title: HIF-2α expression is suppressed in SCLC cells, which survive in moderate and severe hypoxia when HIF-1α is repressed.
abstract: Small cell lung carcinoma (SCLC) is extremely aggressive and frequently metastasizes widely in its early stage. Because tumor hypoxia is related to aggressive tumor behavior and the hypoxic adaptation of SCLC is poorly documented, we stained SCLC tumors arranged in a tissue microarray for hypoxia-inducible factor (HIF)-1α and HIF-2α proteins. We found an overall lack of HIF-2α protein expression, which was confirmed in large tumor sections. HIF-1α protein was strongly expressed in most tumors, frequently adjacent to necrotic regions. In concordance, cultured SCLC but not non-small cell lung carcinoma cells showed no or extremely low levels of HIF-2α mRNA and no HIF-2α protein at hypoxia. HIF-1α was stabilized after 4 hours at hypoxia, and its accumulation increased up to 96 hours. SCLC cells survived well and showed net proliferation and low cell death in modest (1% oxygen) and severe (0.1% oxygen) hypoxia. HIF-1α repression virtually did not influence cell death or viability despite reduced levels of hypoxia-inducible genes, such as BNIP3 and BNIP3L. At 1% oxygen no increased autophagy (LC3B-II activation) or NF-κB signaling were detected, whereas the unfolded protein response was activated at severe hypoxia. Our data indicate that HIFs are not exclusively required for SCLC cell survival at modest or severe hypoxia and that additional, yet uncharacterized, hypoxia-driven adaptation pathways may become activated.
authors: Center for Molecular Pathology, Department of Laboratory Medicine, CREATE Health, Lund University, Skåne University Hospital, Malmö, Sweden.
authors: Matilda
authors: M
authors: Munksgaard Persson
authors: Martin E
authors: ME
authors: Johansson
authors: Nastaran
authors: N
authors: Monsef
authors: Maria
authors: M
authors: Planck
authors: Siv
authors: S
authors: Beckman
authors: Michael J
authors: MJ
authors: Seckl
authors: Lars
authors: L
authors: Rönnstrand
authors: Sven
authors: S
authors: Påhlman
authors: Helen M
authors: HM
authors: Pettersson
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency* / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology; D002470:Cell Survival; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics; D008175:Lung Neoplasms / Q000378:metabolism* / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D014407:Tumor Cells, Cultured; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1