Mesothelin overexpression promotes autocrine IL-6/sIL-6R trans-signaling to stimulate pancreatic cancer cell proliferation
Mesothelin overexpression promotes autocrine IL-6/sIL-6R trans-signaling to stimulate pancreatic cancer cell proliferation
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DOI：
10.1093/carcin/bgr075
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发表时间：
2011-07-01
期刊：
影响因子：
4.7
通讯作者：
Yao, Qizhi
中科院分区：
文献类型：
--
作者：
Bharadwaj, Uddalak;Marin-Muller, Christian;Yao, Qizhi
间充质蛋白(MSLN)在胰腺癌(PC)中的过度表达可促进细胞的存活/增殖和肿瘤进展。在筛选了一些生长因子/细胞因子后，我们发现MSLN在人PC标本和细胞系中的表达与白细胞介素6(IL-6)密切相关。在不同的PC细胞系(MIA-MSLN和Panc1-MSLN)中稳定过表达MSLN可产生较高的IL-6。用小干扰RNA(SiRNA)沉默MSLN可显著降低IL-6水平。用IKK抑制剂维拉内酯阻断MIA-MSLN细胞中观察到的核因子-kappaB(NF-kappaB)的结构性激活也降低了IL-6。SiRNA沉默IL-6抑制细胞增殖和细胞周期进程，诱导细胞凋亡，c-myc/bcl2显著降低。有趣的是，重组IL-6可促进MIA-MSLN细胞的增殖，但不能诱导MIA-V细胞的增殖。虽然IL-6R的信使RNA/蛋白水平没有变化，但MIA-MSLN的可溶性IL-6R(sIL-6R)水平显著升高，并被TACE/ADAM17抑制剂TAPI-1处理后降低，提示MIA-MSLN细胞膜内IL-6R裂解和IL-6反式信号转导可能起作用。用sIL-6R抗体阻断IL-6/sIL-6R轴可抑制基础增殖/存活以及重组人IL-6诱导的细胞增殖。我们的研究结果表明，MSLN激活的NF-kappa B可诱导IL-6表达升高，而IL-6作为一种生长因子通过一种新的自身/旁分泌IL-6/sIL-6R反式信号转导来支持PC细胞的生存/增殖。此外，利用一组不同表达MSLN/IL-6的PC细胞，我们发现MSLN/IL-6轴是PC中一个主要的生存轴，在锚定依赖和独立条件下支持肿瘤细胞的生长。MSLN与IL-6的密切相关性为联合治疗有效控制MSLN过表达的PC提供了新的理论基础。
Mesothelin (MSLN) overexpression in pancreatic cancer (PC) leads to enhanced cell survival/proliferation and tumor progression. After screening for a number of growth factors/cytokines, we found that the MSLN expression correlated closely with interleukin (IL)-6 in human PC specimens and cell lines. Stably overexpressing MSLN in different PC cell lines (MIA-MSLN and Panc1-MSLN) led to higher IL-6 production. Silencing MSLN by small interfering RNA (siRNA) significantly reduced IL-6 levels. Blocking the observed constitutive activation of nuclear factor-kappaB (NF-kappa B) with IKK inhibitor wedelolactone in MIA-MSLN cells also reduced IL-6. Silencing IL-6 by siRNA reduced cell proliferation, cell cycle progression and induced apoptosis with significant decrease of c-myc/bcl-2. Interestingly, recombinant IL-6-induced proliferation of MIA-MSLN cells but not MIA-V cells. Although messenger RNA/protein levels of IL-6R did not vary, soluble IL-6R (sIL-6R) was significantly elevated in MIA-MSLN and was reduced by treatment with the TACE/ADAM17 inhibitor TAPI-1, indicating intramembrane IL-6R cleavage and IL-6 trans-signaling may be operative in MIA-MSLN cells. Blocking the IL-6/sIL-6R axis using sIL-6R antibody abrogated basal proliferation/survival as well as recombinant human IL-6-induced cell proliferation. Our data suggest that MSLN-activated NF-kappa B induces elevated IL-6 expression, which acts as a growth factor to support PC cell survival/proliferation through a novel auto/paracrine IL-6/sIL-6R trans-signaling. In addition, using a panel of PC cells with varying MSLN/IL-6 expressions, we showed that MSLN/IL-6 axis is a major survival axis in PC supporting tumor cell growth under anchorage-dependent and independent conditions. The close correlation between MSLN and IL-6 provides a new rationale for combination therapy for effective control of MSLN-overexpressing PCs.