 466-291 upstream TSS. Both of miR-203 re-expression and PRKCQ suppression resulted in altering migration ability of MDA-MB-231 through regulating AKT pathway and genes involved in breast cancer stem cells, CD44 and ALDH1A3. Expression of CDK5, GIV, and NANOG was significantly downregulated in miR-203 mimic-transfected cells, while PRKCQ siRNA-transfected cells displayed downregulation of OCT3/4, SOX2, and NANOG. Furthermore, we found that miR-224 expression was enhanced while miR-150 was downregulated after ectopic expression of miR-203. CONCLUSION The study highlighted the negative feedback loop between miR-203 and its target PRKCQ and the interplay between them in regulating genes involved in BCSCs. The study also concluded "microRNA-mediated microRNA regulation" as an event in breast cancer cells.
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Affiliation(s)
- Sohair Salem
- Molecular Genetics and Enzymology Department, National Research Centre, Giza, Egypt
| | - Rehab Mosaad
- Molecular Genetics and Enzymology Department, National Research Centre, Giza, Egypt
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21
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Das PK, Siddika MA, Asha SY, Aktar S, Rakib MA, Khanam JA, Pillai S, Islam F. MicroRNAs, a Promising Target for Breast Cancer Stem Cells. Mol Diagn Ther 2021; 24:69-83. [PMID: 31758333 DOI: 10.1007/s40291-019-00439-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Reactivation of the stem cell programme in breast cancer is significantly associated with persistent cancer progression and therapeutic failure. Breast cancer stem cells (BCSCs) are involved in the process of breast cancer initiation, metastasis and cancer relapse. Among the various important cues found in the formation and progression of BCSCs, microRNAs (miRNAs or miRs) play a pivotal role by regulating the expression of various tumour suppressor genes or oncogenes. Accordingly, there is evidence that miRNAs are associated with BCSC self-renewal, differentiation, invasion, metastasis and therapy resistance, and therefore cancer recurrence. miRNAs execute their roles by regulating the expression of stemness markers, activation of signalling pathways or their components and regulation of transcription networks in BCSCs. Therefore, a better understanding of the association between BCSCs and miRNAs has the potential to help design more effective and safer therapeutic solutions against breast cancer. Thus, an miRNA-based therapeutic strategy may open up new horizons for the treatment of breast cancer in the future. In view of this, we present the progress to date of miRNA research associated with stemness marker expression, signalling pathways and activation of transcription networks to regulate the self-renewal, differentiation and therapy resistance properties of BCSCs.
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Affiliation(s)
- Plabon Kumar Das
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, 6205, Bangladesh
| | - Mst Ayesha Siddika
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, 6205, Bangladesh
| | - Saharia Yeasmin Asha
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, 6205, Bangladesh
| | - Suraiya Aktar
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, 6205, Bangladesh
| | - Md Abdur Rakib
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, 6205, Bangladesh
| | - Jahan Ara Khanam
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, 6205, Bangladesh
| | - Suja Pillai
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4029, Australia
| | - Farhadul Islam
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, 6205, Bangladesh. .,Institute for Glycomics, Griffith University, Gold Coast, QLD, 4222, Australia.
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22
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Liang W, Chen X, Zhang S, Fang J, Chen M, Xu Y, Chen X. Mesenchymal stem cells as a double-edged sword in tumor growth: focusing on MSC-derived cytokines. Cell Mol Biol Lett 2021; 26:3. [PMID: 33472580 PMCID: PMC7818947 DOI: 10.1186/s11658-020-00246-5] [Citation(s) in RCA: 99] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 12/27/2020] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSCs) show homing capacity towards tumor sites. Numerous reports indicate that they are involved in multiple tumor-promoting processes through several mechanisms, including immunosuppression; stimulation of angiogenesis; transition to cancer-associated fibroblasts; inhibition of cancer cell apoptosis; induction of epithelial-mesenchymal transition (EMT); and increase metastasis and chemoresistance. However, other studies have shown that MSCs suppress tumor growth by suppressing angiogenesis, incrementing inflammatory infiltration, apoptosis and cell cycle arrest, and inhibiting the AKT and Wnt signaling pathways. In this review, we discuss the supportive and suppressive impacts of MSCs on tumor progression and metastasis. We also discuss MSC-based therapeutic strategies for cancer based on their potential for homing to tumor sites.
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Affiliation(s)
- Wenqing Liang
- Department of Orthopaedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, 355 Xinqiao Road, Dinghai District, Zhoushan, 316000, Zhejiang, People's Republic of China.
| | - Xiaozhen Chen
- College of Medicine, Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Songou Zhang
- College of Medicine, Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Jian Fang
- College of Medicine, Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Meikai Chen
- Department of Orthopaedics, Shaoxing People's Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Yifan Xu
- Department of Orthopaedics, Shaoxing People's Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Xuerong Chen
- Department of Orthopaedics, Shaoxing People's Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
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23
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MicroRNA regulation of cancer stem cells in the pathogenesis of breast cancer. Cancer Cell Int 2021; 21:31. [PMID: 33413418 PMCID: PMC7792222 DOI: 10.1186/s12935-020-01716-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 12/07/2020] [Accepted: 12/16/2020] [Indexed: 02/06/2023] Open
Abstract
Breast cancer is the most common cancer among women and accounts for 30% of all female malignancies worldwide. Breast cancer stem cells (BCSCs) are a small population of breast cancer cells that exhibit multiple characteristics including differentiation capacity, self-renewal and therapeutic resistance. Recently, BCSCs have attracted attention due to their modulation of breast tumor behaviors and drug resistance. miRNAs are small noncoding mRNAs involved in virtually all biological processes, including stem cell development, maintenance and differentiation. In breast cancer, miRNAs appear to be multi-faceted since they can act as either suppressors or oncogenes to regulate breast cancer progression. This review summarizes the critical roles of miRNAs in regulating multiple signaling pathways such as Wnt/β-catenin, Notch, PI3K/AKT/mTOR, BMI-1 and STAT3 that are important for the BCSC maintenance.
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24
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Mendoza-Almanza G, Burciaga-Hernández L, Maldonado V, Melendez-Zajgla J, Olmos J. Role of platelets and breast cancer stem cells in metastasis. World J Stem Cells 2020; 12:1237-1254. [PMID: 33312396 PMCID: PMC7705471 DOI: 10.4252/wjsc.v12.i11.1237] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/23/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
The high mortality rate of breast cancer is mainly caused by the metastatic ability of cancer cells, resistance to chemotherapy and radiotherapy, and tumor regression capacity. In recent years, it has been shown that the presence of breast cancer stem cells is closely associated with the migration and metastatic ability of cancer cells, as well as with their resistance to chemotherapy and radiotherapy. The tumor microenvironment is one of the main molecular factors involved in cancer and metastatic processes development, in this sense it is interesting to study the role of platelets, one of the main communicator cells in the human body which are activated by the signals they receive from the microenvironment and can generate more than one response. Platelets can ingest and release RNA, proteins, cytokines and growth factors. After the platelets interact with the tumor microenvironment, they are called "tumor-educated platelets." Tumor-educated platelets transport material from the tumor microenvironment to sites adjacent to the tumor, thus helping to create microenvironments conducive for the development of primary and metastatic tumors. It has been observed that the clone capable of carrying out the metastatic process is a cancer cell with stem cell characteristics. Cancer stem cells go through a series of processes, including epithelial-mesenchymal transition, intravasation into blood vessels, movement through blood vessels, extravasation at the site of the establishment of a metastatic focus, and site colonization. Tumor-educated platelets support all these processes.
