Calcium Sensor STIM1 in the Progression of Oral Cancer : Focusing on Metastasis

To escape from the primary tumor site, metastatic cancer cells acquire the abilities to invade and migrate partially through Ca2+ signaling-regulated cytoskeleton rearrangement and focal adhesion dynamics. To maintain physiological homeostasis, intracellular Ca2+ pool is tightly controlled via store-operated calcium entry (SOCE), which includes the activation of stromal interaction molecules (STIM) upon Ca2+ depletion within the endoplasmic reticulum, followed by the activation of Ca2+-selective channel ORAI on the plasma membrane to replenish Ca2+ from extracellular space. Several studies have revealed aberrant levels of STIM1 in human cancers such as cervical cancer and colorectal cancer, but whether STIM1 aberrancy affects SOCE activities or other signaling pathways to induce cancer cell migration or invasion were still unclear. Our preliminary results indicated that expression levels of STIM1 were associated with the progression of oral cancer. The present study is therefore aimed to test the hypothesis that dysregulated STIM1 could modulate the migration of oral cancer cells. We report here that STIM1 negatively regulated oral cancer cell migration in-vitro and in-vivo. Reduction of SOCE activities targeting STIM1 or ORAI1 by shRNA in oral squamous cell carcinoma (OSCC) cells, or by small-molecule SOCE inhibitor, increased cancer cell migration. In contrast, cells over-expressing YFP-tagged STIM1 had impeded cell motility. We also examined the negative role of STIM1 on cancer metastasis using xenograft mouse models. The metastatic rate, metastatic number and tumor size at metastatic sites were increased in mice orthotopically implanted with STIM1 silenced OSCC cells, compared to those implanted with control cells. Hence, our data demonstrated a suppressor role of STIM1 in OSCC cell migration and metastasis. Further explorations will aim at understanding the mechanism how STIM1-mediated SOCE contributes to OSCC cell migration and cancer progression.