细胞内鈣離子恆定在癌症進程中，如腫瘤增生、侵襲與轉移都扮演極重要的角色。在腫瘤組織有高度表現之基質交互因子1（stromal interaction molecule 1，STIM1）是位於內質網膜上的鈣離子感測蛋白，藉由活化 “鈣池調控鈣離子流入”（Store-operated calcium entry，SOCE）機制，調控癌细胞内鈣離子恆定進而啟動癌細胞行為。然而，STIM1基因點突變如何影響癌症進程目前未被深入探討。本研究應用COSMIC癌症基因突變資料庫找出六個位於STIM1 cEF-hand的基因變異，其中包含D76G、D76V、D76H、D84Y、D84E以及D84N。接下來，我們釐清這些STIM1基因變異如何改變癌細胞的進展。首先，由量測細胞內部鈣離子變化結果顯示，STIM1基因變異對於SOCE活化的影響。另外，這些基因變異亦參與依賴鈣離子訊號調控之癌細胞爬行行為。同時，STIM1基因變異藉由影響細胞週期調控者p21進而改變癌細胞生長功能。後續利用超高解析度顯微影像技術分析，了解這些基因變異如何影響STIM1在SOCE活化過程中的空間分布情形。綜合以上結果，STIM1 cEF-hand基因變異會透過調控鈣離子信號，影響癌細胞的功能，並在SOCE活化過程中改變STIM1蛋白於動態空間分布之進程。

The intracellular Ca2+ homeostasis plays a vital role in cancer initiation, tumor progression, invasion, and metastasis. Stromal interaction molecule 1 (STIM1), as an endoplasmic reticulum (ER) Ca2+ sensor, can control intracellular Ca2+ homeostasis via store-operated calcium entry (SOCE) and is abundantly expressed in tumor tissues. However, the single-nucleotide polymorphisms of the STIM1 gene in cancer progression remain unclear. First, we analyzed the genomic data of cancer patients from the COSMIC database to investigate which variants of the STIM1 gene involved in tumor cell behaviors. Six somatic variants of the STIM1 gene located in the cEF hand domain are identified, including D76G, D76V, D76H, D84Y, D84E, and D84N mutations. Next, we clarify the impacts of somatic variants in STIM1 cEF-hand domains on cancer cell progression. Intracellular Ca2+ measurement results showed that somatic STIM1 variants impacted SOCE activation. Furthermore, these STIM1 mutations also participate in mediating Ca2+-dependent cancer cell migration. These somatic variants affect cancer cell proliferation via cell cycle regulator, p21. Importantly, the results from two-color mapping dSTORM super-resolution images indicated that these gene variants also affect the spatiotemporal distribution of STIM1 during SOCE activation. Together, somatic variants in the cEF-hand domain affected tumor cellular functions via STIM1-dependent Ca2+ signaling and altered the spatiotemporal dynamics of STIM1 during SOCE activation.

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