鈣離子偵測器STIM1在口腔癌的擴展：聚焦在轉移

自初級腫瘤位置離開，轉移癌細胞需要擁有透過鈣離子調控的細胞骨架重組及局部黏著斑（focal adhesion）動態所驅動的侵入及移動能力。為了維持生理動態平衡，細胞質內鈣離子的濃度受鈣池調控鈣離子進入（store-operated calcium entry，SOCE）之緊密調控，當內質網中鈣離子耗盡，基質交互分子（stromal interaction molecule，STIM）因此活化，進而活化細胞膜上的鈣離子選擇性通道ORAI，以胞外鈣離子補充內質網的不足。許多研究顯示在子宮頸癌與大腸癌中STIM1表現量異常，然而是否因為STIM1表現量異常影響SOCE活性或者是其他訊息傳遞路徑以致於誘發癌細胞的移動或侵入仍然不清楚。我們先前研究指出STIM1和口腔癌的進展有關。本研究因此欲探討失調的STIM1所調控的口腔癌細胞移動之假說。我們在此報導於試管及體內中，STIM1負向調控口腔癌細胞移動。在口腔鱗狀細胞癌（oral squamous cell carcinoma，OSCC）細胞中，利用shRNA對抗STIM1及ORAI1以致於SOCE活性下降，或者透過小分子SOCE抑制劑，皆可見癌細胞移動增加。相反的，過度表現YFP所標記的STIM1之細胞則阻礙其移動。我們也利用異種移植老鼠模型解釋STIM1在癌症轉移上所扮演之負向角色。和控制組的細胞相較之下，利用STIM1靜默之OSCC細胞進行原位移植老鼠，其在轉移速度、轉移數量及轉移位置的腫瘤大小上皆增加。因此，我們的結果證明在癌細胞移動及轉移的能力上，STIM1扮演抑制者的角色。更進一步的探討將著重於了解STIM1所調節的SOCE是如何影響細胞移動與癌症進展之機制。

關鍵字

口腔癌；轉移；移動；基質交互分子；鈣池調控鈣離子進入

並列摘要

To escape from the primary tumor site, metastatic cancer cells acquire the abilities to invade and migrate partially through Ca2+ signaling-regulated cytoskeleton rearrangement and focal adhesion dynamics. To maintain physiological homeostasis, intracellular Ca2+ pool is tightly controlled via store-operated calcium entry (SOCE), which includes the activation of stromal interaction molecules (STIM) upon Ca2+ depletion within the endoplasmic reticulum, followed by the activation of Ca2+-selective channel ORAI on the plasma membrane to replenish Ca2+ from extracellular space. Several studies have revealed aberrant levels of STIM1 in human cancers such as cervical cancer and colorectal cancer, but whether STIM1 aberrancy affects SOCE activities or other signaling pathways to induce cancer cell migration or invasion were still unclear. Our preliminary results indicated that expression levels of STIM1 were associated with the progression of oral cancer. The present study is therefore aimed to test the hypothesis that dysregulated STIM1 could modulate the migration of oral cancer cells. We report here that STIM1 negatively regulated oral cancer cell migration in-vitro and in-vivo. Reduction of SOCE activities targeting STIM1 or ORAI1 by shRNA in oral squamous cell carcinoma (OSCC) cells, or by small-molecule SOCE inhibitor, increased cancer cell migration. In contrast, cells over-expressing YFP-tagged STIM1 had impeded cell motility. We also examined the negative role of STIM1 on cancer metastasis using xenograft mouse models. The metastatic rate, metastatic number and tumor size at metastatic sites were increased in mice orthotopically implanted with STIM1 silenced OSCC cells, compared to those implanted with control cells. Hence, our data demonstrated a suppressor role of STIM1 in OSCC cell migration and metastasis. Further explorations will aim at understanding the mechanism how STIM1-mediated SOCE contributes to OSCC cell migration and cancer progression.

並列關鍵字

oral cancer ； metastasis ； migration ； STIM ； ORAI ； SOCE

參考文獻

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鈣離子偵測器STIM1在口腔癌的擴展：聚焦在轉移

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