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      MART-10, a newly synthesized vitamin D analog, represses metastatic potential of head and neck squamous carcinoma cells

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          Abstract

          Even with multidisciplinary treatment, the prognosis and quality of life of patients diagnosed with head and neck squamous cell carcinoma (HNSCC) are still not satisfactory. Previously, 19-Nor-2α-(3-hydroxypropyl)-1α,25(OH) 2D 3 (MART-10), the new brand 1α,25(OH) 2D 3 analog, has been demonstrated to be an effective drug to inhibit HNSCC growth in vitro. Since most cancer patients die of metastasis, in this study, the antimetastatic effect of MART-10 on HNSCC was investigated. Our results reveal that both 1α,25(OH) 2D 3 and MART-10 effectively repressed the migration and invasion of HNSCC cells, with MART-10 being much more potent than 1α,25(OH) 2D 3. The antimetastatic effect of 1α,25(OH) 2D 3 and MART-10 was mediated by attenuation of epithelial–mesenchymal transition (EMT), which was supported by the finding that the expression of EMT-inducing transcriptional factors, Sail and Twist, was inhibited by 1α,25(OH) 2D 3 and MART-10. The upregulation of E-cadherin and downregulation of N-cadherin in FaDu cells induced by both drugs further confirmed the repression of EMT. In addition, 1α,25(OH) 2D 3 and MART-10 treatment inhibited intracellular MMP-9 expression and extracellular MMP activity in FaDu cells. Collectively, our results suggest that the less-calcemia 1α,25(OH) 2D 3 analog, MART-10, is a promising drug for HNSCC treatment. Further clinical studies are warranted.

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          Most cited references 31

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          Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer.

          A better understanding of drug resistance mechanisms is required to improve outcomes in patients with pancreatic cancer. Here, we characterized patterns of sensitivity and resistance to three conventional chemotherapeutic agents with divergent mechanisms of action [gemcitabine, 5-fluorouracil (5-FU), and cisplatin] in pancreatic cancer cells. Four (L3.6pl, BxPC-3, CFPAC-1, and SU86.86) were sensitive and five (PANC-1, Hs766T, AsPC-1, MIAPaCa-2, and MPanc96) were resistant to all three agents based on GI(50) (50% growth inhibition). Gene expression profiling and unsupervised hierarchical clustering revealed that the sensitive and resistant cells formed two distinct groups and differed in expression of specific genes, including several features of "epithelial to mesenchymal transition" (EMT). Interestingly, an inverse correlation between E-cadherin and its transcriptional suppressor, Zeb-1, was observed in the gene expression data and was confirmed by real-time PCR. Independent validation experiment using five new pancreatic cancer cell lines confirmed that an inverse correlation between E-cadherin and Zeb-1 correlated closely with resistance to gemcitabine, 5-FU, and cisplatin. Silencing Zeb-1 in the mesenchymal lines not only increased the expression of E-cadherin but also other epithelial markers, such as EVA1 and MAL2, and restored drug sensitivity. Importantly, immunohistochemical analysis of E-cadherin and Zeb-1 in primary tumors confirmed that expression of the two proteins was mutually exclusive (P = 0.012). Therefore, our results suggest that Zeb-1 and other regulators of EMT may maintain drug resistance in human pancreatic cancer cells, and therapeutic strategies to inhibit Zeb-1 and reverse EMT should be evaluated.
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            Mechanisms of motility in metastasizing cells.

            Cell migration and invasion are critical parameters in the metastatic dissemination of cancer cells and the formation of metastasis, the major cause of death in cancer patients. Migratory cancer cells undergo dramatic molecular and cellular changes by remodeling their cell-cell and cell-matrix adhesion and their actin cytoskeleton, molecular processes that involve the activity of various signaling networks. Although in the past years, we have substantially expanded our knowledge on the cellular and molecular processes underlying cell migration and invasion in experimental systems, we still lack a clear understanding of how cancer cells disseminate in metastatic cancer patients. Different types of cancer cell migration seem to exist, including single-cell mesenchymal or amoeboid migration and collective cell migration. In most epithelial cancers, loss of the cell-cell adhesion molecule E-cadherin and gain of mesenchymal markers and promigratory signals underlie the conversion of epithelial, differentiated cells to mesenchymal, migratory, and invasive cells, a process referred to as the epithelial-to-mesenchymal transition. Although solitary migrating epithelial cancer cells have mostly undergone epithelial-to-mesenchymal transition (mesenchymal migration), and sometimes even lose their cell-matrix adhesion (amoeboid migration), collective migration of cancer cells in cell sheets, clusters, or streams is also frequently observed. The molecular mechanisms defining the different modes of cancer cell migration remain in most parts to be delineated. (c)2010 AACR.
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              N-cadherin expression and epithelial-mesenchymal transition in pancreatic carcinoma.

              Loss of intercellular adhesion and increased cell motility promote tumor cell invasion. In the present study, E- and N-cadherin, members of the classical cadherin family, are investigated as inducers of epithelial-to-mesenchymal transition (EMT) that is thought to play a fundamental role during the early steps of invasion and metastasis of carcinomas. Cell growth factors are known to regulate cell adhesion molecules. The purpose of the study presented here was to investigate whether a gain in N-cadherin in pancreatic cancer is involved in the process of metastasis via EMT and whether its expression is affected by growth factors. We immunohistochemically examined the expression of N- and E-cadherins and vimentin, a mesenchymal marker, in pancreatic primary and metastatic tumors. Correlations among the expressions of N-cadherin, transforming growth factor (TGF)beta, and fibroblast growth factor 2 was evaluated in both tumors, and the induction of cadherin and vimentin by growth factors was examined in cultured cell lines. N-cadherin expression was observed in 13 of 30 primary tumors and in 8 of 15 metastatic tumors. N-cadherin expression correlated with neural invasion (P = 0.008), histological type (P = 0.043), fibroblast growth factor expression in primary tumors (P = 0.007), and TGF expression (P = 0.004) and vimentin (P = 0.01) in metastatic tumors. Vimentin, a mesenchymal marker, was observed in a few cancer cells of primary tumor but was substantially expressed in liver metastasis. TGF stimulated N-cadherin and vimentin protein expression and decreased E-cadherin expression of Panc-1 cells with morphological change. This study provided the morphological evidence of EMT in pancreatic carcinoma and revealed that overexpression of N-cadherin is involved in EMT and is affected by growth factors.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2016
                17 June 2016
                : 10
                : 1995-2002
                Affiliations
                [1 ]Department of Otolaryngology – Head and Neck Surgery, Chang Gung Memorial Hospital, Keelung, Taiwan, Republic of China
                [2 ]Department of Oral and Maxillofacial Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan, Republic of China
                [3 ]Department of General Dentistry, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, Republic of China
                [4 ]General Surgery Department, Chang Gung Memorial Hospital, Keelung, Taiwan, Republic of China
                [5 ]Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
                [6 ]Faculty of Pharmaceutical Sciences, Teikyo University, Tokyo, Japan
                [7 ]Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
                [8 ]Endocrine Core Laboratory, Boston University School of Medicine, Boston, MA, USA
                [9 ]Zebrafish Center, Chang Gung Memorial Hospital, Keelung, Taiwan, Republic of China
                Author notes
                Correspondence: Kun-Chun Chiang, General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, 222 Mai-Chin Road, Keelung 204, Taiwan, Republic of China, Email robertviolet6292@ 123456yahoo.com.tw
                [*]

                These authors contributed equally to this work

                Article
                dddt-10-1995
                10.2147/DDDT.S107256
                4918737
                27382252
                © 2016 Yang et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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