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Full Text (PDF) Published OnlineFirst May 19, 2020; DOI: 10.1158/1541-7786.MCR-19-1229 MOLECULAR CANCER RESEARCH | REVIEW Key Regulatory miRNAs and their Interplay with Mechanosensing and Mechanotransduction Signaling Pathways in Breast Cancer Progression Hamid Najminejad1, Behrouz Farhadihosseinabadi2,3, Mehran Dabaghian4, Asiyeh Dezhkam5, Esmat Rigi Yousofabadi6, Reza Najminejad7, Meghdad Abdollahpour-Alitappeh8, Mohammad Hossein Karimi9, Nader Bagheri10, Motahareh Mahi-Birjand11, Nasrin Ghasemi12, Mahta Mazaheri1, Seyed Mehdi Kalantar13, Alexander Seifalian14, and Mohammad Hasan Sheikhha15 ABSTRACT ◥ According to the WHO, breast cancer is the most common of miRNAs has been well-defined in the cancer process through cancer in women worldwide. Identification of underlying mechan- advances in molecular-based approaches. miRNAs are small isms in breast cancer progression is the main concerns of groups of RNAs (22 nucleotides) that contribute to various researches. The mechanical forces within the tumor microenvi- biological events in cells. The central role of miRNAs in the ronment, in addition to biochemical stimuli such as different regulation of various mediators involved in the mechanotransduc- growth factors and cytokines, activate signaling cascades, resulting tion signaling has been well clarified over the last decade. Unbal- in various changes in cancer cell physiology. Cancer cell prolifer- anced expression of miRNAs is associated with different patho- ation, invasiveness, migration, and, even, resistance to cancer logic conditions. Overexpression and downregulation of certain therapeutic agents are changed due to activation of mechano- miRNAs were found to be along with dysregulation of mechan- transduction signaling. The mechanotransduction signaling is otransduction signaling effectors. This study aimed to critically frequently dysregulated in breast cancer, indicating its important review the role of miRNAs in the regulation of mediators involved role in cancer cell features. So far, a variety of experimental in the mechanosensing pathways and clarify how the cross-talk investigations have been conducted to determine the main reg- between miRNAs and their targets affect the cell behavior and ulators of the mechanotransduction signaling. Currently, the role physiology of breast cancer cells. Introduction stromal cells, and tissue-specific cells. ECM, as a main niche for normal Breast cancer remains one of the most prevalent cancers among and tumor cells, plays an important role in cell hemostasis (8). women in the world. According to the WHO report in 2018, 627,000 Collagens are a major component of ECM. However, other compart- deaths have been reported from breast cancer, accounting for approx- ments, including hyaluronan and proteoglycans, participate in ECM imately 15% of all cancer-related deaths among women (1). The formation (9, 10). It is well-documented that the physical properties of etiology of breast cancer is a complex phenomenon in which many ECM, including stiffness and topologic features, profoundly affect genetic and epigenetic factors are involved (2, 3). As a tumor grows, its cancer stem cell behaviors (11). In the breast tumor microenviron- genetic and epigenetic features alter as a result of microenvironment ment, overexpression of various ECM components increases the changes and, even, therapeutic pressure. Moreover, changes in the stiffness of tumor niche, which alter the biological behaviors of cancer genetic and epigenetic features of cancer cells mutually have an impact cells (12). Breast cancer cells cultured on a stiff substrate showed an on the cancer microenvironment (4–7). The cancer microenviron- increased expression of breast cancer stem cell markers through ment is composed of many players such as extracellular matrix (ECM), activation of the ILK/PI3K/Akt pathway (12). It is also reported that 1Department of Medical Genetics, Faculty of Medicine, Shahid Sadoughi Uni- Sciences, Yazd, Iran. 13Research and Clinical Center for Infertility, Shahid versity of Medical Sciences, Yazd, Iran. 2Hematopoietic Stem Cell Research Sadoughi University of Medical Sciences, Yazd, Iran. 14Nanotechnology & Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3Neuro- Regenerative Medicine Commercialization Centre (Ltd), The London BioScience science Research Center (NRC), Iran University of Medical Sciences, Tehran, Iran. Innovation Centre, London, United Kingdom. 