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Affiliation(s)
| | | | - Vilma Maldonado
- Laboratorio de Epigenética, Instituto Nacional de Medicina Genómica, Ciudad de México 14610, Mexico
| | - Jorge Melendez-Zajgla
- Génómica funcional del cáncer, Instituto Nacional de Medicina Genómica, Ciudad de México 14610, Mexico
| | - Jorge Olmos
- Biotecnología Marina, Centro de Investigación Científica y de Estudios Superiores de Ensenada, Ensenada 22860, Mexico
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25
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Yanagi H, Watanabe T, Nishimura T, Hayashi T, Kono S, Tsuchida H, Hirata M, Kijima Y, Takao S, Okada S, Suzuki M, Imaizumi K, Kawada K, Minami H, Gotoh N, Shimono Y. Upregulation of S100A10 in metastasized breast cancer stem cells. Cancer Sci 2020; 111:4359-4370. [PMID: 32976661 PMCID: PMC7734155 DOI: 10.1111/cas.14659] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 09/12/2020] [Accepted: 09/14/2020] [Indexed: 12/24/2022] Open
Abstract
Metastatic progression remains the major cause of death in human breast cancer. Cancer cells with cancer stem cell (CSC) properties drive initiation and growth of metastases at distant sites. We have previously established the breast cancer patient‐derived tumor xenograft (PDX) mouse model in which CSC marker CD44+ cancer cells formed spontaneous microscopic metastases in the liver. In this PDX mouse, the expression levels of S100A10 and its family proteins were much higher in the CD44+ cancer cells metastasized to the liver than those at the primary site. Knockdown of S100A10 in breast cancer cells suppressed and overexpression of S100A10 in breast cancer PDX cells enhanced their invasion abilities and 3D organoid formation capacities in vitro. Mechanistically, S100A10 regulated the matrix metalloproteinase activity and the expression levels of stem cell–related genes. Finally, constitutive knockdown of S100A10 significantly reduced their metastatic ability to the liver in vivo. These findings suggest that S100A10 functions as a metastasis promoter of breast CSCs by conferring both invasion ability and CSC properties in breast cancers.
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Affiliation(s)
- Hisano Yanagi
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Japan.,Department of Medical Oncology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Takashi Watanabe
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Japan
| | - Tatsunori Nishimura
- Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Takanori Hayashi
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Japan
| | - Seishi Kono
- Division of Breast and Endocrine Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hitomi Tsuchida
- Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Munetsugu Hirata
- Department of Breast Surgery, Fujita Health University School of Medicine, Toyoake, Japan
| | - Yuko Kijima
- Department of Breast Surgery, Fujita Health University School of Medicine, Toyoake, Japan
| | - Shintaro Takao
- Division of Breast and Endocrine Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Seiji Okada
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
| | - Motoshi Suzuki
- Department of Molecular Oncology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Kazuyoshi Imaizumi
- Department of Respiratory Medicine, Fujita Health University School of Medicine, Fujita Health University School of Medicine, Toyoake, Japan
| | - Kenji Kawada
- Department of Medical Oncology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Hironobu Minami
- Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Noriko Gotoh
- Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Yohei Shimono
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Japan.,Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.,Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe, Japan
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26
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Ko CCH, Chia WK, Selvarajah GT, Cheah YK, Wong YP, Tan GC. The Role of Breast Cancer Stem Cell-Related Biomarkers as Prognostic Factors. Diagnostics (Basel) 2020; 10:diagnostics10090721. [PMID: 32961774 PMCID: PMC7555329 DOI: 10.3390/diagnostics10090721] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 09/13/2020] [Accepted: 09/16/2020] [Indexed: 02/06/2023] Open
Abstract
Breast cancer is one of the leading causes of cancer-related deaths in women worldwide, and its incidence is on the rise. A small fraction of cancer stem cells was identified within the tumour bulk, which are regarded as cancer-initiating cells, possess self-renewal and propagation potential, and a key driver for tumour heterogeneity and disease progression. Cancer heterogeneity reduces the overall efficacy of chemotherapy and contributes to treatment failure and relapse. The cell-surface and subcellular biomarkers related to breast cancer stem cell (BCSC) phenotypes are increasingly being recognised. These biomarkers are useful for the isolation of BCSCs and can serve as potential therapeutic targets and prognostic tools to monitor treatment responses. Recently, the role of noncoding microRNAs (miRNAs) has extensively been explored as novel biomarker molecules for breast cancer diagnosis and prognosis with high specificity and sensitivity. An in-depth understanding of the biological roles of miRNA in breast carcinogenesis provides insights into the pathways of cancer development and its utility for disease prognostication. This review gives an overview of stem cells, highlights the biomarkers expressed in BCSCs and describes their potential role as prognostic indicators.
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Affiliation(s)
- Clarence Ching Huat Ko
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia; (C.C.H.K.); (W.K.C.)
- Department of Biomedical Science, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Malaysia;
| | - Wai Kit Chia
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia; (C.C.H.K.); (W.K.C.)
| | - Gayathri Thevi Selvarajah
- Department of Veterinary Clinical Studies, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 Serdang, Malaysia;
- Institute of Biosciences, Universiti Putra Malaysia, 43400 UPM, Serdang, Malaysia
| | - Yoke Kqueen Cheah
- Department of Biomedical Science, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Malaysia;
- Institute of Biosciences, Universiti Putra Malaysia, 43400 UPM, Serdang, Malaysia
| | - Yin Ping Wong
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia; (C.C.H.K.); (W.K.C.)
- Correspondence: (Y.P.W.); (G.C.T.); Tel.: +603-91459508 (Y.P.W.); +603-91455362 (G.C.T.)
| | - Geok Chin Tan
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia; (C.C.H.K.); (W.K.C.)
- Correspondence: (Y.P.W.); (G.C.T.); Tel.: +603-91459508 (Y.P.W.); +603-91455362 (G.C.T.)
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27
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Zhao F, Zhong M, Pei W, Tian B, Cai Y. miR-376c-3p modulates the properties of breast cancer stem cells by targeting RAB2A. Exp Ther Med 2020; 20:68. [PMID: 32963598 PMCID: PMC7490793 DOI: 10.3892/etm.2020.9196] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 07/21/2020] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs/miRs) negatively regulate gene expression and participate in various cellular processes. miRNA dysregulation is associated with cancer progression. The present study aimed to identify the miRNAs that participate in breast cancer tumorigenesis and determine the mechanism that underlies this. miRNA microarray data analysis and validation assays indicated that miR-376c-3p was downregulated in breast tumour tissues and breast cancer stem cells (BCSCs) compared with adjacent non-cancerous tissues and MCF-10A cells, respectively. Ras-related protein Rab-2A (RAB2A) was predicted as a target of miR-376c-3p, which was confirmed by conducting further experiments. miR-376c-3p regulated the BCSC population and the expression of stem cell regulatory genes by targeting RAB2A. By performing mammosphere, Cell Counting Kit-8, colony formation and transwell invasion assays, it was demonstrated that miR-376c-3p also inhibited BCSC self-renewal, proliferation and invasion by regulating RAB2A expression. Using a xenograft mouse model, it was revealed that miR-376c-3p overexpression suppressed breast cancer growth in vivo. In conclusion, the results indicated that miR-376c-3p targeted RAB2A to regulate BCSC fate and properties; therefore, miR-376c-3p may serve as a potential therapeutic target for breast cancer.
