研究益生菌在胰臟癌的抗癌療效

Studies on Anti-pancreatic Cancer Effects of Probiotics

陳婉(王亭)(Wan-Ting Chen)

指導教授 ： 劉光耀 ； 詹明修

中山醫學大學/醫學院/生化微生物免疫研究所/碩士(2017年)

摘要

胰臟癌為極為惡性之癌症之一，在西方國家為癌症第四大死因，在台灣為癌症第八大死因。 微生物相與多種慢性疾病包括癌症有著密切的關連，自流行病學及微生物相的研究，牙周病菌與胰臟癌具相關性。 另一方面，口服益生菌對於病人的過敏及腸道疾病之改善已具成效，然對於癌症是否有療效仍有待釐清。 本研究針對益生菌是否可抑制胰臟癌的惡化進行研究。 本研究中，我們利用動物模式探討口服益生菌對於胰臟癌惡化的影響與機制。使用LSL-KrasG12D; Pdx-1-Cre基因轉殖胰臟癌動模式證實牙周致病菌Prophyromonas gingivalis塗抹於口腔，會增加胰臟癌惡化程度。所有的生物標記與胰臟重量、癌化範圍、惡化程度、纖維化程度，以及上皮間質轉換的狀況 (N-Cadherin、αSMA、SNAIL-1、Vimentin及ZEB1) 在口腔塗抹Prophyromonas gingivalis (P. gingivalis) 組別的基因轉殖小鼠胰臟組織中都顯著增加。相同的動物模式也被用於評估給予益生菌對癌症發展的作用。我們的結果證實給予小鼠口服益生菌顯著抑制了致癌基因KrasG12D所誘導的胰臟癌發展，並扭轉了P. gingivalis刺激癌症的惡化。給予益生菌治療的組別在細胞增生標誌物PCNA的表現量低於未經處理的對照組別與口腔塗抹P. gingivalis的LSL-KrasG12D; Pdx-1-Cre基因轉殖小鼠。在益生菌治療的LSL-KrasG12D; Pdx-1-Cre基因轉殖小鼠胰臟癌組織中觀察到上述的EMT標記物也會顯著的降低。我們的研究結果表明，補充益生菌可有效減少胰臟癌的發生，並抑制胰臟癌的轉移。 這一新興戰略將為我們對抗胰腺癌帶來了新希望。

關鍵字

胰臟癌 ； 牙周病 ； 牙齦卟益生菌

並列摘要

Pancreatic cancer is one of the most malignant tumors which is the fourth leading cause of cancer death in western countries and the eighth in Taiwan. Microbiota has been shown to play an important roles in the pathogenesis of many chronic diseases including cancer. Recent epidemiological studies and microbiome analysis have suggested that periodontal disease may be associated with the progression of pancreatic cancer. On the other hand, oral intake of probiotics is beneficial for patients with allergic disease and inflammatory bowel diseases. However, the effect of probiotics on cancer regression still needs more investigations. In this study, we explored the effects and the mechanism of oral administration of probiotics on pancreatic cancer deterioration using a disease animal model. Using LSL-KrasG12D;Pdx-1-Cre transgenic (TG) pancreatic cancer mouse model, we conformed that oral smear of a periodontitis pathogen Porphyromonas gingivalis (P. gingivalis) significantly promoted pancreatic cancer deterioration. All biomarkers including the pancreas weight, lesion area, pathological grades, fibrosis, and epithelial-mesenchymal transition (N-Cadherin, αSMA, SNAIL-1, Vimentin and ZEB1) in pancreatic tissues were significantly increased in the TG mouse group with P. gingivalis treatment. To evaluate the protective effect of probiotics on cancer progression, our results demonstrated that oral administration of probiotics significantly suppressed oncogenic KrasG12D-induced pancreatic cancer development and reversed P. gingivalis-stimulated cancer deterioration in mice. The expression of cell proliferation marker, PCNA treated with probiotics group was lower than the non-treated and P. gingivalis treated KrasG12D/-Pdx-1-Cre transgenic mice. The expression of the aforementioned EMT markers in pancreatic cancer tissue were also significantly reduced in KrasG12D/-Pdx-1-Cre transgenic mice treated with the probiotics. Our results suggest that a diet supplement of probiotics may effectively reduce the occurrence of pancreatic cancer, and inhibit pancreatic cancer metastasis. This emerging strategy will give us new hope for anti-pancreatic cancer.

並列關鍵字

Pancreatic cancer ； Periodontal disease ； Porphyromonas gingivalis ； Probiotics

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