胰臟癌是一種高度惡性的疾病，致死率很高，全球胰臟癌病人的五年存活率為8%左右。癌細胞具有轉移或原位擴展的能力，因此可以被診斷為切除腫瘤的患者大約只有20％。Gemcitabine（GEM）是治療胰臟癌常用的第一線抗癌藥物，但是病人對於化療後的結果並不佳。我們先前的研究發現，抑制胰臟癌細胞的自噬作用會使癌細胞對於抗癌藥物的敏感度增加，且骨橋蛋白（OPN）會誘導胰臟癌細胞產生自噬作用。我們也發現胰臟癌細胞株(PANC-1)經過GEM處理後，PANC-1會增加OPN的分泌和上調調控ABC轉運蛋白的表現。因此本研究想探討OPN是否可以刺激自噬活性以調節ABC轉運蛋白，進而維持胰臟癌的抗藥性。在動物實驗中，我們使用三種小鼠腫瘤模型來探討OPN對於胰臟癌抗藥性的潛在影響為何，分別是基因轉植Pdx1-Cre; LSL-KrasG12D/+; p53Lox/Lox (KPC)和KPC Spp1-/-（KPC OPN剔除）的自發性產生腫瘤小鼠，以及皮下和原位轉植腫瘤小鼠模型。在細胞實驗，我們建立PANC-1　shOPN、shATG5、shATG7和shBECN1細胞株，利用細胞存活和死亡檢測，細胞抗藥性活性檢測，生物能量檢測和西方墨點法，證實OPN誘導的自噬作用對於胰臟癌抗藥性的影響和機制。在小鼠模型研究中，我們證實抑制OPN表現可以增強GEM毒殺腫瘤的作用，且延長小鼠的存活。在細胞實驗，我們也驗證從腫瘤細胞釋放的OPN能夠抵抗GEM的毒殺，並且保護細胞免於細胞凋亡。此外在GEM的刺激後，OPN可以增加腫瘤細胞的ABC轉運蛋白活性，並且增強ATP的產生。在機制的部分，我們也發現OPN可以透過AMPK/ULK1/ATG5的調控產生自噬作用，進而影響ABC轉運蛋白。綜合以上研究，我們證實OPN是透過調節AMPK/ULK/ATG5來影響自噬作用的活性，以維持細胞的能量，進而提高胰臟癌的抗藥性，因此OPN/自噬作用/ABC轉運蛋白可以作為治療胰臟癌的標靶。

Pancreatic cancer (PC) is a highly lethal disease with a 5-year survival rate around 8%. Approximately less than 20% of patients were diagnosed at the resectable stage due to the presence of metastases or local extension. Gemcitabine (GEM) is the first-line drug for PC treatment. However, the patient’s response rate is low. Our previous study found that autophagy blockade sensitizes PC to GEM and osteopontin (OPN) can stimulate autophagy in PC. We also found that GEM treatment increased the OPN secretion and up-regulated ABC transporters in PC cell line PANC-1. Taken together, we are interested in investigating whether OPN can stimulate autophagic activity through regulation of ABC transporters to maintain chemo-resistance ability in PC. In vivo experiments, we used three kinds of tumor mouse models, Pdx1-Cre; LSL-KrasG12D/+; p53Lox/Lox (KPC) and KPC Spp1−/− (KPC OPN knockout) transgenic mice, subcutaneous and orthotopic syngeneic tumor models to determine the therapeutic efficiency of targeting OPN in PC therapy. In vitro experiments, PANC-1 shATG5, shATG7, shBECN1 and shOPN cell lines were established to examine the role and mechanism(s) of OPN-mediated autophagy in chemo-resistance of PC by cell viability assay, cell death assay, MDR assay, bioenergetic analysis and western blotting. In this study, we have observed targeting OPN prolongs survival and potentiates the tumoricidal effect of GEM in mouse models. In vitro experiments, we have indicated that endogenously OPN released from tumor cells is able to protect cells against apoptosis by GEM treatment. OPN up-regulates ABC transporters activities and enhances ATP production after GEM stimulation. OPN induces autophagic activity to increase the expression of ABCG2 through AMPK/ULK1/ATG5. In conclusions, we provided evidence that OPN influences autophagic activity to maintain cellular energy by regulating AMPK/ULK1/ATG5 to promote the chemo-resistance ability in PC, suggesting that OPN/autophagy/ ABCG2 axis is a potential therapeutic target for PC.

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