title: Interplay between heme oxygenase-1 and miR-378 affects non-small cell lung carcinoma growth, vascularization, and metastasis.
abstract: OBJECTIVE
  Heme oxygenase-1 (HO-1, HMOX1) can prevent tumor initiation; while in various tumors, it has been demonstrated to promote growth, angiogenesis, and metastasis. Here, we investigated whether HMOX1 can modulate microRNAs (miRNAs) and regulate human non-small cell lung carcinoma (NSCLC) development.
  
  
  RESULTS
  Stable HMOX1 overexpression in NSCLC NCI-H292 cells up-regulated tumor-suppressive miRNAs, whereas it significantly diminished the expression of oncomirs and angiomirs. The most potently down-regulated was miR-378. HMOX1 also up-regulated p53, down-regulated angiopoietin-1 (Ang-1) and mucin-5AC (MUC5AC), reduced proliferation, migration, and diminished angiogenic potential. Carbon monoxide was a mediator of HMOX1 effects on proliferation, migration, and miR-378 expression. In contrast, stable miR-378 overexpression decreased HMOX1 and p53; while enhanced expression of MUC5AC, vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and Ang-1, and consequently increased proliferation, migration, and stimulation of endothelial cells. Adenoviral delivery of HMOX1 reversed miR-378 effect on the proliferation and migration of cancer cells. In vivo, HMOX1 overexpressing tumors were smaller, less vascularized and oxygenated, and less metastatic. Overexpression of miR-378 exerted opposite effects. Accordingly, in patients with NSCLC, HMOX1 expression was lower in metastases to lymph nodes than in primary tumors.
  
  
  CONCLUSIONS
  In vitro and in vivo data indicate that the interplay between HMOX1 and miR-378 significantly modulates NSCLC progression and angiogenesis, suggesting miR-378 as a new therapeutic target. REBOUND TRACK: This work was rejected during standard peer review and rescued by Rebound Peer Review (Antioxid Redox Signal 16, 293-296, 2012) with the following serving as open reviewers: James F. George, Mahin D. Maines, Justin C. Mason, and Yasufumi Sato.
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Skrzypek
authors.forename: Magdalena
authors.initials: M
authors.lastname: Tertil
authors.forename: Slawomir
authors.initials: S
authors.lastname: Golda
authors.forename: Maciej
authors.initials: M
authors.lastname: Ciesla
authors.forename: Kazimierz
authors.initials: K
authors.lastname: Weglarczyk
authors.forename: Guillaume
authors.initials: G
authors.lastname: Collet
authors.forename: Alan
authors.initials: A
authors.lastname: Guichard
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kozakowska
authors.forename: Jorge
authors.initials: J
authors.lastname: Boczkowski
authors.forename: Halina
authors.initials: H
authors.lastname: Was
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gil
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Kuzdzal
authors.forename: Lucie
authors.initials: L
authors.lastname: Muchova
authors.forename: Libor
authors.initials: L
authors.lastname: Vitek
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Loboda
authors.forename: Alicja
authors.initials: A
authors.lastname: Jozkowicz
authors.forename: Claudine
authors.initials: C
authors.lastname: Kieda
authors.forename: Jozef
authors.initials: J
authors.lastname: Dulak
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002248:Carbon Monoxide / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D008207:Lymphatic Metastasis; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D018384:Oxidative Stress; D034622:RNA Interference; D059467:Transcriptome; D047368:Tumor Burden
chemical_list: D000970:Antineoplastic Agents; C526012:MIRN378 microRNA, human; D035683:MicroRNAs; D002248:Carbon Monoxide; D004317:Doxorubicin; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D005472:Fluorouracil