STIM2 Regulates NFAT1/TGF-β1 Pathway To Potentiate Epithelial-mesenchymal Transition(EMT)and Promote Breast Cancer Metastasis

Stromal interaction molecule(STIM)1 and 2 are calcium-sensing molecules that link calcium depletion of the endoplasmic reticulum with opening of plasma membrane calcium channels.Both STIM1 and STIM2 are important elements of Store-operated Ca2+entry(SOCE),which regulate intracellular Ca2+.Ca2+,as an important secondary messenger,involved in many biological function,including the development of cancer.These means STIM1 and STIM2 may regulate the metastatic potential of cancer cells through regulate the concentration of Ca2+.Uncover the relationship between STIMs and metastatic of cancer cells will help us to prevent the metastatic of cancer cells and improve prognosis.Tissue microarray,Lenti virus,Cytosolic Ca2+measurement,Immunofluorescence and IPA analysis were used to analysis the the different expression of STIMs in cancer and normal breast tissue and the relationship between STIMs and EMT of breast cancer cells.The results indicated that the expression of STIMs in cancer tissue are higher than normal breast tissue.Distinct from STIM1,the expression of STIM2 may regulate EMT in breast cancer cells.This difference may due to STIM2 is specifically involved in receptor-operated Ca2+ entry(ROCE).Inaddition,as downstream molecule of STIM2,nuclear factor of activated T cells(NFAT1)could regulat the expression and secretion of TGF-β1 which could promote the EMT of breast cancer cells.Consequently,our results demonstrate that STIM2 specifically regulates NFAT1 via ROCE,and regulates the expression and secretion of TGF-β1 to promote EMT in breast cancer cells,leading to metastasis of breast cancer.As a central link of this axis,STIM2 activation not only serves as a prognostic factor to predict clinical outcomes for breast cancer patients,but also a therapeutic target since knockdown of STIM2 efficiently inhibits breast cancer metastasis via suppressing the activity of TGF-β1 signaling.