HIF-2 alpha Expression Is Suppressed in SCLC Cells, Which Survive in Moderate and Severe Hypoxia When HIF-1 alpha Is Repressed
2012 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 180, no 2, 494-504 p.Article in journal (Refereed) Published
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)-1 alpha and HIF-2 alpha proteins. We found an overall lack of HIF-2 alpha protein expression, which was confirmed in large tumor sections. HIF-1 alpha 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-2 alpha mRNA and no HIF-2 alpha protein at hypoxia. HIF-1 alpha 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-1 alpha 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-kappa B 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.
Place, publisher, year, edition, pages
Elsevier , 2012. Vol. 180, no 2, 494-504 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-75470DOI: 10.1016/j.ajpath.2011.10.014ISI: 000299918800007OAI: oai:DiVA.org:liu-75470DiVA: diva2:507082
Funding Agencies|Swedish Cancer Society||Childrens Cancer Foundation of Sweden||Swedish Foundation of Strategic Research||SSF Strategic Center for Translational Cancer Research-CREATE Health||Strategic Cancer Research Program||BioCARE||Hans von Kantzows Foundation||Gunnar Nilssons Cancer Foundation||Skane University Hospital||2012-03-022012-03-022012-03-02