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Affiliation(s)
- Feng Zhao
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China
| | - Ming Zhong
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China
| | - Wenjiang Pei
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China
| | - Baoxing Tian
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China
| | - Yantao Cai
- Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China
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28
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Shibuya N, Kakeji Y, Shimono Y. MicroRNA-93 targets WASF3 and functions as a metastasis suppressor in breast cancer. Cancer Sci 2020; 111:2093-2103. [PMID: 32307765 PMCID: PMC7293106 DOI: 10.1111/cas.14423] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 03/23/2020] [Accepted: 04/07/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer cells with cancer stem cell (CSC) properties initiate both primary tumor formation and metastases at distant sites. Acquisition of CSC properties is highly associated with epigenetic alterations, including those mediated by microRNAs (miRNAs). We have previously established the breast cancer patient‐derived tumor xenograft (PDX) mouse model in which CSC marker CD44+ cancer cells formed spontaneous microscopic metastases in the liver. In this PDX mouse, we found that the expression levels of 3 miRNAs (miR‐25, miR‐93, and miR‐106b) in the miR‐106b‐25 cluster were much lower in the CD44+ human cancer cells metastasized to the liver than those at the primary site. Constitutive overexpression of miR‐93 suppressed invasive ability and 3D‐organoid formation capacity of breast cancer cells in vitro and significantly suppressed their metastatic ability to the liver in vivo. Wiskott‐Aldrich syndrome protein family member 3 (WASF3), a regulator of both cytoskeleton remodeling and CSC properties, was identified as a functional target of miR‐93: overexpression of miR‐93 reduced the protein level of WASF3 in breast cancer cells and WASF3 rescued the miR‐93‐mediated suppression of breast cancer cell invasion. These findings suggest that miR‐93 functions as a metastasis suppressor by suppressing both invasion ability and CSC properties in breast cancers.
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Affiliation(s)
- Naoki Shibuya
- Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.,Division of Gastrointestinal Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yoshihiro Kakeji
- Division of Gastrointestinal Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yohei Shimono
- Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.,Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Japan
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29
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Senthil Kumar KJ, Gokila Vani M, Hsieh HW, Lin CC, Liao JW, Chueh PJ, Wang SY. MicroRNA-708 activation by glucocorticoid receptor agonists regulate breast cancer tumorigenesis and metastasis via downregulation of NF-κB signaling. Carcinogenesis 2019; 40:335-348. [PMID: 30726934 DOI: 10.1093/carcin/bgz011] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 01/06/2019] [Accepted: 01/22/2019] [Indexed: 02/06/2023] Open
Abstract
Therapeutic administration of glucocorticoids (GCs) is frequently used as add-on chemotherapy for palliative purposes during breast cancer treatment. Recent studies have shown that GC treatment induces microRNA-708 in ovarian cancer cells, resulting in impaired tumor cell proliferation and metastasis. However, the regulatory functions of GCs on miR-708 and its downstream target genes in human breast cancer cells (BCCs) are poorly understood. In this study, we found that treatment with either the synthetic GC dexamethasone (DEX) or the natural GC mimic, antcin A (ATA) significantly increased miR-708 expression by transactivation of glucocorticoid receptor alpha (GRα) in MCF-7 and MDA-MB-231 human BCCs. Induction of miR-708 by GR agonists resulted in inhibition of cell proliferation, cell-cycle progression, cancer stem cell (CSC)-like phenotype and metastasis of BCCs. In addition, GR agonist treatment or miR-708 mimic transfection remarkably inhibited IKKβ expression and suppressed nuclear factor-kappaB (NF-κB) activity and its downstream target genes, including COX-2, cMYC, cyclin D1, Matrix metalloproteinase (MMP)-2, MMP-9, CD24, CD44 and increased p21CIP1 and p27KIP1 that are known to be involved in proliferation, cell-cycle progression, metastasis and CSC marker protein. BCCs xenograft models indicate that treatment with GR agonists significantly reduced tumor growth, weight and volume. Overall, our data strongly suggest that GR agonists induced miR-708 and downstream suppression of NF-κB signaling, which may be applicable as a novel therapeutic intervention in breast cancer treatment.
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Affiliation(s)
- K J Senthil Kumar
- Department of Forestry, National Chung Hsing University, Taichung, Taiwan.,National Chung Hsing University/University of California at Davis, Plant and Food Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
| | - M Gokila Vani
- Department of Forestry, National Chung Hsing University, Taichung, Taiwan.,National Chung Hsing University/University of California at Davis, Plant and Food Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
| | | | | | - Jiunn-Wang Liao
- Graduate Institute of Veterinary Pathology, National Chung Hsing University, Taichung, Taiwan
| | - Pin-Ju Chueh
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.,Department of Biotechnology, Asia University, Taichung, Taiwan
| | - Sheng-Yang Wang
- Department of Forestry, National Chung Hsing University, Taichung, Taiwan.,National Chung Hsing University/University of California at Davis, Plant and Food Biotechnology Center, National Chung Hsing University, Taichung, Taiwan.,Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan
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30
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MicroRNAs Contribute to Breast Cancer Invasiveness. Cells 2019; 8:cells8111361. [PMID: 31683635 PMCID: PMC6912645 DOI: 10.3390/cells8111361] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 10/25/2019] [Accepted: 10/28/2019] [Indexed: 12/24/2022] Open
Abstract
Cancer statistics in 2018 highlight an 8.6 million incidence in female cancers, and 4.2 million cancer deaths globally. Moreover, breast cancer is the most frequent malignancy in females and twenty percent of these develop metastasis. This provides only a small chance for successful therapy, and identification of new molecular markers for the diagnosis and prognostic prediction of metastatic disease and development of innovative therapeutic molecules are therefore urgently required. Differentially expressed microRNAs (miRNAs) in cancers cause multiple changes in the expression of the tumorigenesis-promoting genes which have mostly been investigated in breast cancers. Herein, we summarize recent data on breast cancer-specific miRNA expression profiles and their participation in regulating invasive processes, in association with changes in cytoskeletal structure, cell-cell adhesion junctions, cancer cell-extracellular matrix interactions, tumor microenvironments, epithelial-to-mesenchymal transitions and cancer cell stem abilities. We then focused on the epigenetic regulation of individual miRNAs and their modified interactions with other regulatory genes, and reviewed the function of miRNA isoforms and exosome-mediated miRNA transfer in cancer invasiveness. Although research into miRNA’s function in cancer is still ongoing, results herein contribute to improved metastatic cancer management.
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31
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Nasr MA, Salah RA, Abd Elkodous M, Elshenawy SE, El-Badri N. Dysregulated MicroRNA Fingerprints and Methylation Patterns in Hepatocellular Carcinoma, Cancer Stem Cells, and Mesenchymal Stem Cells. Front Cell Dev Biol 2019; 7:229. [PMID: 31681762 PMCID: PMC6811506 DOI: 10.3389/fcell.2019.00229] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 09/26/2019] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the top causes of cancer mortality worldwide. Although HCC has been researched extensively, there is still a need for novel and effective therapeutic interventions. There is substantial evidence that initiation of carcinogenesis in liver cirrhosis, a leading cause of HCC, is mediated by cancer stem cells (CSCs). CSCs were also shown to be responsible for relapse and chemoresistance in several cancers, including HCC. MicroRNAs (miRNAs) constitute important epigenetic markers that regulate carcinogenesis by acting post-transcriptionally on mRNAs, contributing to the progression of HCC. We have previously shown that co-culture of cancer cells with mesenchymal stem cells (MSCs) could induce the reprogramming of MSCs into CSC-like cells. In this review, we evaluate the available data concerning the epigenetic regulation of miRNAs through methylation and the possible role of this regulation in stem cell and somatic reprogramming in HCC.
