title: Latexin is down-regulated in hematopoietic malignancies and restoration of expression inhibits lymphoma growth.
abstract: Latexin is a negative regulator of hematopoietic stem cell number in mice. Its dysregulated expression in other tumors led us to hypothesize that latexin may have tumor suppressor properties in hematological malignancies. We found that latexin was down-regulated in a variety of leukemia and lymphoma cell lines as well as in CD34+ cells from the blood and marrow of patients with these malignancies. 5-aza-2'-deoxycytodine treatment and bisulfite sequencing revealed hypermethylation of latexin promoter in tumor cells. Retrovirus-mediated latexin overexpression in A20 mouse lymphoma cells inhibited their in vitro growth by 16 fold and in vivo tumor volume by 2 fold. Latexin caused growth inhibition of lymphoma cells by significantly increasing apoptosis through the down-regulation of anti-apoptotic genes Bcl-2 and Pim-2. The molecular mechanism underlying latexin-mediated tumor inhibition was not through its canonical carboxypeptidase inhibitor activity. These results are consistent with a tumor suppressor role for latexin and suggest that latexin may have clinical efficacy in the treatment of malignancies.
authors.affiliation: Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Dianna
authors.initials: D
authors.lastname: Howard
authors.forename: Kyle
authors.initials: K
authors.lastname: Rector
authors.forename: Carol
authors.initials: C
authors.lastname: Swiderski
authors.forename: Jason
authors.initials: J
authors.lastname: Brandon
authors.forename: Lawrence
authors.initials: L
authors.lastname: Schook
authors.forename: Jayesh
authors.initials: J
authors.lastname: Mehta
authors.forename: J Scott
authors.initials: JS
authors.lastname: Bryson
authors.forename: Subbarao
authors.initials: S
authors.lastname: Bondada
authors.forename: Ying
authors.initials: Y
authors.lastname: Liang
mesh_terms: D000818:Animals; D000941:Antigens / Q000235:genetics* / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001374:Azacitidine / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007202:Indicators and Reagents; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D000941:Antigens; D018952:Antigens, CD34; D007202:Indicators and Reagents; C086812:Lxn protein, rat; D001374:Azacitidine