title: Inhibition of Mxi1 suppresses HIF-2alpha-dependent renal cancer tumorigenesis.
abstract: In clear cell renal cancers, the primary molecular defect is inactivation of the von Hippel-Lindau (VHL) gene. Loss of pVHL, the VHL gene product, leads to constitutive activation of hypoxia-inducible factor (HIF) signaling. While downregulation of HIF suppresses tumor formation by pVHL-defective renal carcinoma cells, the relative contribution of individual HIF regulated genes to HIF-dependent tumorigenesis remains under investigation. Mxi1, a c-Myc antagonist, is a HIF target gene that inhibits mitochondrial biogenesis, reprograms cellular energy metabolism, and protects cells from c-Myc-dependent apoptosis in vitro. In the present study we show that Mxi1 is overexpressed in primary human clear cell kidney cancers. Inhibition of Mxi1 in pVHL-defective kidney cancer cells using shRNA alters their cell cycle parameters, inhibits their ability to invade matrigel, and suppresses their ability to form tumors in vivo. Compared to Mxi1-proficient tumors, Mxi1-deficient tumors display reduced cellular proliferation. These results establish Mxi1 as an important downstream target of HIF that contributes to pVHL-deficient renal cancer tumorigenesis.
authors.affiliation: Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Chun Chui
authors.initials: CC
authors.lastname: Tsao
authors.forename: Bin T
authors.initials: BT
authors.lastname: Teh
authors.forename: Eric
authors.initials: E
authors.lastname: Jonasch
authors.forename: Nicole
authors.initials: N
authors.lastname: Shreiber-Agus
authors.forename: Eleni
authors.initials: E
authors.lastname: Efstathiou
authors.forename: Anh
authors.initials: A
authors.lastname: Hoang
authors.forename: Bogdan
authors.initials: B
authors.lastname: Czerniak
authors.forename: Christopher
authors.initials: C
authors.lastname: Logothetis
authors.forename: Paul G
authors.initials: PG
authors.lastname: Corn
mesh_terms: D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D049109:Cell Proliferation; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D007680:Kidney Neoplasms / Q000378:metabolism*; D007797:Laminin / Q000737:chemistry; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D011509:Proteoglycans / Q000737:chemistry; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D003094:Collagen; D004338:Drug Combinations; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007797:Laminin; D011509:Proteoglycans; D016271:Proto-Oncogene Proteins c-myc; D025521:Tumor Suppressor Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497442:HIF1A protein, human; C079440:MXI1 protein, human; C059485:matrigel; C497446:VHL protein, human