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Affiliation(s)
- Mohamed A Nasr
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - Radwa Ayman Salah
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - M Abd Elkodous
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - Shimaa E Elshenawy
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
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32
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Regulation of the Notch-ATM-abl axis by geranylgeranyl diphosphate synthase inhibition. Cell Death Dis 2019; 10:733. [PMID: 31570763 PMCID: PMC6768865 DOI: 10.1038/s41419-019-1973-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 09/09/2019] [Accepted: 09/12/2019] [Indexed: 12/21/2022]
Abstract
Notch proteins drive oncogenesis of many cancers, most prominently T-cell acute lymphoblastic leukemia (T-ALL). Because geranylgeranylated Rab proteins regulate Notch processing, we hypothesized that inhibition of geranylgeranyl diphosphate synthase (GGDPS) would impair Notch processing and reduce viability of T-ALL cells that express Notch. Here, we show that GGDPS inhibition reduces Notch1 expression and impairs the proliferation of T-ALL cells. GGDPS inhibition also reduces Rab7 membrane association and depletes Notch1 mRNA. GGDPS inhibition increases phosphorylation of histone H2A.X, and inhibitors of ataxia telangiectasia-mutated kinase (ATM) mitigate GGDPS inhibitor-induced apoptosis. GGDPS inhibition also influences c-abl activity downstream of caspases, and inhibitors of these enzymes prevent GGDPS inhibitor-induced apoptosis. Surprisingly, induction of apoptosis by GGDPS inhibition is reduced by co-treatment with γ-secretase inhibitors. While inhibitors of γ-secretase deplete one specific form of the Notch1 intracellular domain (NICD), they also increase Notch1 mRNA expression and increase alternate forms of Notch1 protein expression in cells treated with a GGDPS inhibitor. Furthermore, inhibitors of γ-secretase and ATM increase Notch1 mRNA stability independent of GGDPS inhibition. These results provide a model by which T-ALL cells use Notch1 to avoid DNA-damage-induced apoptosis, and can be overcome by inhibition of GGDPS through effects on Notch1 expression and its subsequent response.
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33
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Mukohyama J, Isobe T, Hu Q, Hayashi T, Watanabe T, Maeda M, Yanagi H, Qian X, Yamashita K, Minami H, Mimori K, Sahoo D, Kakeji Y, Suzuki A, Dalerba P, Shimono Y. miR-221 Targets QKI to Enhance the Tumorigenic Capacity of Human Colorectal Cancer Stem Cells. Cancer Res 2019; 79:5151-5158. [PMID: 31416845 DOI: 10.1158/0008-5472.can-18-3544] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Revised: 06/29/2019] [Accepted: 08/07/2019] [Indexed: 12/11/2022]
Abstract
miRNAs are key players in the integrated regulation of cellular processes and shape many of the functional properties that define the "cancer stem cell" (CSC) phenotype. Little is known, however, about miRNAs that regulate such properties in human colorectal carcinoma. In this study, we compared the expression levels of 754 miRNAs between paired samples of EpCAM+/CD44+ cancer cells (enriched in CSCs) and EpCAM+/CD44neg cancer cells (with CSC depletion) sorted in parallel from human primary colorectal carcinomas and identified miR-221 as the miRNA that displayed the highest level of preferential expression in EpCAM+/CD44+ cancer cells. High levels of miR-221 expression were associated with Lgr5+ cells in mouse colon crypts and reduced survival in patients with colorectal carcinoma. Constitutive overexpression of miR-221 enhanced organoid-forming capacity of both conventional colorectal carcinoma cell lines and patient-derived xenografts (PDX) in vitro. Importantly, constitutive downregulation of miR-221 suppressed organoid-forming capacity in vitro and substantially reduced the tumorigenic capacity of CSC populations from PDX lines in vivo. Finally, the most abundant splicing isoform of the human Quaking (QKI) gene, QKI-5, was identified as a functional target of miR-221; overexpression of miR-221-reduced QKI-5 protein levels in human colorectal carcinoma cells. As expected, overexpression of QKI-5 suppressed organoid-forming capacity in vitro and tumorigenic capacity of colorectal carcinoma PDX cells in vivo. Our study reveals a mechanistic link between miR-221 and QKI and highlights their key role in regulating CSC properties in human colorectal cancer. SIGNIFICANCE: These findings uncover molecular mechanisms underlying the maintenance of cancer stem cell properties in colon cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5151/F1.large.jpg.
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Affiliation(s)
- Junko Mukohyama
- Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.,Division of Gastrointestinal Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.,Department of Pathology and Cell Biology, Department of Medicine (Division of Digestive and Liver Diseases), Herbert Irving Comprehensive Cancer Center (HICCC) and Columbia Stem Cell Initiative (CSCI), Columbia University, New York, New York
| | - Taichi Isobe
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California
| | - Qingjiang Hu
- Department of Surgery and Science, Kyushu University Hospital, Fukuoka, Japan.,Department of Surgery, Kyushu University Beppu Hospital, Beppu, Oita, Japan
| | - Takanori Hayashi
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Takashi Watanabe
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Masao Maeda
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Hisano Yanagi
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Xin Qian
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California
| | - Kimihiro Yamashita
- Division of Gastrointestinal Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Hironobu Minami
- Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Koshi Mimori
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Oita, Japan
| | - Debashis Sahoo
- Department of Computer Science and Engineering, Department of Pediatrics, University of California San Diego (UCSD), San Diego, California
| | - Yoshihiro Kakeji
- Division of Gastrointestinal Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Akira Suzuki
- Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Piero Dalerba
- Department of Pathology and Cell Biology, Department of Medicine (Division of Digestive and Liver Diseases), Herbert Irving Comprehensive Cancer Center (HICCC) and Columbia Stem Cell Initiative (CSCI), Columbia University, New York, New York
| | - Yohei Shimono
- Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan. .,Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.,Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
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34
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Cancer stem cell fate determination: a nuclear phenomenon. THE NUCLEUS 2019. [DOI: 10.1007/s13237-019-00281-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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35
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Afshar E, Hashemi-Arabi M, Salami S, Peirouvi T, Pouriran R. Screening of acetaminophen-induced alterations in epithelial-to-mesenchymal transition-related expression of microRNAs in a model of stem-like triple-negative breast cancer cells: The possible functional impacts. Gene 2019; 702:46-55. [PMID: 30898700 DOI: 10.1016/j.gene.2019.02.106] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 02/04/2019] [Accepted: 02/22/2019] [Indexed: 12/21/2022]
Abstract
Current protocols for therapy inefficiently targets triple negative breast cancer and barely eradicate cancer stem cells. Elucidation of the pleiotropic effect of clinically proven therapeutics on cancer cells shed light on novel application of old friends. The pleiotropic effect of acetaminophen (APAP) on breast cancer was previously reported. In a cell model of triple negative breast cancer with stem-like CD44high/CD24low phenotype, we screened the impacts of APAP (1 mM, 72 h) on the Epithelial to mesenchymal transition (EMT)-related expression of miRs. APAP significantly overexpressed hsa-miR-130a-3p, 192-5p, 214-3p, 101-3p, 30d-5p, 10a-5p, 99a-5p, 200c-3p, 143-3p, 30b-5p and let-7f-5p showed significant overexpression, but suppressed the expression of hsa-miR-7-5p, 149-3p, 215, 150-5p, 205-5p, 206, 10b-5p, 20b-5p, 145-5p, 26b-5p, 223-3p, 17-5p, 186-5p, 146a-5p and let-7c. It also altered on the expression of selected EMT-related genes, significantly upregulated the expression of KRT19, AKT2, CD24, and TIMP1; but downregulated the expression of MMP2, ALDH1, MMP9, TWIST, NOTCH1, and AKT1. Such shifts in expression profiles increased the population of the cells with CD44high/CD24high, and CD44low/CD24high phenotypes, significantly reduced the Twist protein and shifted the balance of E-cadherin and Vimentin proteins in favor of differentiation. Treated cells showed a significant reduction of in vitro migration and were significantly chemosensitized to Camptothecin. In conclusion, APAP, at a safe clinical dose, induced a set of targeted alterations in the EMT-related miRs which implicate, even in part, significant mitigation in chemoresistance and in vitro migration. Further studies should also be piloted to elucidate the most crucial miRs and to evaluate its clinical effectiveness.
