大腸直腸癌是全球癌症排名第三，不論發生率、死亡率都相當高，一旦病人初診即為轉移型大腸癌，五年存活率僅剩12%，是目前臨床上相當棘手的問題。許多研究發現，發炎或是代謝疾病例如肥胖都會導致癌症的進程，又肥胖所致的高血脂病症常常伴隨著慢性發炎，因此有關高血脂相關性的發炎對於大腸癌轉移的影響是本篇的研究方向。首先，利用人體脂肪細胞中含量最豐富的油酸(Oleic acid, OA)作為高血脂的模式，藉由將癌細胞打入小鼠尾靜脈，使癌細胞於血流中循環，並且觀察肺部組織癌細胞外滲現象(extravasation)，結果顯示有加入OA處理的組別相較一般組別細胞還要多，然而有預先處理Aspirin或是Curcumin的組別，可以有效抑制OA所造成的細胞extravasation，同樣的結果也可以在由DSS所引發的發炎模式以及由高脂飼料所引發的肥胖鼠模式看到，說明高血脂以及發炎對於癌細胞extravasation具有相關性。此外，在體外細胞實驗中，有處理OA的組別，細胞爬行能力、侵入能力、抗失巢凋亡能力有明顯上升，以及上皮與間質細胞間轉換、基質金屬蛋白酶的標記也皆有增加，顯示出OA會促使細胞的轉移能力增強。同時，有處理OA的組別，發炎相關的基因像是COX-2, IL-8, IL-6, ANGPTL4等，皆可以被OA所誘導上升。此外，外加IL-8也可看到OA下游所調控的基因上升以及相關轉移性功能試驗的增強；另一方面，若是預先knockdown IL-8的表現，可以抑制原先OA所誘導的基因上升、細胞爬行與侵入實驗。總結來說，由上述實驗結果可以得知，高血脂相關性的發炎可以促進大腸直腸癌細胞轉移。

Colorectal cancer (CRC) is a leading common cancer around the world. The overall survival rate worsens with increasing clinical stage with only 12% of patients with metastatic cancer being alive at 5 years. Many researches show CRC progression is linked with inflammation and metabolic diseases including obesity. In order to identify whether metabolic disorder such as hyperlipidemia enhances tumor cell metastasis, we conducted tail vein injection of CRC cells in mice and found that more oleic acid (OA)-treated cells in frozen sections of lung tissues were observed than those untreated cells. However, pre-treating aspirin or curcumin inhibited extravasation of tumor cells, which consistent in DSS-induced inflammation model, suggesting inflammation might play a crucial role in hyperlipidemia-induced cancer metastasis. In addition, the mRNA expression of inflammatory cytokines such as IL-6, IL-8 and cyloxygenase-2 (COX-2) were also induced in OA-treated cells. Our previous results showed that angiopoietin-like 4 (ANGPTL4), a lipid metabolic protein, regulates metastasis and is the downstream of COX-2 in head and neck cancer. Here, we found the increased expression of ANGPTL4 and epithelial-mesenchymal transition (EMT) / matrix metalloproteinases (MMPs) markers that were associated with hyperlipidemia-induced cancer metastasis. The ability of CRC cell migration and invasion was promoted by OA treatment. Moreover, the increased expression level in IL-8 was found in OA-treated CRC cells by protein array. Knockdown IL-8 inhibited OA-induced cell metastasis behavior and mRNA expression of EMT / MMPs marker, which was reversed by adding IL-8 recombinant protein. In summary, these results indicate that hyperlipidemia-associated inflammation enhanced CRC metastasis.

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