15Genetics and Biotechnology Lab, 4Research and Development Department, Razi Vaccine and serum Research Research and Clinical Center for Infertility, Shahid Sadoughi University of Institute, Agricultural Research Education and Extension Organization (AREEO), Medical Sciences, Yazd, Iran. Karaj, Iran. 5Department of Midwifery, School of Nursing and Midwifery, Iran- Corresponding Authors: Alexander Seifalian, The London BioScience Innova- shahr University of Medical Sciences, Iranshahr, Iran. 6Department of Genetics, tion Centre, 2 Royal College Street, London NW1 0NH, United Kingdom. Iranshahr University of Medical Sciences, Iranshahr, Iran. 7Department of Internal Phone: 4420-7691-1122; E-mail: [email protected]; and Mohammad Hasan Medicine, Faculty of Medicine, Rafsanjan University of Medical Sciences, Raf- Sheikhha, Shahid Sadoughi University of Medical Sciences, No. 2 Bouali Ave, sanjan, Iran. 8Cellular and Molecular Biology Research Center, Larestan Univer- Safayeh, Yazd 8916877391, Iran. Phone: 9835-3824-7085; Fax: 9835-3824-7087; sity of Medical Sciences, Larestan, Iran. 9Transplant Research Center, Shiraz E-mail: [email protected] University of Medical Sciences, Shiraz, Iran. 10Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Mol Cancer Res 2020;18:1113–28 Sciences, Shahrekord, Iran. 11Infectious Disease Research Center, Birjand Uni- doi: 10.1158/1541-7786.MCR-19-1229 versity of Medical Sciences, Birjand, Iran. 12Abortion Research Centre, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Ó2020 American Association for Cancer Research. AACRJournals.org | 1113 Downloaded from mcr.aacrjournals.org on October 2, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst May 19, 2020; DOI: 10.1158/1541-7786.MCR-19-1229 Najminejad et al. the adhesion of breast cancer stem cells to ECM components, such as Interestingly, there is a cross-talk between mechanotransduction hyaluronic acid through CD44, increases the expression of genes and cytokine-induced signaling pathways, leading to modulation of involved in cancer stem cell development and drug resistance, includ- cell behaviors within a tissue (36). Wendt and colleagues reported that ing NANOG/SOX2 and Multi Drug Resistance 1, respectively (13). treatment of MDA-MB-231 breast cancer cells with TGFb significantly Topologic features of ECM also alter the migration of cancer cells so increases the expression of the proline-rich tyrosine kinase 2 (Pyk2) that breast cancer cell invasion is facilitated when the collagen fibers gene (37). Pyk2, as a member of the FAK family, participates in actin radially align relative to tumors (14). These data showed that ECM reorganization (38). Wendt and colleagues showed that TGFb pro- must be considered as an important environmental factor that can motes the expression of Pyk2 through activation of Src and Smad4 affect the biological behaviors of breast cancer cells (Fig. 1.) In addition signaling pathways, leading to epithelial-to-mesenchymal transition to ECM, tumor cells encounter with different mechanical forces that (EMT)-mediated cancer cell invasion (37). It is a clear example of how alter their biological behavior. In recent years, various studies have interactions between mechanical and chemical signals can increase the been carried out to find the effect of different mechanical stresses on invasion of cancer cells. Changes in proliferation and progression of the various characteristics of cancer cells such as proliferation, inva- cancer cells can also occur due to interaction between mechanotrans- siveness, and metastasis (15–17). It is well documented that the duction mediators and oncogenes (39). Qin and colleagues showed mechanical signals possess a pivotal role in the cancer progression, that MDA-MB-231 breast cancer cells under low shear stress exhibit an in which many oncogene signaling pathways interact with those increased cell proliferation through activation of the MAPK/ERK/YAP activated by mechanical forces (18). Therefore, the cytoskeleton signaling (39). contractility of tumor cells by activation of mechanotransduction Angiogenesis is a critical stage in cancer progression. In the cancer pathways in response to the physical stimuli profoundly affect cell microenvironment, vessels have a nonconventional morphology and attachment, cellular shape, cell proliferation, and migration through arrangement with more permeability than normal vasculature (40). various players such as miRNAs (18). There are various reasons that justify this phenomenon. As the tumor miRNAs are a part of the noncoding RNA family, which play a key size increases, the need for the entrance of nutrients is responded by regulatory role in gene expression (19, 20). Currently, the relationship creating new vessels within the tumor microenvironment (41). between dysregulation of miRNAs and different pathogenic condi- Because of various mechanical forces in the tumor area, endothelial tions, especially cancer, has been well established so that the evaluation cells acquire
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