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Affiliation(s)
- Elham Afshar
- Cell Death and Differentiation Signaling Research Lab, Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Center for Biotechnology, Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad, Telangana, India
| | - Masoud Hashemi-Arabi
- Cell Death and Differentiation Signaling Research Lab, Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; International Branch, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Siamak Salami
- Cell Death and Differentiation Signaling Research Lab, Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Tahmineh Peirouvi
- Department of Histology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Ramin Pouriran
- International Branch, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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36
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Gupta I, Sareyeldin RM, Al-Hashimi I, Al-Thawadi HA, Al Farsi H, Vranic S, Al Moustafa AE. Triple Negative Breast Cancer Profile, from Gene to microRNA, in Relation to Ethnicity. Cancers (Basel) 2019; 11:cancers11030363. [PMID: 30871273 PMCID: PMC6468678 DOI: 10.3390/cancers11030363] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 03/01/2019] [Accepted: 03/06/2019] [Indexed: 12/15/2022] Open
Abstract
Breast cancer is the most frequent cause of cancer-related deaths among women worldwide. It is classified into four major molecular subtypes. Triple-negative breast cancers (TNBCs), a subgroup of breast cancer, are defined by the absence of estrogen and progesterone receptors and the lack of HER-2 expression; this subgroup accounts for ~15% of all breast cancers and exhibits the most aggressive metastatic behavior. Currently, very limited targeted therapies exist for the treatment of patients with TNBCs. On the other hand, it is important to highlight that knowledge of the molecular biology of breast cancer has recently changed the decision-making process regarding the course of cancer therapies. Thus, a number of new techniques, such as gene profiling and sequencing, proteomics, and microRNA analysis have been used to explore human breast carcinogenesis and metastasis including TNBC, which consequently could lead to new therapies. Nevertheless, based on evidence thus far, genomics profiles (gene and miRNA) can differ from one geographic location to another as well as in different ethnic groups. This review provides a comprehensive and updated information on the genomics profile alterations associated with TNBC pathogenesis associated with different ethnic backgrounds.
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Affiliation(s)
- Ishita Gupta
- College of Medicine, Qatar University, Doha P. O. Box:2713, Qatar.
| | | | - Israa Al-Hashimi
- College of Medicine, Qatar University, Doha P. O. Box:2713, Qatar.
| | | | - Halema Al Farsi
- College of Medicine, Qatar University, Doha P. O. Box:2713, Qatar.
| | - Semir Vranic
- College of Medicine, Qatar University, Doha P. O. Box:2713, Qatar.
| | - Ala-Eddin Al Moustafa
- College of Medicine, Qatar University, Doha P. O. Box:2713, Qatar.
- Biomedical Research Centre, Qatar University, Doha P.O Box: 2713, Qatar.
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37
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Kim S, Trudo SP, Gallaher DD. Apiaceous and Cruciferous Vegetables Fed During the Post-Initiation Stage Reduce Colon Cancer Risk Markers in Rats. J Nutr 2019; 149:249-257. [PMID: 30649390 DOI: 10.1093/jn/nxy257] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 07/20/2018] [Accepted: 09/13/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Vegetable consumption reduces colon cancer risk when fed in the initiation stage of carcinogenesis; however, the effect of vegetable consumption during the post-initiation stage has rarely been examined. OBJECTIVE We investigated the chemopreventive effects of feeding apiaceous and cruciferous vegetables on colon cancer risk in the post-initiation stage. METHODS Thirty male Wistar rats (∼5 wk, 92 g) were subcutaneously injected with 1,2-dimethylhydrazine 1 time/wk for 2 wk. One week after the last dose, rats were randomly assigned to 3 groups: the basal diet, an apiaceous vegetable-containing diet (API; 21% fresh wt/wt), or a cruciferous vegetable-containing diet (CRU; 21% fresh wt/wt). All diets contained ∼20% protein, 7% fat, and 63% digestible carbohydrate. Experimental diets were fed for 10 wk, after which colons were harvested. RESULTS CRU reduced aberrant crypt foci (ACF) number compared to the basal group (P = 0.014) and API (P = 0.013), whereas API decreased the proportion of dysplastic ACF relative to the basal group (P < 0.05). Both CRU and API reduced doublecortin-like kinase 1-positive marker expression relative to basal by 57.9% (P = 0.009) and 51.4% (P < 0.02). The numbers of CD44-positive ACF did not differ between the groups. We identified 14 differentially expressed microRNAs (miRNAs). Of these, expression of 6 miRNAs were greater or tended to be greater (P ≤ 0.10) in one or both vegetable-containing groups compared to the basal group. Bioinformatic analysis of these expression changes in miRNA predicted a change in WNT/β-catenin signaling, indicating downregulation of β-catenin in the vegetable-fed groups. Consistent with this bioinformatics analysis, β-catenin-accumulated ACF were decreased in CRU (93.1%, P = 0.012), but not in API (54.4%, P = 0.125), compared to the basal group. CONCLUSION Both apiaceous and cruciferous vegetables, fed post-initiation, reduce colonic preneoplastic lesions as well as cancer stem cell marker expression in rats, possibly by suppressing oncogenic signaling through changes in miRNA expression.
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Affiliation(s)
- Sangyub Kim
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN
| | - Sabrina P Trudo
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN.,School of Human Environmental Sciences, University of Arkansas, Fayetteville, AR
| | - Daniel D Gallaher
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN
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38
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Xiong Y, Gu Y, Wang F, Li L, Zhu M, Wang N, Mi H, Qiu X. LINC01857 as an oncogene regulates CREB1 activation by interacting with CREBBP in breast cancer. J Cell Physiol 2019; 234:14031-14039. [PMID: 30628071 DOI: 10.1002/jcp.28090] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 12/07/2018] [Indexed: 12/29/2022]
Abstract
Breast cancer is a one of the most malignant threats among women worldwide. However, the mechanism underlying breast cancer development remains unclear. Long noncoding RNAs (lncRNAs) have been reported to participate in breast cancer. Whether lncRNA LINC01857 is involved in breast cancer requires investigation. In this study, we found that LINC01857 was highly expressed in breast cancer tissues and cells (p < 0.05). High LINC01857 expression predicted poor prognosis in breast cancer patients. Functionally, LINC01857 silencing impaired proliferation and enhanced apoptosis of breast cancer cells ( p < 0.05). Decreased LINC01857 inhibited breast cancer cells migration and invasion ability ( p < 0.05). In terms of mechanism, LINC01857 promoted H3K27Ac deposition on CREB1 promoter and initiated its transcription by recruiting CREBBP. Overexpression of CREB1 reversed the biological behavior of breast cancer cells induced by LINC01857 silencing ( p < 0.05). Taken together, our findings demonstrated that LINC01857 promoted breast cancer development by promoting H3K27Ac and CREB1 transcription via enhancing CREBBP enrichment in the CREB1 promoter region.
