title: Homeobox gene Dlx-2 is implicated in metabolic stress-induced necrosis.
abstract: BACKGROUND
  In contrast to tumor-suppressive apoptosis and autophagic cell death, necrosis promotes tumor progression by releasing the pro-inflammatory and tumor-promoting cytokine high mobility group box 1 (HMGB1), and its presence in tumor patients is associated with poor prognosis. Thus, necrosis has important clinical implications in tumor development; however, its molecular mechanism remains poorly understood.
  
  
  RESULTS
  In the present study, we show that Distal-less 2 (Dlx-2), a homeobox gene of the Dlx family that is involved in embryonic development, is induced in cancer cell lines dependently of reactive oxygen species (ROS) in response to glucose deprivation (GD), one of the metabolic stresses occurring in solid tumors. Increased Dlx-2 expression was also detected in the inner regions, which experience metabolic stress, of human tumors and of a multicellular tumor spheroid, an in vitro model of solid tumors. Dlx-2 short hairpin RNA (shRNA) inhibited metabolic stress-induced increase in propidium iodide-positive cell population and HMGB1 and lactate dehydrogenase (LDH) release, indicating the important role(s) of Dlx-2 in metabolic stress-induced necrosis. Dlx-2 shRNA appeared to exert its anti-necrotic effects by preventing metabolic stress-induced increases in mitochondrial ROS, which are responsible for triggering necrosis.
  
  
  CONCLUSIONS
  These results suggest that Dlx-2 may be involved in tumor progression via the regulation of metabolic stress-induced necrosis.
authors.affiliation: Department of Molecular Biology, College of Natural Sciences, Pusan National University, Pusan 609-735, Korea.
authors.forename: Su Yeon
authors.initials: SY
authors.lastname: Lee
authors.forename: Hyun Min
authors.initials: HM
authors.lastname: Jeon
authors.forename: Cho Hee
authors.initials: CH
authors.lastname: Kim
authors.forename: Min Kyung
authors.initials: MK
authors.lastname: Ju
authors.forename: Hye Sun
authors.initials: HS
authors.lastname: Bae
authors.forename: Hye Gyeong
authors.initials: HG
authors.lastname: Park
authors.forename: Sung-Chul
authors.initials: SC
authors.lastname: Lim
authors.forename: Song Iy
authors.initials: SI
authors.lastname: Han
authors.forename: Ho Sung
authors.initials: HS
authors.lastname: Kang
mesh_terms: D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002449:Cell Aggregation; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000172:deficiency; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D009336:Necrosis; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D010539:Permeability; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D000954:Antigens, Surface; D017382:Reactive Oxygen Species; C092261:antigen Dlx-2; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate