STIM1 Mediates Hypoxia-Driven Hepatocarcinogenesis via Interaction with HIF-1

Cell Rep. 2015 Jul 21;12(3):388-95. doi: 10.1016/j.celrep.2015.06.033. Epub 2015 Jul 9.


Hypoxia and intracellular Ca(2+) transients are fundamental traits of cancer, whereas the route and regulation of Ca(2+) mobilization in hypoxic tumorigenesis are unknown. Here, we show that stromal-interaction molecule 1 (STIM1), an ER Ca(2+) sensor, correlates with elevated hypoxia-inducible factor-1 alpha (HIF-1α) in hypoxic hepatocarcinoma cells (HCCs) and is upregulated during hepatocarcinoma growth. HIF-1 directly controls STIM1 transcription and contributes to store-operated Ca(2+) entry (SOCE). STIM1-mediated SOCE is also required for HIF-1 accumulation in hypoxic HCCs via activation of Ca(2+)/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 impaired growth of tumors treated with YC-1. These results suggest a mutual dependency and regulation of STIM1 and HIF-1 in controlling Ca(2+) mobilization and hypoxic tumor growth and highlight a potential target for early hypoxia-related intervention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Carcinogenesis
  • Cell Hypoxia / physiology
  • Hep G2 Cells
  • Heterografts
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Male
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Nude
  • Neoplasm Proteins / metabolism*
  • Stromal Interaction Molecule 1


  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Membrane Proteins
  • Neoplasm Proteins
  • STIM1 protein, human
  • Stromal Interaction Molecule 1
  • Calcium