鈣離子及黏著分子的調控對癌細胞遷移之影響

Abstract

Ca2+信號參與許多重要的生理活動，包括細胞遷移，但Ca2+如何調控細胞遷移仍是一個謎。以往的文獻報導表明， 維持鈣離子衡定的重要組成部分SOCE可能促進或抑制不同類型的癌症轉移。我們的數據還表明，這種差異源於不同癌症類型細胞基質粘附力的不同，因為SOCE增加或減少細胞活力取決於細胞基質粘附力的基礎強度。因此，我們假設SOCE與細胞基質粘附相互作用，調節癌細胞的遷移。 為了驗證我們的假設，我們建立了一個數學熱圖模型來描述SOCE和細胞基質粘附的不同活性如何相互作用，從而產生相應的細胞動力圖。然後，我們在移行癌細胞中過表達或敲除關鍵粘附分子Paxillin和關鍵SOCE組成蛋白STIM1，並測量其動力變化。我們的實驗結果與數學模型的預測相吻合，支持SOCE與細胞基質粘附的相互作用。我們目前正朝著兩個方向努力:首先，我們將闡明SOCE和細胞基質黏附相互作用的分子機制，具體是通過Ca2+調節黏附力直接作用還是通過Ca2+介導的細胞分化間接作用。其次，我們將檢驗我們的數學模型是否可以用於預測癌症轉移和患者預後。這些方法將提高我們對癌細胞遷移的理解，從而開發出新的治療策略。

Ca2+ signaling is involved in many important physiological activities including cell migration, but how Ca2+ regulates cell migration remains elusive. Previous literature reports showed that store-operated Ca2+ entry (SOCE) might promote or inhibit cancer metastasis in different cancer types. Our data also indicated that such differences stemmed from different cell-matrix adhesion strengths in different cancer types, because SOCE increased or decreased cell motility depending on the basal strengths of cell-matrix adhesion forces. We thus hypothesized that SOCE interacted with cell-matrix adhesion to modulate cancer cell migration. To verify our hypothesis, we established a mathematical heat map model to describe how different activities of SOCE and cell-matrix adhesion interacted to produce corresponding cell motilities. Then we overexpressed or knocked-down the key adhesion molecule PXN and key SOCE molecule STIM1 in migrating cancer cells and measured their motilities. Indeed, our experimental results matched the prediction from the mathematical model, supporting the interaction between SOCE and cell-matrix adhesion. We are currently working on two directions: First, we will elucidate the molecular mechanisms how SOCE and cell-matrix adhesion interact, specifically whether the interaction is directly through Ca2+-modulated adhesion forces or indirectly through Ca2+-mediated cell differentiation. Second, we will examine whether our mathematical model could be employed to predict cancer metastasis and patient prognosis. These approaches will improve our understanding of cancer cell migration so novel therapeutic strategies can be developed accordingly.