Interleukin-6 trans-signaling increases the expression of carcinoembryonic antigen-related cell adhesion molecules 5 and 6 in colorectal cancer cells.
Interleukin-6 trans-signaling increases the expression of carcinoembryonic antigen-related cell adhesion molecules 5 and 6 in colorectal cancer cells.
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DOI：
10.1186/s12885-015-1950-1
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发表时间：
2015-12-16
期刊：
影响因子：
3.8
通讯作者：
Kalthoff H
中科院分区：
文献类型：
--
作者：
Holmer R;Wätzig GH;Tiwari S;Rose-John S;Kalthoff H
结直肠癌(CRC)是欧洲与癌症相关的死亡的五大最常见原因之一。癌胚抗原相关细胞黏附分子5(CEACAM5)是结直肠癌最重要的肿瘤相关抗原之一，参与细胞的黏附、迁移、失巢、肿瘤侵袭和转移。它的家族成员CEACAM6在结肠腺瘤和结肠癌中也表达上调，是生存不良的独立预测因素。以前的研究已经报道了CEACAM5的上调与白细胞介素6(IL-6)之间的联系。IL-6在结直肠癌的发生发展中起着重要作用，其信号传导途径有两条(经典信号通路和反式信号通路)。然而，这种联系还不能被其他研究证实，IL-6反式信号在CEACAM5上调中的作用还没有阐明。此外，IL-6对CEACAM6表达的影响尚未被研究。采用逆转录聚合酶链式反应、Western印迹、流式细胞术或定量聚合酶链式反应等方法检测细胞因子IL-6、IL-6受体(IL-6R)、糖蛋白130、CEACAM5和CEACAM6的表达。用IL-6或Hyper-IL-6(介导IL-6反式信号转导)与结肠癌细胞系共同孵育，用定量聚合酶链式反应或Western印迹法检测CEACAMs的表达。用信号转导和转录激活因子-3(STAT3)的磷酸化抑制剂FLLL31来确定STAT3的磷酸化作用。我们证实了结肠癌细胞株表达IL-6和IL-6R。我们观察到经典的IL-6信号仅微弱上调CEACAM5和CEACAM6，而IL-6反式信号强烈上调CEACAM5和CEACAM6。这种上调依赖于STAT3的磷酸化。我们的数据显示，促炎症细胞因子IL-6的反式信号上调了肿瘤相关抗原CEACAM5/6的表达。这一机制可能有助于IL-6的促肿瘤作用，因此可能成为治疗干预的靶点，特别是通过特定的抑制剂，如sgp130Fc。本文的在线版本(doi：10.1186/s12885-0151950-1)包含补充材料，授权用户可以使用。
Colorectal cancer (CRC) is among the five most frequent causes for cancer-related deaths in Europe. One of the most important tumor-associated antigens for CRC is carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), which is involved in cell adhesion, migration, anoikis, tumor invasion and metastasis. Its family member CEACAM6 is also upregulated in adenomas and carcinomas of the colon and an independent predictor of poor survival. Previous studies have reported a link between upregulation of CEACAM5 and interleukin-6 (IL-6). IL-6 plays an important role in CRC progression, and signaling is mediated via two pathways (classic and trans-signaling). However, this link could not be confirmed by other studies, and the role of IL-6 trans-signaling in the CEACAM5 upregulation has not been elucidated. Moreover, the impact of IL-6 on the expression of CEACAM6 has not yet been examined. The expression of IL-6, IL-6 receptor (IL-6R), glycoprotein (gp) 130, CEACAM5 and CEACAM6 was analyzed by RT-PCR, Western blot, flow cytometry or qPCR. Colon cell lines were incubated with IL-6 or Hyper-IL-6 (mediating IL-6 trans-signaling), and subsequently, the expression of CEACAMs was determined by qPCR or Western blot. FLLL31, an inhibitor of the phosphorylation of signal transducer and activator of transcription-3 (STAT3), was used to determine the role of STAT3 phosphorylation. We confirmed that colon carcinoma cell lines express IL-6 and IL-6R. We observed only a weak upregulation of CEACAM5 and CEACAM6 by classic IL-6 signaling, but a strong increase by IL-6 trans-signaling. This upregulation depended on the phosphorylation of STAT3. Our data show the upregulation of the tumor-associated antigens CEACAM5/6 by trans-signaling of the pro-inflammatory cytokine IL-6. This mechanism may contribute to the tumor-promoting role of IL-6 and could therefore be a target for therapeutic intervention in particular by specific inhibitors such as sgp130Fc. The online version of this article (doi:10.1186/s12885-015-1950-1) contains supplementary material, which is available to authorized users.