鈣離子是在一般細胞及癌細胞中已知的第二訊息傳遞因子，因此，細胞質中的鈣離子濃度會去影響不同的細胞功能，如細胞增生、移動和基因表現。鈣池調控鈣離子流入（SOCE）是在非興奮性細胞中主要造成鈣離子進入細胞的機制，基質交互分子（STIM1是位於內質網膜上的鈣離子感測蛋白，當內質網中的鈣離子濃度下降時， STIM1會被活化去和鈣池調控鈣離子通道蛋白Orai1產生交互作用，進而啟動SOCE。由於STIM1是調控非興奮性細胞鈣離子流入的關鍵分子，有些研究發現STIM1會參與細胞運動性及增生。我利用藥理和基因方法來研究STIM1在癌症中之扮演角色。STIM1表現降低會抑制子宮頸癌細胞增生，增加p21同時降低Cdc25C的蛋白質表現，使細胞週期停留在G2/M期；並且p21蛋白量的增加，是由於蛋白質降解酶受部分抑制。接下來在重度合併免疫缺失小鼠中以皮下注射方式打入不同STIM1含量的子宮頸癌細胞株，發現STIM1含量高的細胞株會促進腫瘤生成及增加血管密度，而由STIM1含量低的細胞株則會延遲腫瘤生長並降低血管密度。而將生成的腫瘤處理以鈣池調控鈣離子通道抑制劑SKF96365和2-APB時，也會抑制腫瘤形成和血管新生。我也分析了STIM1蛋白含量和子宮頸癌預後之間的關係，在75%的子宮頸癌臨床檢體中，STIM1蛋白質含量皆有過度表現的情形，並發現STIM1表現量，會和腫瘤大小及其骨盆淋巴結轉移與否這兩個在初期子宮頸癌代表不良預後的因素，呈現正相關性。整體而言，我認為STIM1在子宮頸癌進程中扮演重要角色，並可能提供予未來臨床應用。

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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