探討癌細胞所分泌的骨橋蛋白-a調控肺癌細胞生長的機制

骨橋蛋白(Osteopontin，簡寫為OPN)是一個分泌型的磷酸化醣蛋白，在乳癌、前列腺癌、大腸癌、頭頸癌、肝癌與肺癌都有過度表現的情形，且在肺癌細胞中，過度表現的OPN與腫瘤的惡化及病人較差的預後有正相關性。OPN有三種剪接變異型，OPN-a、OPN-b及OPN-c，在肺癌病人組織及肺癌細胞株中OPN-a的表現量最高。以OPN-a處理肺癌細胞株時可觀察到CL1-5細胞生長受到抑制，但是卻不影響A549。進一步在這二株細胞中分析已知的OPN受體integrin及CD44表現後，我們發現OPN-a對細胞生長的影響是來自於integrin β3 (ITGβ3)表現量的差異，在原本不受影響的A549、H460及H1299細胞中過度表現ITGβ3之後，OPN-a即可抑制這三株細胞的生長；而抑制CL1-5的ITGβ3後，OPN-a不但失去抑制細胞生長的能力，還可以透過活化CD44/NF-kB這條訊息傳遞路徑促進細胞生長。也就是說，OPN-a對於肺癌細胞的生長是促進還是抑制取決於和何種受體結合。但是對於可表現ITGβ3的癌症細胞而言，OPN-a的存在對生長不利，這跟OPN普遍被認為是一個致癌蛋白的印象是矛盾的。因此我們假設，腫瘤表現出的OPN-a可能會刺激微環境中的其他細胞，例如纖維母細胞、免疫細胞等放出有利腫瘤細胞發展的細胞激素來促進腫瘤的生成。我們的結果也證實了這點，不論以含有OPN-a的條件培養液或是純化之OPN-a刺激纖維母細胞或是脾臟細胞後，所取得之條件培養液皆能促進CL1-5及LLC1細胞的生長。綜合以上結果，雖然OPN-a對於癌細胞本身的生長所扮演的角色是由細胞所表現的受體控制，但是來自於微環境的訊號則可以彌補或反過來促進腫瘤細胞生長，使腫瘤趨向惡化。

關鍵字

骨橋蛋白；肺癌；生長抑制

並列摘要

Osteopontin (OPN), a phosphorylated glycoprotein, is frequently overexpressed in cancer. Among the three OPN isoforms, OPN-a is the most highly expressed in lung cancer cell lines and lung tumors. Overexpression of OPN-a greatly reduced CL1-5 lung adenocarcinoma cell growth but had no effect on growth in A549 lung adenocarcinoma cells. Examination of the expression of integrins and CD44, which are possible OPN-a receptors, revealed that differences in integrin β3 levels might explain this discrepancy between CL1-5 and A549 cells. When integrin β3 was ectopically expressed in A549 cells, OPN-a inhibited their growth, whereas OPN-a increased cell growth following integrin β3 knockdown in CL1-5 cells. This OPN-a-induced increase in growth appeared to result from activation of the CD44/NFkB pathway. However, OPN-a inhibits the growth of cells with high integrin β3 levels is contradictory to the impression of OPN as an oncoprotein. Therefore, we hypothesised that cancer-secreted-OPN-a may stimulate cells in the microenvironment, such as fibroblast, immune cells, etc., to release cytokines in favour of cell growth. Our results revealed that OPN-a stimulated fibroblasts or splenocytes releasing cytokines into condition medium to promote CL1-5 and LLC1 growth. Thus, OPN-a not only interacts integrin β3 and CD44 to affect lung cancer cell growth but also through modulating microenvironment to create a better condition for tumorigenesis.

並列關鍵字

Osteopontin ； integrin β3 ； CD44 ； NF-kB

參考文獻

Afify, A., Purnell, P. & Nguyen, L. (2009) Role of CD44s and CD44v6 on human breast cancer cell adhesion, migration, and invasion. Exp Mol Pathol 86, 95-100.

Ahmed, M., Behera, R., Chakraborty, G. et al. (2011) Osteopontin: a potentially important therapeutic target in cancer. Expert Opin Ther Targets 15, 1113-1126.

Ailane, S., Long, P., Jenner, P. & Rose, S. (2013) Expression of integrin and CD44 receptors recognising osteopontin in the normal and LPS-lesioned rat substantia nigra. Eur J Neurosci 38, 2468-2476.

Anborgh, P.H., Mutrie, J.C., Tuck, A.B. & Chambers, A.F. (2011) Pre- and post-translational regulation of osteopontin in cancer. J Cell Commun Signal 5, 111-122.

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探討癌細胞所分泌的骨橋蛋白-a調控肺癌細胞生長的機制

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