探討骨頭分泌之SDF-1在調控肺癌細胞轉移至骨骼的機轉

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题名:	探討骨頭分泌之SDF-1在調控肺癌細胞轉移至骨骼的機轉
其它题名:	Role of Bone-Derived SDF-1 in Lung Cancer Metastasis to Bone
作者:	湯智昕
贡献者:	中國醫藥大學藥理學科
日期:	2010-07
上传时间:	2010-09-05 15:23:00 (UTC+8)
摘要:	臨床上發現乳癌、前列線癌和肺癌是常見轉移至骨骼的腫瘤，傳統上可將腫瘤轉移至骨骼區分成破骨性(osteolytic) 及造骨性(osteoblastic) 兩類，在破骨性的癌轉移中，通常伴隨著破骨細胞數目的增加及骨吸收作用的提昇。在最近的報告中指出由造骨細胞或骨髓細胞所分泌的chemokine stromal-cell-derived factor 1(SDF-1or CXCL12) 可以刺激血球源細胞驅化回骨頭。由資料檢索我們推測骨骼內的造骨細胞或骨髓細胞所分泌的SDF-1 具有調控肺癌細胞轉移至骨骼之能力。由我們的結果發現表現較高SDF-1 接受器(CXCR4)的肺癌細胞株(A549)較表現較低CXCR4 的肺癌細胞株(H928 及H1299)的侵入能力較高。而給予SDF-1, steoblast conditioned medium (OBCM) and stromal cell conditioned medium (SCCM)都可以增加肺癌細胞的侵入能力。另外給予肺癌細胞SDF-1 也會增加細胞內metalloproteinase-9 (MMP-9)的表現。因此本計劃第一年發現SDF-1/CXCR4 的交互作用參與在肺癌細胞轉移至骨骼的機轉當中，而MMP-9 是否為最重要調控細胞轉移的分子。分析骨骼所分泌的SDF-1 經由那些訊息傳遞路徑參與肺癌細胞轉移至骨骼的作用，應是一個治療肺癌細胞轉移至骨骼的指標。由我們的結果發現SDF-1 只會促進mitogen-activated protein kinase (MAPKs)中的extracellular signal-regulated kinase (ERK) 磷酸化而並不會影響p38, JNK 及Akt 的磷酸化。另外轉殖NF-kB oligonucleotide (ODN)則可以抑制由SDF-1 所增加MMP-9 promoter activity 但AP-1 及scramble ODN 並無此作用。因此在第二年的期間我們發現ERK 及NF-kB 參與SDF-1 所增加癌細胞侵入及MMP-9 的表現當中及其相互的調控作用。 Bone is one of the most common sites of metastasis in human breast, prostate, and lung cancers, as well as other cancers. It has been traditional to think of bone metastasis as either osteolytic or osteoblastic, with entirely different factors being responsible for each. In addition, cancer cells (osteolytic) have a strong predilection for metastasizing to bone, and causes increased size of osteolysis bone with increased number of osteoclasts. Stromal-cell-derived factor 1(SDF-1or CXCL12), has been found to play an important role in tumorigenicity, proliferation, metastasis and angiogenesis in many cancers. It has been reported that SDF-1 constitutively secreted by osteoblasts and bone marrow stromal cells and plays a key role for homing of hematopoietic cells to the bone marrow. Our data showed that SDF-1 receptor (CXCR4) mRNA and surface expression of CXCR4 in lung cancer cell lines, especially higher in those with high invasiveness (A549) as compared with lower level in H928 cells and H1299 cells. SDF-1, osteoblast conditioned medium (OBCM) and stromal cell conditioned medium all induced the invasiveness of lung cancer cell. In addition, SDF-1 also induced the metalloproteinase-9 (MMP-9) expression. The analysis of cell signaling for SDF-1/CXCR4 in lung cancer cells is crucial for the development of novel approaches for treatment of cancer. Our data also showed that SDF-1 induced the ERK phosphorylation but not p38, JNK and Akt. In addition, SDF-1-induced MMP-9 promoter activity was antagonized by NF-kB oligonucleotide (ODN) but not by AP-1-binding site (AP-1 ODN) or scrambled ODN. Therefore, ERK and NF-kB signaling pathway is involved in SDF-1-mediated metastasis activity and MMP-9 expression in human lung cancer cells.
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