Gordon Kelly J, Dong Mei, Chislock Elizabeth M, Fields Timothy A, Blobe Gerard C
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Carcinogenesis. 2008 Feb;29(2):252-62. doi: 10.1093/carcin/bgm249. Epub 2007 Nov 13.
Epithelial to mesenchymal transitions (EMTs) contribute to increases in cellular motility and invasiveness during embryonic development and tumorigenesis. The transforming growth factor beta (TGF-beta) signaling pathway is a key regulator of EMT. The TGF-beta superfamily coreceptor, the type III TGF-beta receptor (TbetaRIII or betaglycan), is required for EMT during embryonic heart development and palate fusion. Here, we establish that in a pancreatic cancer model of EMT, TbetaRIII expression is specifically lost during EMT at the mRNA and protein levels, whereas levels of the TGF-beta type I and type II receptors are maintained at the mRNA level. Loss of TbetaRIII expression at the protein level precedes the loss of E-cadherin and cytoskeletal reorganization during early stages of EMT. However, maintaining TbetaRIII expression does not block these aspects of EMT, but instead suppresses the increased motility and invasiveness associated with EMT. Reciprocally, shRNA-mediated knockdown of endogenous TbetaRIII increases cellular motility without affecting Snail or E-cadherin levels. The ability of TbetaRIII to suppress motility and invasiveness does not depend on its cytoplasmic domain or its coreceptor function. Instead, this suppression of invasion is partially mediated by ectodomain shedding of TbetaRIII, generating soluble TbetaRIII (sTbetaRIII). In human pancreatic cancer specimens, TbetaRIII expression decreases at both the mRNA and protein levels, with the degree of loss correlating with worsening tumor grade. Taken together, these studies support a role for loss of TbetaRIII expression during the EMT of pancreatic cancer progression, with a specific role for sTbetaRIII in suppressing EMT-associated increases in motility and invasion.
上皮-间质转化（EMT）在胚胎发育和肿瘤发生过程中促进细胞运动性和侵袭性增加。转化生长因子β（TGF-β）信号通路是EMT的关键调节因子。TGF-β超家族共受体，即III型TGF-β受体（TβRIII或β聚糖），在胚胎心脏发育和腭融合过程中的EMT中是必需的。在此，我们证实，在胰腺癌EMT模型中，TβRIII在mRNA和蛋白质水平上在EMT过程中特异性缺失，而TGF-β I型和II型受体的水平在mRNA水平上保持不变。在EMT早期，TβRIII蛋白水平的缺失先于E-钙黏蛋白的缺失和细胞骨架重组。然而，维持TβRIII表达并不能阻止EMT的这些方面，而是抑制与EMT相关的运动性和侵袭性增加。相反，shRNA介导的内源性TβRIII敲低增加细胞运动性，而不影响Snail或E-钙黏蛋白水平。TβRIII抑制运动性和侵袭性的能力不依赖于其胞质结构域或其共受体功能。相反，这种对侵袭的抑制部分由TβRIII的胞外域脱落介导，产生可溶性TβRIII（sTβRIII）。在人类胰腺癌标本中，TβRIII在mRNA和蛋白质水平上均降低，缺失程度与肿瘤分级恶化相关。综上所述，这些研究支持TβRIII表达缺失在胰腺癌进展的EMT过程中的作用，以及sTβRIII在抑制与EMT相关的运动性和侵袭性增加中的特定作用。
