胰臟癌是一個具有破壞性且預後不佳的疾病。胰臟腫瘤周圍有明顯的不正常纖維化組織生長是其主要特徵。胰臟癌預後不佳的原因之一是因為胰臟星狀細胞不正常的活化與增生。以往的文獻指出，胰臟星狀細胞的活化會造成胰臟纖維化(pancreatic fibrosis)，而該纖維化現象也會使化療藥物不易通透進而影響導致藥效不佳的情形。活化的胰臟星狀細胞會與胰臟癌細胞緊密地交互作用，並且產生細胞外基質堆積，以幫助胰臟癌進程。另外，活化的胰臟星狀細胞具有較強的抗細胞凋亡的能力。CCAAT/enhancer binding protein delta (CEBPD)是一個轉錄因子，已知參與在細胞的免疫，發炎反應，分化以及凋亡。然而，CEBPD在胰臟星狀細胞當中所扮演的角色，以及後續對胰臟癌的影響仍未被清楚探討。在本研究中，我們發現TGFβ1可以誘發胰臟星狀細胞中CEBPD的表現。一些有關於胰臟星狀細胞纖維化有關的基因，如：HIF1-α、α-SMA及HDGF的mRNA表現量都會被TGF1或大量增加的CEBPD所刺激增加。同時，也會因為CEBPD的剔除(knockdown)而表現量降低。在正常氧氣濃度環境下，CEBPD可增加HIF1-α基因的啟動子活性。在胰臟星狀細胞中，減少CEBPD的表現會增加MMS所誘發的細胞凋亡能力。而加入HDGF則可降低MMS所誘發的細胞凋亡。將分別CEBPD、HIF1-α或HDGF減少的胰臟星狀細胞與胰臟癌細胞共同培養，發現胰臟纖維化的形成有降低的情形，並且胰臟癌細胞的生長速度也會被抑制。綜合以上結果，CEBPD會調控胰臟星狀細胞的活化以及其抗細胞凋亡的能力，且被CEBPD所調控的HIF1-α與HDGF對胰臟纖維化以及胰臟星狀細胞的抗凋亡有所貢獻。

Pancreatic cancer is a destructive disease with a poor prognosis and characterized by a prominent desmoplastic reaction. A major reason for the poor prognosis is chemotherapy resistance. Pancreatic stellate cells (PSCs) are the major source of pancreatic fibrosis. Importantly, fibrosis has been suggested to contribute in chemotherapy resistance of pancreatic cancers. When PSCs activated, it changes its phenotype from quiescent and differentiate to myofibroblast, and interacts with cancer cells closely to make extracellular matrix (ECM) deposition to further result in fibrosis. Increase of anti-apoptotic activity is a feature in fibrotic cells. CCAAT/enhancer binding protein delta (CEBPD) is a transcription factor which participates in many immune and inflammatory responses, cell differentiation, and apoptosis. However, the function of CEBPD in PSCs and consequent effects in cancer development remain largely uninvestigated. In this study, we found that TGFβ1 can induce the expression of CEBPD in PSCs. In gene expression, HIF1-α, α-SMA and HDGF mRNAs were induced in PSCs treated with TGFβ1 or exogenously expressed CEBPD. Meanwhile, HIF1-α, α-SMA, and HDGF transcripts were decreased in CEBPD-knockdown PSCs upon TGFβ1 treatment. Additionally, CEBPD can enhance HIF1-α promoter activity in normoxia. Interestingly, CEBPD-knockdown PSCs sensitized to MMS-induced apoptosis. The pre-treatment of HDGF protected cell to MMS-induced apoptosis. Furthermore, the conditioned medium of CEBPD- or HIF1-α- or HDGF-knockdown PSCs can reduce pancreatic fibrosis and proliferation of pancreatic cancer cells. Our results showed that CEBPD contributed to the activation and anti-apoptotic activity of PSCs. The transcripts of α-SMA, HIF1-α and HDGF genes were responsive to induction of CEBPD in PSCs, which contributes to the formation of fibrosis and anti-apoptosis of PSCs.

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