HIF-2α deletion promotes Kras-driven lung tumor development
Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. The oxygen-sensitive hypoxia inducible factor (HIF) transcriptional regulators HIF-1α and HIF-2α are overexpressed in many human NSCLCs, and constitutive HIF-2α activity can promote murine lung tumor progression, sug...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2014
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| Online Access: | http://hdl.handle.net/1721.1/84643 https://orcid.org/0000-0001-5785-8911 |
| _version_ | 1826215176271036416 |
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| author | Mazumdar, Jolly Hickey, Michele M. Pant, Dhruv K. Durham, Amy C. Sweet-Cordero, Alejandro Vachani, Anil Chodosh, Lewis A. Kissil, Joseph L. Simon, M. Celeste Keith, Brian Jacks, Tyler E |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Mazumdar, Jolly Hickey, Michele M. Pant, Dhruv K. Durham, Amy C. Sweet-Cordero, Alejandro Vachani, Anil Chodosh, Lewis A. Kissil, Joseph L. Simon, M. Celeste Keith, Brian Jacks, Tyler E |
| author_sort | Mazumdar, Jolly |
| collection | MIT |
| description | Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. The oxygen-sensitive hypoxia inducible factor (HIF) transcriptional regulators HIF-1α and HIF-2α are overexpressed in many human NSCLCs, and constitutive HIF-2α activity can promote murine lung tumor progression, suggesting that HIF proteins may be effective NSCLC therapeutic targets. To investigate the consequences of inhibiting HIF activity in lung cancers, we deleted Hif-1α or Hif-2α in an established Kras[superscript G12D]-driven murine NSCLC model. Deletion of Hif-1α had no obvious effect on tumor growth, whereas Hif-2α deletion resulted in an unexpected increase in tumor burden that correlated with reduced expression of the candidate tumor suppressor gene Scgb3a1 (HIN-1). Here, we identify Scgb3a1 as a direct HIF-2α target gene and demonstrate that HIF-2α regulates Scgb3a1 expression and tumor formation in human Kras[superscript G12D]-driven NSCLC cells. AKT pathway activity, reported to be repressed by Scgb3a1, was enhanced in HIF-2α-deficient human NSCLC cells and xenografts. Finally, a direct correlation between HIF-2α and SCGB3a1 expression was observed in approximately 70% of human NSCLC samples analyzed. These data suggest that, whereas HIF-2α overexpression can contribute to NSCLC progression, therapeutic inhibition of HIF-2α below a critical threshold may paradoxically promote tumor growth by reducing expression of tumor suppressor genes, including Scgb3a1. |
| first_indexed | 2024-09-23T16:18:47Z |
| format | Article |
| id | mit-1721.1/84643 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:18:47Z |
| publishDate | 2014 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/846432022-09-29T19:28:01Z HIF-2α deletion promotes Kras-driven lung tumor development Mazumdar, Jolly Hickey, Michele M. Pant, Dhruv K. Durham, Amy C. Sweet-Cordero, Alejandro Vachani, Anil Chodosh, Lewis A. Kissil, Joseph L. Simon, M. Celeste Keith, Brian Jacks, Tyler E Koch Institute for Integrative Cancer Research at MIT Jacks, Tyler E. Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. The oxygen-sensitive hypoxia inducible factor (HIF) transcriptional regulators HIF-1α and HIF-2α are overexpressed in many human NSCLCs, and constitutive HIF-2α activity can promote murine lung tumor progression, suggesting that HIF proteins may be effective NSCLC therapeutic targets. To investigate the consequences of inhibiting HIF activity in lung cancers, we deleted Hif-1α or Hif-2α in an established Kras[superscript G12D]-driven murine NSCLC model. Deletion of Hif-1α had no obvious effect on tumor growth, whereas Hif-2α deletion resulted in an unexpected increase in tumor burden that correlated with reduced expression of the candidate tumor suppressor gene Scgb3a1 (HIN-1). Here, we identify Scgb3a1 as a direct HIF-2α target gene and demonstrate that HIF-2α regulates Scgb3a1 expression and tumor formation in human Kras[superscript G12D]-driven NSCLC cells. AKT pathway activity, reported to be repressed by Scgb3a1, was enhanced in HIF-2α-deficient human NSCLC cells and xenografts. Finally, a direct correlation between HIF-2α and SCGB3a1 expression was observed in approximately 70% of human NSCLC samples analyzed. These data suggest that, whereas HIF-2α overexpression can contribute to NSCLC progression, therapeutic inhibition of HIF-2α below a critical threshold may paradoxically promote tumor growth by reducing expression of tumor suppressor genes, including Scgb3a1. 2014-02-03T16:35:33Z 2014-02-03T16:35:33Z 2010-08 2010-02 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/84643 Mazumdar, J., M. M. Hickey, D. K. Pant, A. C. Durham, A. Sweet-Cordero, A. Vachani, T. Jacks, et al. “HIF-2 deletion promotes Kras-driven lung tumor development.” Proceedings of the National Academy of Sciences 107, no. 32 (August 10, 2010): 14182-14187. https://orcid.org/0000-0001-5785-8911 en_US http://dx.doi.org/10.1073/pnas.1001296107 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Mazumdar, Jolly Hickey, Michele M. Pant, Dhruv K. Durham, Amy C. Sweet-Cordero, Alejandro Vachani, Anil Chodosh, Lewis A. Kissil, Joseph L. Simon, M. Celeste Keith, Brian Jacks, Tyler E HIF-2α deletion promotes Kras-driven lung tumor development |
| title | HIF-2α deletion promotes Kras-driven lung tumor development |
| title_full | HIF-2α deletion promotes Kras-driven lung tumor development |
| title_fullStr | HIF-2α deletion promotes Kras-driven lung tumor development |
| title_full_unstemmed | HIF-2α deletion promotes Kras-driven lung tumor development |
| title_short | HIF-2α deletion promotes Kras-driven lung tumor development |
| title_sort | hif 2α deletion promotes kras driven lung tumor development |
| url | http://hdl.handle.net/1721.1/84643 https://orcid.org/0000-0001-5785-8911 |
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