| Summary: | 碩士 === 國立成功大學 === 藥理學研究所 === 98 === Calcium (Ca2+) is known as a general second messenger in different cell types, including cancer cells. Thus, cytosolic Ca2+ concentration affects various ranges of cell functions, such as proliferation, migration, and gene expression. Store-operated calcium entry (SOCE) is the predominant Ca2+ entry mechanism in nonexcitable cells. Stromal interaction molecule 1 (STIM1) functions as a Ca2+ sensor on the endoplasmic reticulum (ER). STIM1 can be activated in response to diminished ER luminal Ca2+ levels and initiates SOCE by interacting with Ca2+ release activated Ca2+ (CRAC) channel protein Orai1. Since STIM1 is critical for the regulation of Ca2+ influx in nonexcitable cells, several studies show that STIM1 is also involved in the regulation of cell mobility and proliferation. Here, we use a combination of pharmacological and genetic approaches to investigate the role of STIM1 in cancer proliferation. Knockdown of STIM1 inhibited cervical cancer cell proliferation and caused cell cycle arrest at S and G2/M phase by p21 upregulation and Cdc25C downregulation. And STIM1 silencing can partially inhibit the proteasomal degradation of p21 protein and causes p21 upregulation. I next subcutaneously injected various clones of cervical cancer cells with differential STIM1 expression in SCID mouse model. STIM1 overexpression enhanced tumor formation and increased tumor vessel density. In contrast, STIM1 knockdown retarded tumor growth and decreased vessel density. Treatment with SOC channel inhibitors, SKF96365 and 2-aminoethoxydiphenyl borate (2-APB), also inhibited tumor formation and angiogenesis. I also examined the association between cervical cancer prognosis and STIM1 protein level. I found that STIM1 was overexpressed in 75% of surgical specimens (n=30). In addition, the expression level of STIM1 in tumor tissues was closely correlated with tumor size and pelvic lymph node metastasis, which are two major poor prognostic factors for early-stage cervical cancer. Taken together, I suggest that STIM1 plays an important role in regulating cervical cancer cell progression.
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