Abstract 502: Sp1 and HIFs mediate synergistic activation of ICAM1 gene under serum starved hypoxia and promotes growth of ovarian cancer
Authors: Koizume Shiro , Ito Shin , Nakamura Yoshiyasu , Yoshihara Mitsuyo , Takano Yasuo , Miyagi Yohei 
Published: May 2015

Cancer tissues are generally exposed to severe hypoxia conditions due to sparse and aberrant vasculature. Hypoxia-inducible factors HIF-1α and HIF-2α (HIF1 and HIF2, respectively) are major transcription factors required for adaptive responses to hypoxia. HIFs complexed with arylhydrocarbon receptor nuclear translocator bind target genes and act as enhancer of transcriptional regulation. This conventional mechanism regulates genes such as VEGF, GLUT1, and HO to improve mild to severe hypoxia conditions. It is likely that various oxygen concentrations and their duration exist within tumor tissue. It appears that adaptive response by HIFs is a major way to overcome stresses under milder hypoxia. However, majority of tumor tissues of many cancer types are known to undergo more severe hypoxic conditions. Thus, additional molecular mechanisms supporting HIFs signaling may be required to enhance survival activity of cancer cells.

We have previously demonstrated that FVII gene, which is essential for initiation of extrinsic blood coagulation can be induced in ovarian clear cell carcinoma (CCC) cells in response to hypoxia. Activation of this gene potentially results in thrombotic events frequently observed in cancer patients. We have demonstrated that a physical interaction between Sp1 and HIF2 is a major cause of the activation of this gene under hypoxia. Furthermore, FVII activation is synergistically enhanced when cells are cultured under ischemic condition, in which hypoxia and serum-free conditions coexist.

We envisioned that genes regulated by this mechanism are responsible for adaptive response to hypoxia with severity and/or duration characteristic to CCC tissues. Furthermore, ovarian cancer is a most malignant among gynecological diseases. CCC is highly tolerant to chemotherapy and the prognosis is poor. Thus, we first explored genes those are regulated by both Sp1 and HIFs in CCC cells by cDNA microarray analysis. We found that Sp1 and hypoxia inducible factors activate multiple genes under the ischemic condition in CCC cells. Among genes which meet this criteria, ICAM1 is one of a most dramatically induced gene. This transcriptional induction involves activation of NFκB associated with mTOR and autonomously produced TNFα.

We further performed xenograft tumor experiments to test whether ICAM1 can be induced and contributes to CCC progression in vivo. It was found that ICAM1 is dramatically induced within xenograft tumor tissues. Tumor growth was evidently suppressed when ICAM1 inducton was abrogated by shRNA transfection. Thus, interplay among transcription factors associated with serum deficiency results in cancer progression. This study highlights importance of adaptive response to serum-starved condition as to how cancer cells overcome severe hypoxic stress.

Citation Format: Shiro Koizume, Shin Ito, Yoshiyasu Nakamura, Mitsuyo Yoshihara, Yasuo Takano, Yohei Miyagi. Sp1 and HIFs mediate synergistic activation of ICAM1 gene under serum starved hypoxia and promotes growth of ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 502. doi:10.1158/1538-7445.AM2014-502