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Affiliation(s)
- Youyi Xiong
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuanting Gu
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Fang Wang
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lin Li
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mingzhi Zhu
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Nan Wang
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hailong Mi
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xinguang Qiu
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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39
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Shimono Y, Mukohyama J, Isobe T, Johnston DM, Dalerba P, Suzuki A. Organoid Culture of Human Cancer Stem Cells. Methods Mol Biol 2019; 1576:23-31. [PMID: 27654995 DOI: 10.1007/7651_2016_13] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Organoid culture is a three-dimensional culture method that enables ex vivo analysis of stem cell behavior and differentiation. This method is also applicable to the studies on stem cell characters of human cancer stem cells. The components of organoid culture include Matrigel® and a culture medium containing growth factor cocktails that mimic the microenvironments of organ stem cell niches. Here, we describe the basic methods for the organoid culture of dissociated or FACS-sorted human cancer stem cells. Then, we introduce a method to dissociate the organoids for serial passage and propagation.
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Affiliation(s)
- Yohei Shimono
- Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
| | - Junko Mukohyama
- Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Taichi Isobe
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA
| | - Darius M Johnston
- Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA
| | - Piero Dalerba
- Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
| | - Akira Suzuki
- Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
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40
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Jia B, Liu W, Gu J, Wang J, Lv W, Zhang W, Hao Q, Pang Z, Mu N, Zhang W, Guo Q. MiR-7-5p suppresses stemness and enhances temozolomide sensitivity of drug-resistant glioblastoma cells by targeting Yin Yang 1. Exp Cell Res 2018; 375:73-81. [PMID: 30586549 DOI: 10.1016/j.yexcr.2018.12.016] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Revised: 12/10/2018] [Accepted: 12/20/2018] [Indexed: 12/27/2022]
Abstract
Glioblastoma multiforme (GBM) is the most malignant tumor of the central nervous system, and chemoresistance blunts the effect of temozolomide (TMZ) in the treatment of GBM. Clarifying the underlying mechanism of chemoresistance might yield novel strategies to improve the patients' response to chemotherapeutics. Mounting evidence indicates that microRNAs (miRNAs) are involved in chemoresistance and tumorigenesis. At present, miR-7-5p has been recognized as a tumor suppressor involved in multiple cancers. However, the biological effects of miR-7-5p in TMZ resistance have not been illuminated. In this study, we used RNA sequencing and high-throughput screening techniques, which revealed that miR-7-5p is significantly downregulated in TMZ resistant LN229 cells (LN229/TMZ-R) compared to control cells (LN229), and low miR-7-5p expression was correlated with recurrence in GBM patients. Ectopic overexpression of miR-7-5p sensitized LN229/TMZ-R cells to TMZ and suppressed the stemness of glioblastoma stem cells (GSCs). Further experiments demonstrated that miR-7-5p exerts its role by directly targeting the 3'-untranslated region of Yin Yang 1 (YY1). Our findings suggest that combinational use of miR-7-5p and TMZ might be a promising therapeutic strategy to increase the long-term drug response in GBM patients.
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Affiliation(s)
- Bo Jia
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Wei Liu
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Jintao Gu
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Jiancai Wang
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China
| | - Weifeng Lv
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Wangqian Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Qiang Hao
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Zhijun Pang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Nan Mu
- Department of Pathophysiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
| | - Wei Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China.
| | - Qingdong Guo
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
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41
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Zhang Y, Wang G. MicroRNA-183 inhibits A375 human melanoma cell migration and invasion by targeting Ezrin and MMP-9. Oncol Lett 2018; 17:548-554. [PMID: 30655800 DOI: 10.3892/ol.2018.9603] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 06/28/2018] [Indexed: 12/13/2022] Open
Abstract
To assess the influence of microRNA-183 (miR-183) on the migration and invasion of A375 human melanoma cells, an A375 cell line with stable miR-183 overexpression or knockdown was constructed using lentiviral transfection. The change of miR-183 expression in these cells and in non-transfected controls was verified using reverse transcription-quantitative polymerase chain reaction. The impact of miR-183 on experimental A375 cell migration and invasion was assessed using a scratch and Transwell assay. The expression of Ezrin and matrix metalloprotease-9 (MMP-9), which are two mediator proteins that serve roles in tumor cell migration and invasion, were analyzed in each cell group via western blotting. The results of the present study indicated that miR-183 overexpression significantly inhibits A375 cell migration and invasion, which may be facilitated by miR-183 knockdown. Furthermore, Ezrin and MMP-9 protein levels were negatively associated with miR-183 expression, indicating that miR-183 may function as a tumor suppressor by inhibiting the expression of these two proteins. Additionally, miR-183 downregulation may be associated with the progression of melanoma.
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Affiliation(s)
- Yusen Zhang
- Department of Plastic Surgery, People's Hospital of Zhengzhou, Henan Agricultural University, Zhengzhou, Henan 450000, P.R. China
| | - Guoqiang Wang
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture, Henan Agricultural University, Zhengzhou, Henan 450000, P.R. China
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Troschel FM, Böhly N, Borrmann K, Braun T, Schwickert A, Kiesel L, Eich HT, Götte M, Greve B. miR-142-3p attenuates breast cancer stem cell characteristics and decreases radioresistance in vitro. Tumour Biol 2018; 40:1010428318791887. [PMID: 30091683 DOI: 10.1177/1010428318791887] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Effectively targeting cancer stem cells, a subpopulation of tumorigenic, aggressive, and radioresistant cells, holds therapeutic promise. However, the effects of the microRNA miR-142-3p, a small endogenous regulator of gene expression on breast cancer stem cells, have not been investigated. This study identifies the influence of miR-142-3p on mammary stemness properties and breast cancer radioresistance to establish its role in this setting. miR-142-3p precursor transfection was performed in MDA-MB-468, HCC1806, and MCF-7 cells, and stem cell markers CD44, CD133, ALDH1 activity and mammosphere formation were measured. β-catenin, the canonical wnt signaling effector protein, was quantified by Western blots and cell fluorescence assays both in miR-142-3p-overexpressing and anti-miR-142-3p-treated cells. Radiation response was investigated by colony formation assays. Levels of BRCA1, BRCA2, and Bod1 in miR-142-3p-overexpressing cells as well as expression of miR-142-3p, Bod1, KLF4, and Oct4 in sorted CD44+/CD24-/low cells were determined by quantitative polymerase chain reaction. miR-142-3p overexpression resulted in a strong decline in breast cancer stem cell characteristics with a decrease in CD44, CD133, ALDH1, Bod1, BRCA2, and mammosphere formation as well as reduced survival after irradiation. miR-142-3p expression was strongly reduced in sorted CD44+/CD24-/low stem cells, while Bod1, Oct4, and KLF4 were overexpressed. β-catenin levels strongly decreased after miR-142-3p overexpression, but not after anti-miR-142-3p treatment. We conclude that miR-142-3p downregulates cancer stem cell characteristics and radioresistance in breast cancer, mediated by a reduced role of β-catenin in miR-142-3p-overexpressing cells. miR-142-3p might therefore help to target cancer stem cells.
