胰腺癌是一種高侵略性的腫瘤，並且伴隨著不良的預後。目前胰腺癌可用的治療方法與療效仍然有限。因此了解胰臟癌發病分子機制，對於早期的診斷、預後的預測和治療方法的發展都是有用的。眾所周知，自體分泌的調控訊號可以維持癌細胞生長。調控胞外作用的小型GTPase Rab37其功能與腫瘤的生成相關，但是其角色在胰腺癌中的機制仍然不明確。骨橋蛋白(OPN)是細胞分泌的細胞激素蛋白，能促進癌化的過程，也是胰腺癌的血清標誌物。此細胞激素誘導腫瘤具有幹細胞(CSC)的特性及轉移的能力可能是透過活化ERK1/2。我們利用組織微陣列的方法發現Rab37的表現量與胰腺癌的生成呈正相關。在體外實驗中，相對於對照組，過度表現Rab37的PANC-1細胞株具有較高轉移的能力和腫瘤幹細胞的特性，並且分泌較多的骨橋蛋白。相反的，降低MIA PaCa-2的Rab37表現會減少癌細胞轉移的能力和腫瘤幹細胞的特性，並且減少骨橋蛋白的分泌。原位注射癌細胞的老鼠實驗與體外實驗結果一致，發現Rab37高表現可以增強腫瘤的增生和轉移，相反地，降低癌細胞Rab37的表現反而能抑制腫瘤的生成和轉移。在機制上，我們也發現骨橋蛋白的分泌可以透過Rab37所調控，並且活化ERK路徑導致上皮變間質型的轉換(EMT)和增加腫瘤幹細胞的特性。除此之外，我們還證實KRAS的突變會促進Rab37的表現，進一步增加骨橋蛋白的分泌。相反的，降低KRAS突變的表現會造成胰腺癌細胞的Rab37表現量降低和骨橋蛋白的分泌減少。臨床資料也顯示胰腺癌中Rab37的表現量、骨橋蛋白的分泌和KRAS的突變，三者之間具有相關性；KRAS/Rab37/OPN的高表現與胰腺癌的低生存率也具有相關性。綜合以上，我們證實KRAS突變所誘導的Rab37可以調控骨橋蛋白的分泌，進而使ERK的活性增加，導致胰腺癌的癌化。因此，Rab37 在胰腺癌中可能扮演一個致癌因子，並且是具有潛力的胰腺癌治療標靶。

Pancreatic cancer is a highly aggressive tumor with dismal outcomes. The efficacy of current available treatments for pancreatic cancer remain limited. For this reason, a better understanding of the fundamental molecular mechanism underlying pancreatic cancer pathogenesis would be useful for early diagnosis, prediction of prognosis, and development of effective therapies. It is well known that autocrine signaling can provide self-sustaining growth signals to cancer cells. The small GTPase Rab37 that regulates exocytosis has been involved in tumorigenesis; however, its role in pancreatic cancer remains unclear. Osteopontin, a secreted protein involving in cancer progression, serves as a serum marker for pancreatic cancer. This cytokine has been reported to induce cancer stem cell (CSC) ability and metastasis through activation of ERK1/2. Previously, we have found that Rab37 expression is positively associated with pancreatic cancer progression using tissue microarrays. In vitro results showed that, as compared with control cells, Rab37-overexpressing PANC-1 stable cells displayed high metastatic ability, high CSC activity, and increased osteopontin secretion, but Rab37-knockdown MiaPaCa-2 cells did not. Consistent with the in vitro results, high expression of Rab37 enhanced tumor proliferation and metastasis, while knockdown of Rab37 suppressed these effects in an orthotopic mouse model. Mechanistically, Rab37-induced osteopontin can promote EMT and CSC activity through ERK. Furthermore, we demonstrated that overexpression of mutant KRAS up-regulated Rab37 and increased osteopontin secretion, whereas knockdown of mutant KRAS counteracted the effects in pancreatic cancer cells. Clinical data also showed a positive correlation among Rab37 expression, osteopontin secretion, and KRAS mutation, and that high KRAS/Rab37/OPN expression was associated with poor survival. Taken together, we here identify that KRAS mutation-induced upregulation of Rab37 mediates osteopontin secretion and thus ERK activation, driving the progression of pancreatic cancer. Rab37 may therefore acts as an oncogenic factor in pancreatic cancer and represent a potential therapeutic target.

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