Τίτλος:
Silencing of Profilin-1 suppresses cell adhesion and tumor growth via predicted alterations in integrin and Ca2+ signaling in T24M-based bladder cancer models
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Bladder cancer (BC) is the second most common malignancy of the genitourinary system, characterized by the highest recurrence rate of all cancers. Treatment options are limited; thus a thorough understanding of the underlying molecular mechanisms is needed to guide the discovery of novel therapeutic targets. Profilins are actin binding proteins with attributed pleiotropic functions to cytoskeletal remodeling, cell adhesion, motility, even transcriptional regulation, not fully characterized yet. Earlier studies from our laboratory revealed that decreased tissue levels of Profilin-1 (PFN1) are correlated with BC progression to muscle invasive disease. Herein, we describe a comprehensive analysis of PFN1 silencing via shRNA, in vitro (by employing T24M cells) and in vivo [(with T24M xenografts in non-obese diabetic severe combined immunodeficient mice (NOD/SCID) mice]. A combination of phenotypic and molecular assays, including migration, proliferation, adhesion assays, flow cytometry and total mRNA sequencing, as well as immunohistochemistry for investigation of selected findings in human specimens were applied. A decrease in BC cell adhesion and tumor growth in vivo following PFN downregulation are observed, likely associated with the concomitant downregulation of Fibronectin receptor, Endothelin-1, and Actin polymerization. A decrease in the levels of multiple key members of the non-canonical Wnt/Ca2+ signaling pathway is also detected following PFN1 suppression, providing the groundwork for future studies, addressing the specific role of PFN1 in Ca2+ signaling, particularly in the muscle invasive disease.
Συγγραφείς:
Frantzi, M.
Klimou, Z.
Makridakis, M.
Zoidakis, J.
Latosinska, A.
Borràs, D.M.
Janssen, B.
Giannopoulou, I.
Lygirou, V.
Lazaris, A.C.
Anagnou, N.P.
Mischak, H.
Roubelakis, M.G.
Vlahou, A.
Περιοδικό:
OncoTargets and therapy
Εκδότης:
Impact Journals, LLC
Λέξεις-κλειδιά:
calcium ion; carrier proteins and binding proteins; cyclic AMP responsive element binding protein; endothelin 1; fibronectin receptor; integrin; lentivirus vector; messenger RNA; profilin 1; short hairpin RNA; unclassified drug; Wnt protein; Wnt5b protein; actin; calcium; endothelin 1; PFN1 protein, human; profilin; small interfering RNA; very late activation antigen 5, actin polymerization; adult; aged; animal experiment; animal model; animal tissue; apoptosis; Article; bladder cancer; calcium signaling; cancer inhibition; cell adhesion; cell migration; cell motility; cell proliferation; clinical article; colony formation; computer model; controlled study; down regulation; female; gene silencing; human; human tissue; in vitro study; in vivo study; male; metastasis; middle aged; mouse; nonhuman; prediction; tumor growth; tumor xenograft; animal; bladder; bladder tumor; cell motion; disease exacerbation; drug screening; flow cytometry; genetics; immunohistochemistry; metabolism; muscle tumor; nonobese diabetic mouse; pathology; protein multimerization; RNA interference; SCID mouse; secondary; tumor cell line; Wnt signaling, Actins; Animals; Calcium; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Progression; Down-Regulation; Endothelin-1; Flow Cytometry; Humans; Immunohistochemistry; Integrin alpha5beta1; Male; Mice; Mice, Inbred NOD; Mice, SCID; Muscle Neoplasms; Profilins; Protein Multimerization; RNA Interference; RNA, Small Interfering; Urinary Bladder; Urinary Bladder Neoplasms; Wnt Signaling Pathway; Xenograft Model Antitumor Assays
DOI:
10.18632/oncotarget.12218
