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HIF-2α Expression Is Suppressed in SCLC Cells, Which Survive in Moderate and Severe Hypoxia When HIF-1α Is Repressed.

Persson, Matilda Munksgaard; Johansson, Martin LU ; Monsef, Nastaran; Planck, Maria LU ; Beckman, Siv LU ; Seckl, Michael J; Rönnstrand, Lars LU ; Påhlman, Sven LU and Pettersson, Helen LU (2012) In American Journal of Pathology 180(2). p.494-504
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
American Journal of Pathology
volume
180
issue
2
pages
494 - 504
publisher
American Society for Investigative Pathology
external identifiers
  • wos:000299918800007
  • pmid:22115707
  • scopus:84855998771
ISSN
1525-2191
DOI
10.1016/j.ajpath.2011.10.014
language
English
LU publication?
yes
id
467bd5ea-eef3-4e32-89c3-5a2399a582f4 (old id 2220355)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22115707?dopt=Abstract
date added to LUP
2011-12-03 10:09:37
date last changed
2017-08-06 03:26:07
@article{467bd5ea-eef3-4e32-89c3-5a2399a582f4,
  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.},
  author       = {Persson, Matilda Munksgaard and Johansson, Martin and Monsef, Nastaran and Planck, Maria and Beckman, Siv and Seckl, Michael J and Rönnstrand, Lars and Påhlman, Sven and Pettersson, Helen},
  issn         = {1525-2191},
  language     = {eng},
  number       = {2},
  pages        = {494--504},
  publisher    = {American Society for Investigative Pathology},
  series       = {American Journal of Pathology},
  title        = {HIF-2α Expression Is Suppressed in SCLC Cells, Which Survive in Moderate and Severe Hypoxia When HIF-1α Is Repressed.},
  url          = {http://dx.doi.org/10.1016/j.ajpath.2011.10.014},
  volume       = {180},
  year         = {2012},
}