Magnusson Cecilia, Ehrnström Roy, Olsen Jørgen, Sjölander Anita
Division of Cell and Experimental Pathology, Lund University, Malmö University Hospital, Malmö, Sweden.
Cancer Res. 2007 Oct 1;67(19):9190-8. doi: 10.1158/0008-5472.CAN-07-0771.
Increased levels of inflammatory mediators such as cysteinyl leukotrienes (CysLT) have been found in and around tumors. These data, along with our previous observation that the G-protein-coupled receptor CysLT(1)R, which signals survival and proliferation, is up-regulated in colon cancer, suggest an important role for CysLT(1)R in tumor development. The objective of this study was to examine the expression and function of the low-affinity CysLT2 receptor (CysLT2R) in colon cancer. We found lower expression levels of CysLT2R compared with CysLT(1)R in cancer cell lines as well as clinical tumor material. Interestingly, CysLT2R, like CysLT(1)R, was found to be one of few G-protein-coupled receptors that are located both at the plasma membrane and the nuclear membrane. No effect of CysLT2R signaling on cell proliferation was observed, nor was there a correlation between CysLT2R and different proliferation markers such as Ki-67 and cyclooxygenase-2 in the tumor material. Instead, we found that activation of this receptor in colon cancer cells led to cellular differentiation similar to the effects of butyrate treatment. In accordance with this finding, we found that reduced expression of CysLT2R in colon cancer was associated with poor prognosis. We report the novel finding that CysLT2R signaling leads to terminal differentiation of colon carcinoma cells and growth inhibition, and that its expression is relatively high in less malignant forms of colon cancer. These data suggest that the balance between these two receptors is important for tumor progression and disease outcome.
在肿瘤内部及周围已发现炎症介质水平升高，如半胱氨酰白三烯（CysLT）。这些数据，连同我们之前的观察结果，即信号传导生存和增殖的G蛋白偶联受体CysLT(1)R在结肠癌中上调，提示CysLT(1)R在肿瘤发展中起重要作用。本研究的目的是检测低亲和力CysLT2受体（CysLT2R）在结肠癌中的表达及功能。我们发现，与癌细胞系以及临床肿瘤材料中的CysLT(1)R相比，CysLT2R的表达水平较低。有趣的是，与CysLT(1)R一样，CysLT2R是少数位于质膜和核膜的G蛋白偶联受体之一。未观察到CysLT2R信号传导对细胞增殖有影响，在肿瘤材料中CysLT2R与不同的增殖标志物如Ki-67和环氧化酶-2之间也无相关性。相反，我们发现激活结肠癌细胞中的该受体可导致细胞分化，类似于丁酸盐处理的效果。与此发现一致，我们发现结肠癌中CysLT2R表达降低与预后不良相关。我们报告了一项新发现，即CysLT2R信号传导导致结肠癌细胞终末分化和生长抑制，且其在恶性程度较低的结肠癌中表达相对较高。这些数据表明，这两种受体之间的平衡对肿瘤进展和疾病转归很重要。
