Abstract A198: A novel regulatory circuit involving STIM1 and HIF-1 mediates hypoxia-driven hepatocarcinogenesis

Abstract

Abstract Hypoxia and intracellular Ca2+ transient are fundamental traits of cancer. Signaling cascades initiated or regulated by HIF-1 is essential for hypoxic responses. Stromal-interaction molecule 1 (STIM1) is well known as a Ca2+ sensor on endoplasmic reticulum (ER) that mediates SOCE activation and promotes tumor invasion and migration. However, there was no general consensus about the relationship between HIF-1 and STIM1. Also, the significance of STIM1, as well as the Ca2+ mobilization route in cancer cells during hypoxia remains unknown. Our results show that STIM1 correlates with elevated hypoxia-inducible factor-1 alpha (HIF-1α) in hypoxic hepatocarcinoma cells (HCC) and is upregulated during hepatocarcinoma growth. HIF-1 directly transcripts STIM1 and contributes to store-operated Ca2+ entry (SOCE), while STIM1-mediated SOCE is also required for HIF-1 accumulation in hypoxic HCC, via activating Ca2+/calmodulin-dependent protein kinase II and p300. Administration of YC-1, a HIF-1 inhibitor, or knockdown of HIF1A significantly diminishes hypoxia-enhanced STIM1 and suppresses tumorigenesis. Moreover, ectopic expression of STIM1 or HIF-1α partially reverses the impaired growth of the tumor treated with YC-1. These results suggest a mutual dependency and regulation of STIM1 and HIF-1 in controlling Ca2+ mobilization and hypoxic tumor growth, and highlight a potential target for early hypoxia-related intervention. Citation Format: Yongsheng Li. A novel regulatory circuit involving STIM1 and HIF-1 mediates hypoxia-driven hepatocarcinogenesis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A198.