Store-operated Ca 2+ entry (SOCE) is the principal Ca 2+ entry mechanism in nonexcitable cells. Stromal-interaction molecule 1 (STIM1) is an endoplasmic reticulum Ca 2+ sensor that triggers SOCE activation. However, the role of STIM1 in regulating cancer progression remains controversial and its clinical relevance is unclear. Here we show that STIM1-dependent signaling is important for cervical cancer cell proliferation, migration, and angiogenesis. STIM1 overexpression in tumor tissue is noted in 71% cases of early-stage cervical cancer. In tumor tissues, the level of STIM1 expression is significantly associated with the risk of metastasis and survival. EGF-stimulated cancer cell migration requires STIM1 expression and EGF increases the interaction between STIM1 and Orai1 in juxta-membrane areas, and thus induces Ca 2+ influx. STIM1 involves the activation of Ca 2+ -regulated protease calpain, as well as Ca 2+ -regulated cytoplasmic kinase Pyk2, which regulate the focal-adhesion dynamics of migratory cervical cancer cells. Because of an increase of p21 protein levels and a decrease of Cdc25C protein levels, STIM1-silencing in cervical cancer cells significantly inhibits cell proliferation by arresting the cell cycle at the S and G2/M phases. STIM1 also regulates the production of VEGF in cervical cancer cells. Interference with STIM1 expression or blockade of SOCE activity inhibits tumor angiogenesis and growth in animal models, confirming the crucial role of STIM1-mediated Ca 2+ influx in aggravating tumor development in vivo. These results make STIM1-dependent signaling an attractive target for therapeutic intervention.

Purpose: Acquisition of epithelial-mesenchymal transition (EMT) by primary carcinoma cells is associated with disrupted epithelial integrity, local invasion, and ultimately metastasis. Little is known about the existence and function of EMT in cervical cancer. This study aims to investigate the regulation of EMT in cervical squamous cell carcinoma. Experimental Design: We investigated the molecular events of EMT in surgical specimens, which present the progression of cervical carcinoma.Two cervical cancer cell lines and the primary culture of normal cervical epithelia were used to study the regulatory mechanisms of EMT. Results: The chronic epidermal growth factor (EGF) treatment induces the elongation of cell shape, increases cell scattering, and enhances cell invasion. EGF treatment down-regulates E-cadherin and up-regulates vimentin in cervical cancer cells.These characteristics are consistent with the morphologic changes, molecular events, and functional significance of EMT. EGF receptor (EGFR) signaling inactivates glycogen synthase kinase-3h, which results in the nuclear accumulation of up-regulated Snail and then leads to EMT program. a 5 h 1 integrin signaling and extracellular matrix fibronectin can modulate EGF-induced EMT. Importantly, the immunofluorescent stainings of surgical specimens indicate that cervical carcinoma progression is accompanied by EGFR overexpression, which is in parallel with decreased E-cadherin and increased vimentin. Up-regulation and nuclear accumulation of Snail correlate with EMT program in tumor tissues. Conclusion: EGF cooperates with a 5 h 1 integrin signaling to induce EMT in cervical cancer cells via up-regulated Snail. Blockade of EGFR activity or expression may provide a potential target for the treatment of cervical cancer progression.During metastatic progression, polarized epithelial tumor cells convert into motile mesenchymal cells, invade the basement membrane beneath, enter blood vessels, and disseminate into secondary organ. The initial stage of these processes is associated with morphogenetic changes referred to as epithelial-mesenchymal transition (EMT), which is characterized by morphologic changes from epithelial cells to fibroblast-like cells, disassembly of intercellular junctions, and increased cell motility (1, 2). Down-regulation of E-cadherin was considered as a critical step in EMT process, and the down-regulation of which can be achieved by transcriptional suppression mediated by transcription factors Snail, Slug,. This results in the disruption of intracellular adhesion junctions formed by E-cadherin/h-catenin complexes.Cervical cancer is the second most common cancer among women worldwide (6). A growing body of evidence has accumulated to indicate that oncogenic types of human papillomavirus serve as an important factor in the development of the precursors of cervical cancer. However, only a small fraction of those infected by human papillomavirus develops cancer, indicating that other factors contribute to the progression to cervical can...

Intracellular Ca2+ is one of the crucial signalings that modulate various cellular functions. The dysregulation of Ca2+ homeostasis has been suggested as an important event in driving the expression of the malignant phenotypes, such as proliferation, migration, invasion, and metastasis. Cell migration is an early prerequisite for tumor metastasis that has a significant impact on patient prognosis. During cell migration, the exquisite spatial and temporal organization of intracellular Ca2+ provides a rapid and robust way for the selective activation of signaling components that play a central role in cytoskeletal reorganization, traction force generation, and focal adhesion dynamics. A number of known molecular components involved in Ca2+ influx pathways, including stromal interaction molecule (STIM)/Orai-mediated store-operated Ca2+ entry (SOCE) and the Ca2+-permeable transient receptor potential (TRP) channels, have been implicated in cancer cell migration and tumor metastasis. The clinical significance of these molecules, such as STIM proteins and the TRPM7 channel, in tumor progression and their diagnostic and prognostic potentials have also been demonstrated in specific cancer types. In this review, we summarize the recent advances in understanding the important roles and regulatory mechanisms of these Ca2+ influx pathways on malignant behaviors of tumor cells. The clinical implications in facilitating current diagnostic and therapeutic procedures are also discussed.