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Affiliation(s)
- Fabian M Troschel
- 1 Department of Radiation Therapy-Radiation Oncology, University Hospital Münster, Münster, Germany
| | - Nicolas Böhly
- 1 Department of Radiation Therapy-Radiation Oncology, University Hospital Münster, Münster, Germany
| | - Katrin Borrmann
- 1 Department of Radiation Therapy-Radiation Oncology, University Hospital Münster, Münster, Germany
| | - Timo Braun
- 1 Department of Radiation Therapy-Radiation Oncology, University Hospital Münster, Münster, Germany
| | - Alexander Schwickert
- 2 Department of Gynecology and Obstetrics, University Hospital Münster, Münster, Germany
| | - Ludwig Kiesel
- 2 Department of Gynecology and Obstetrics, University Hospital Münster, Münster, Germany
| | - Hans Theodor Eich
- 1 Department of Radiation Therapy-Radiation Oncology, University Hospital Münster, Münster, Germany
| | - Martin Götte
- 2 Department of Gynecology and Obstetrics, University Hospital Münster, Münster, Germany
| | - Burkhard Greve
- 1 Department of Radiation Therapy-Radiation Oncology, University Hospital Münster, Münster, Germany
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Zhang Y, Xu B, Zhang XP. Effects of miRNAs on functions of breast cancer stem cells and treatment of breast cancer. Onco Targets Ther 2018; 11:4263-4270. [PMID: 30100733 PMCID: PMC6065473 DOI: 10.2147/ott.s165156] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Breast cancer is one of the most common malignancies for women, which accounts for 30% of all female malignancies. The formation of breast cancer stem cells (BCSCs) is attributed to the acquisition of stemness of tumor cells. With self-renewal potential, these stem cells are insensitive to either radiotherapy or chemotherapy but are significant in regulating tumor behaviors and drug resistance. MicroRNA (miRNA) is a kind of noncoding small RNA for negatively regulating gene expressions. Research findings suggest that many miRNAs specifically regulate the expression of target genes and signal pathways of BCSCs. They play an important role in self-renewal, growth, and metastasis of breast cancer cells as potential targets for treating breast cancer. These signal pathways include phosphatase and tensin homolog deleted on chromosome 10-phosphatidylinositol 3-kinase/Akt, Wnt/β-catenin, Notch, and so on. This paper reviews the progress of research about miRNAs in self-renewal, metastasis, epithelial-mesenchymal transition and metastasis, mediation of resistance to chemotherapies, and treatment of breast cancer.
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Affiliation(s)
- Ying Zhang
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Bin Xu
- Department of Surgery, Zhejiang Rehabilitation Medical Center, Hangzhou, China
| | - Xi-Ping Zhang
- Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province, China,
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miR-140-5p inhibits the proliferation and enhances the efficacy of doxorubicin to breast cancer stem cells by targeting Wnt1. Cancer Gene Ther 2018; 26:74-82. [PMID: 30032164 DOI: 10.1038/s41417-018-0035-0] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 05/16/2018] [Accepted: 05/25/2018] [Indexed: 02/06/2023]
Abstract
MicroRNAs (miRNAs) are a group of small non-coding single-stranded RNAs molecules, the dysregulation of which plays a critical role in the initiation and biological progression of malignancies. The current study demonstrated that miR-140-5p was frequently downregulated in breast cancer stem cells (BCSCs), and miR-140-5p mimics could inhibit the proliferation of BCSCs. Moreover, Wnt1 was a direct target of miR-140-5p, as was proved by luciferase reporter assays. miR-140-5p mimics could downregulate the wnt1 mRNA and protein levels in MCF-7 and MDA-MB-231 cells. Furthermore, miR-140 mimics could enhance the sensitivity of BCSCs to doxorubicin (Dox) through the Wnt1/ABCB1 pathway both in vitro and vivo. Our findings have presented a novel miRNA-mediated regulatory network for BCSCs, which may provide a potential therapeutic target for breast cancer.
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Gao W, Hua J, Jia Z, Ding J, Han Z, Dong Y, Lin Q, Yao Y. Expression of miR-146a-5p in breast cancer and its role in proliferation of breast cancer cells. Oncol Lett 2018; 15:9884-9888. [PMID: 29928360 PMCID: PMC6004703 DOI: 10.3892/ol.2018.8589] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 03/07/2018] [Indexed: 12/16/2022] Open
Abstract
In the present study, the expression level of microRNA-146a-5p (miR-146a-5p) in breast cancer tissue and cell lines was investigated and its effects on proliferation of breast cancer cells. miR-146a-5p expression was detected by reverse transcription-quantitative polymerase chain reaction in breast cancer tissues, paraneoplastic tissue (collected by The Department of Oncology of Changhai Hospital from January 2014 to June 2015), breast cancer cell line MCF-7 and normal breast epithelial cell line MCF 10A. Bioinformatics analysis was conducted to forecast target genes of miR-146a-5p, which was further verified by fluorescent reporter gene detection. The results demonstrated the expression level of miR-146a-5p in breast cancer tissue was significantly higher, compared with paraneoplastic tissue (P<0.01), and the expression level of miR-146a-5p in MCF-7 cells was significantly higher, compared with MCF 10A cells (P<0.01). Overexpression of miR-146a-5p in MCF-7 cells can promote the proliferation, and low expression miR-146a-5p in MCF-7 can inhibit the proliferation. BRCA1 was further identified as a target gene of miR-146a-5p by bioinformatics analysis and fluorescent reporter gene detection. It was concluded that miR-146a-5p is expressed in breast cancer tissue and breast cancer cell line and may regulate the proliferation of MCF-7 via BRCA1.
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Affiliation(s)
- Wei Gao
- Department of Radiation Oncology, 9th People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 201999, P.R. China
| | - Jing Hua
- Department of Emergency, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China
| | - Zhaoyang Jia
- Department of Radiation Oncology, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, P.R. China
| | - Jiping Ding
- Department of Radiation Oncology, 9th People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 201999, P.R. China
| | - Zengwei Han
- Department of Radiation Oncology, 9th People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 201999, P.R. China
| | - Yun Dong
- Department of Radiation Oncology, 9th People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 201999, P.R. China
| | - Qing Lin
- Department of Radiation Oncology, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, P.R. China
| | - Yuan Yao
- Department of Radiation Oncology, 9th People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 201999, P.R. China
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Al-Harbi B, Hendrayani SF, Silva G, Aboussekhra A. Let-7b inhibits cancer-promoting effects of breast cancer-associated fibroblasts through IL-8 repression. Oncotarget 2018; 9:17825-17838. [PMID: 29707149 PMCID: PMC5915157 DOI: 10.18632/oncotarget.24895] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Accepted: 02/27/2018] [Indexed: 12/23/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs) are major players in the development and spread of breast carcinomas through non-cell-autonomous signaling. These paracrine effects are under the control of several genes and microRNAs. We present here clear evidence that let-7b, a tumor suppressor microRNA, plays key roles in the persistent activation of breast stromal fibroblasts and their functional interplay with cancer cells. We have first shown that let-7b is down-regulated in CAFs as compared to their corresponding normal adjacent fibroblasts, and transient specific let-7b inhibition permanently activated breast fibroblasts through induction of the IL-6-related positive feedback loop. More importantly, let-7b-deficient cells promoted the epithelial-to-mesenchymal transition process in breast cancer cells in an IL-8-dependent manner, and also enhanced orthotopic tumor growth in vivo. On the other hand, overexpression of let-7b by mimic permanently suppressed breast myofibroblasts through blocking the positive feedback loop, which inhibited their paracrine pro-carcinogenic effects. Furthermore, we have shown that let-7b negatively controls IL-8, which showed higher expression in the majority of CAF cells as compared to their adjacent normal counterparts, indicating that IL-8 plays a major role in the carcinoma/stroma cross-talk. These findings support targeting active stromal fibroblasts through restoration of let-7b/IL-8 expression as a therapeutic option for breast carcinomas.
