title: Mechanistic contribution of ubiquitous 15-lipoxygenase-1 expression loss in cancer cells to terminal cell differentiation evasion.
abstract: Loss of terminal cell differentiation promotes tumorigenesis. 15-Lipoxygenase-1 (15-LOX-1) contributes to terminal cell differentiation in normal cells. The mechanistic significance of 15-LOX-1 expression loss in human cancers to terminal cell differentiation suppression is unknown. In a screen of 128 cancer cell lines representing more than 20 types of human cancer, we found that 15-LOX-1 mRNA expression levels were markedly lower than levels in terminally differentiated cells. Relative expression levels of 15-LOX-1 (relative to the level in terminally differentiated primary normal human-derived bronchial epithelial cells) were lower in 79% of the screened cancer cell lines than relative expression levels of p16 (INK4A), which promotes terminal cell differentiation and is considered one of the most commonly lost tumor suppressor genes in cancer cells. 15-LOX-1 was expressed during terminal differentiation in three-dimensional air-liquid interface cultures, and 15-LOX-1 expression and terminal differentiation occurred in immortalized nontransformed bronchial epithelial but not in lung cancer cell lines. 15-LOX-1 expression levels were lower in human tumors than in paired normal lung epithelia. Short hairpin RNA-mediated downregulation of 15-LOX-1 in Caco-2 cells blocked enterocyte-like differentiation, disrupted tight junction formation, and blocked E-cadherin and ZO-1 localization to the cell wall membrane. 15-LOX-1 episomal expression in Caco-2 and HT-29 colon cancer cells induced differentiation. Our findings indicate that 15-LOX-1 downregulation in cancer cells is an important mechanism for terminal cell differentiation dysregulation and support the potential therapeutic utility of 15-LOX-1 reexpression to inhibit tumorigenesis.
authors: Department of Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Micheline J
authors: MJ
authors: Moussalli
authors: Yuanqing
authors: Y
authors: Wu
authors: Xiangsheng
authors: X
authors: Zuo
authors: Xiu L
authors: XL
authors: Yang
authors: Ignacio Ivan
authors: II
authors: Wistuba
authors: Maria G
authors: MG
authors: Raso
authors: Jeffrey S
authors: JS
authors: Morris
authors: Jessica L
authors: JL
authors: Bowser
authors: John D
authors: JD
authors: Minna
authors: Reuben
authors: R
authors: Lotan
authors: Imad
authors: I
authors: Shureiqi
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology / Q000201:enzymology; D015820:Cadherins / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000473:pathology*; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D015820:Cadherins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D001093:Arachidonate 15-Lipoxygenase; D000469:Alkaline Phosphatase