Lipid starvation and hypoxia synergistically activate ICAM1 and multiple genes in an Sp1-dependent manner to promote the growth of ovarian cancerReport as inadecuate

Lipid starvation and hypoxia synergistically activate ICAM1 and multiple genes in an Sp1-dependent manner to promote the growth of ovarian cancer - Download this document for free, or read online. Document in PDF available to download.

Molecular Cancer

, 14:77

First Online: 08 April 2015Received: 05 January 2015Accepted: 23 March 2015DOI: 10.1186-s12943-015-0351-z

Cite this article as: Koizume, S., Ito, S., Nakamura, Y. et al. Mol Cancer 2015 14: 77. doi:10.1186-s12943-015-0351-z


BackgroundElucidation of the molecular mechanisms by which cancer cells overcome hypoxia is potentially important for targeted therapy. Complexation of hypoxia-inducible factors HIFs with aryl hydrocarbon receptor nuclear translocators can enhance gene expression and initiate cellular responses to hypoxia. However, multiple molecular mechanisms may be required for cancer cells to adapt to diverse microenvironments. We previously demonstrated that a physical interaction between the ubiquitously expressed transcription factor Sp1 and HIF2 is a major cause of FVII gene activation in poor prognostic ovarian clear cell carcinoma CCC cells under hypoxia. Furthermore, it was found that FVII activation is synergistically enhanced when serum-starved cells are cultured under hypoxic conditions. In this study, we investigated whether HIFs and transcription factor Sp1 cooperate to activate multiple genes in CCC cells under conditions of serum starvation and hypoxia SSH and then contribute to malignant phenotypes.

MethodsTo identify genes activated under hypoxic conditions in an Sp1-dependent manner, we first performed cDNA microarray analyses. We further investigated the molecular mechanisms of synergistic gene activations including the associated serum factors by various experiments such as real-time RT-PCR, western blotting and chromatin immunoprecipitation. The study was further extended to animal experiments to investigate how it contributes to CCC progression in vivo.

ResultsICAM1 is one such gene dramatically induced by SSH and is highly induced by SSH and its synergistic activation involves both the mTOR and autonomously activated TNFα-NFκB axes. We identified long chain fatty acids LCFA as a major class of lipids that is associated with albumin, a serum factor responsible for synergistic gene activation under SSH. Furthermore, we found that ICAM1 can be induced in vivo to promote tumor growth.

ConclusionSp1 and HIFs collaborate to activate genes required for the adaptation of CCC cells to severe microenvironments, such as LCFA starvation and hypoxia. This study highlights the importance of transcriptional regulation under lipid starvation and hypoxia in the promotion of CCC tumor growth.

KeywordsHypoxia Sp1 Lipid starvation ICAM1 Ovarian cancer Electronic supplementary materialThe online version of this article doi:10.1186-s12943-015-0351-z contains supplementary material, which is available to authorized users.

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Author: Shiro Koizume - Shin Ito - Yoshiyasu Nakamura - Mitsuyo Yoshihara - Mitsuko Furuya - Roppei Yamada - Etsuko Miyagi - Fumiki


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