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Affiliation(s)
- Bothina Al-Harbi
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Siti-Fauziah Hendrayani
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Gabriela Silva
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,Current/Present address: Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal
| | - Abdelilah Aboussekhra
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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Yin Y, Cai J, Meng F, Sui C, Jiang Y. MiR-144 suppresses proliferation, invasion, and migration of breast cancer cells through inhibiting CEP55. Cancer Biol Ther 2018; 19:306-315. [PMID: 29561704 PMCID: PMC5902245 DOI: 10.1080/15384047.2017.1416934] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 12/08/2017] [Accepted: 12/10/2017] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE The study aimed to investigate the molecular mechanism of miR-144 and CEP55 as well as the influence of their interaction on the cell proliferation, migration, invasion, cell cycle and cell apoptosis in breast cancer. METHODS In this study, The Cancer Genome Atlas (TCGA, https://tcga-data.nci.nih.gov/ ) database was used for microarray analysis. The expressions of miR-144 and CEP55 in 40 adjacent tissues and 36 tumor tissues were examined by western blot, qRT-PCR and immunohistochemistry. The target relationship between miR-144 and CEP55 was predicted and confirmed by TargetScan and luciferase reporter assay. The cell proliferation, cell cycle and cell apoptosis in different groups were detected by MTT and flow cytometry assays, while wound healing and transwell assays were used for the cell migration and invasion tests. The regulatory effects of miR-144 and CEP55 on breast tumor were verified through nude mouse model in vivo experiment. RESULTS MiR-144 was down-regulated in breast cancerous tissues and cells, whereas CEP55 expression was up-regulated in breast cancerous tissues. Moreover, there existed a target relationship between miR-144 and CEP55 and negative correlation on their expressions. MiR-144 could down-regulate CEP55 expression, thereby inhibiting proliferation, invasion, migration, retarding cell cycle and accelerating cell apoptosis. MiR-144 could inhibit cell progression through down-regulating CEP55 in vivo. CONCLUSION MiR-144 suppressed cell proliferation, migration, invasion and induced cell cycle arrest and cell apoptosis by repressing CEP55. This might provide a promising therapy for clinical treatment.
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Affiliation(s)
- Yuanqin Yin
- Biotherapy Laboratory, Cancer Institute, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jingjing Cai
- Department of Medicine, General Hospital of Fushun Mining Bureau, Fushun, Liaoning, China
| | - Fandong Meng
- Biotherapy Laboratory, Cancer Institute, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Chengguang Sui
- Biotherapy Laboratory, Cancer Institute, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Youhong Jiang
- Biotherapy Laboratory, Cancer Institute, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
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Çağlar HO, Yılmaz Süslüer S, Kavaklı Ş, Gündüz C, Ertürk B, Özkınay F, Haydaroğlu A. Meme kanseri kök hücrelerinde elajik asit ile indüklenmiş miRNA’ların ifadesi ve elajik asidin apoptoz üzerine etkisi. EGE TIP DERGISI 2018. [DOI: 10.19161/etd.399234] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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49
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Muhammad N, Bhattacharya S, Steele R, Ray RB. Anti-miR-203 suppresses ER-positive breast cancer growth and stemness by targeting SOCS3. Oncotarget 2018; 7:58595-58605. [PMID: 27517632 PMCID: PMC5295456 DOI: 10.18632/oncotarget.11193] [Citation(s) in RCA: 125] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 07/19/2016] [Indexed: 12/21/2022] Open
Abstract
Breast cancer is a major public health problem worldwide in women and existing treatments are not adequately effective for this deadly disease. microRNAs (miRNAs) regulate the expression of many target genes and play pivotal roles in the development, as well as in the suppression of many cancers including breast cancer. We previously observed that miR-203 was highly upregulated in breast cancer tissues and in ER-positive breast cancer cell lines. In our present study, we observed that anti-miR-203 suppresses breast cancer cell proliferation in vitro. Orthotopic implantation of miR-203 depleted MCF-7 cells into nude mice displays smaller tumor growth as compared to control MCF-7 cells. Furthermore, miR-203 expression is significantly higher in ER-positive breast cancer patients as compared to ER-negative patients. We identified suppressor of cytokine signaling 3 (SOCS3) as a direct target of miR-203. Here we observed that miR-203 expression is inversely correlated with SOCS3 expression in ER-positive breast cancer samples. Additionally, we found that anti-miR-203 suppressed the expression of pStat3, pERK and c-Myc in MCF-7 and ZR-75-1 cells. We also demonstrated that anti-miR-203 decreased mammospheres formation and expression of stem cell markers in MCF-7 and ZR-75-1 cells. Taken together, our data suggest that anti-miR-203 has potential as a novel therapeutic strategy in ER-positive breast cancer treatment.
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Affiliation(s)
- Naoshad Muhammad
- Department of Pathology, Saint Louis University, St. Louis, Missouri, USA
| | | | - Robert Steele
- Department of Pathology, Saint Louis University, St. Louis, Missouri, USA
| | - Ratna B Ray
- Department of Pathology, Saint Louis University, St. Louis, Missouri, USA.,Cancer Center, Saint Louis University, St. Louis, Missouri, USA
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Teng Y, Su X, Zhang X, Zhang Y, Li C, Niu W, Liu C, Qu K. miRNA-200a/c as potential biomarker in epithelial ovarian cancer (EOC): evidence based on miRNA meta-signature and clinical investigations. Oncotarget 2018; 7:81621-81633. [PMID: 27835595 PMCID: PMC5348417 DOI: 10.18632/oncotarget.13154] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 10/12/2016] [Indexed: 01/17/2023] Open
Abstract
Extensive effort has been put on miRNA expression signatures in epithelial ovarian cancer (EOC). Unfortunately, consistent conclusion rarely yielded from diverse studies, mainly due to the high inter-lab variability and small sample sizes. To overcome above limitations, an integrated analysis of miRNA expression signature was performed by employing Robust Rank Aggregation (RRA) method. Diagnostic analysis, Kaplan-Meier survival curves and pathway enrichment analysis were used to investigate the clinical values and biological functions of meta-signature miRNAs. A total of 519 EOC and 248 noncancerous samples were included. Seven mostly dysregulated miRNAs were identified by RRA method and two miRNAs (miR-200a-3p and miR-200c-3p) remained statistically significant after Bonferroni-correction. Diagnostic meta-analysis showed reliable diagnostic capacity of miR-200a-3p (with a pooled sensitivity of 0.84 and specificity of 0.83) and miR-200c-3p (with a pooled sensitivity of 0.75 and specificity of 0.66) for EOC. Pathway enrichment analysis and expression correlation analysis suggested miR-200a/c might contribute EOC progression by affecting cellular adhesion process. Kaplan-Meier survival analysis based on two independent cohorts revealed a strong association between miR-200a/c and overall survival in EOC patients. miR-200a/c was identified as the mostly dysregulated miRNAs in EOC and might be novel diagnostic and prognostic biomarkers for patients with EOC.
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Affiliation(s)
- Yue Teng
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Xuan Su
- Department of Head and Neck of Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Xing Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Yan Zhang
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Chen Li
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Wenquan Niu
- State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Chang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Kai Qu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
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