Background: Hypoxia is a pivotal initiator of tumor angiogenesis and growth through the stabilization of hypoxia-inducible factors (HIFs). This study set out to examine the involvement of HIF-1a and HIF-2a in colon cancer and ascertained whether ORAI3 was involved in the pathway. Materials and methods: Patients and murine models as well as human colorectal adenocarcinoma tumor (CW2) cells were included to examine the levels of ORAI1/3 and HIF-1/2a levels. Calcium imaging was utilized to ascertain the activity of calcium channel. Scratch assay was used to assess the migration capacity of the cells. Results: Tumors from murine colon cancer xenograft models and patients with colon cancer displayed high ORAI1/3 and HIF-1/2a levels. Hypoxia treatment, mimicking the tumor microenvironment in vitro, increased ORAI1/3 and HIF-1/2a expression as well as store-operated Ca2ţ entry (SOCE). Of note is that HIF-1/2a silencing decreased SOCE, and HIF-1/2a overexpression facilitated SOCE. Furthermore, ORAI3 rather than ORAI1 expression was inhibited by HIF-1/2a silencing while increased by ML228. Luciferase assay also confirmed that ORAI3 was elevated in the presence of ML228, indicating the linkage between HIF-1/2a and ORAI3. Additionally, colony-forming potential and cell migration capacity were decreased in siHIF-1a and siHIF2a as well as siORAI3 cells, and the facilitating effect of ML228 on cell migration and colony-forming potential was also decreased in siORAI3 CW-2 cells, which points out the importance of ORAI3 in HIF1/2a pathway. Conclusion: Our findings allow to conclude that both HIF-1a and HIF-2a facilitate ORAI3 expression, hence enhancing colon cancer progression.  Kulcsszavak: store-operated Ca2t entry, ORAI3, colon cancer, HIF1/2a