TβRIII suppresses non-small cell lung cancer invasiveness and tumorigenicity
TβRIII suppresses non-small cell lung cancer invasiveness and tumorigenicity
复制标题
DOI：
10.1093/carcin/bgm289
复制
发表时间：
2008-03-01
期刊：
影响因子：
4.7
通讯作者：
Blobe, Gerard C.
中科院分区：
文献类型：
--
作者：
Finger, Elizabeth C.;Turley, Ryan S.;Blobe, Gerard C.
转化生长因子-β (TGF-β) 超家族在肺发育、调节细胞增殖、分支形态发生、分化和凋亡中具有重要作用。尽管大多数肺癌对 TGF-β 的肿瘤抑制作用产生抗药性，并且有报道称 TGF-β 信号通路的一种成分（包括 T beta RII、Smad2 和 Smad4）丢失或突变，但突变在非小细胞肺癌 (NSCLC) 中并不常见。在这里，我们证明 TGF-β 超家族共同受体，即 III 型 TGF-β 受体（T beta RIII 或 Betaglycan）在大多数 NSCLC 样本中在 mRNA 和蛋白质水平上丢失，其丢失与肿瘤分级和疾病进展的增加相关。 38.5% 的 NSCLC 样本中发生 TGFBR3 基因组位点杂合性丢失，并且与 T beta RIII 表达降低相关，表明杂合性丢失是 T beta RIII 丢失的一种机制。在 NSCLC H460 细胞模型中，恢复 T beta RIII 表达可减少软琼脂中的集落形成。在 NSCLC A549 细胞模型中，在存在或不存在 TGF-β 1 的情况下，恢复 T beta RIII 表达可显着降低细胞通过 Matrigel 的迁移和侵袭，并降低体内致瘤性。 shRNA介导的内源性TβRIII表达沉默以相反的方式增强了通过Matrigel的侵袭。从机制上讲，T beta RIII 的功能（至少部分是通过胞外域脱落）产生可溶性 T beta RIII，从而能够抑制细胞侵袭。总而言之，这些结果支持 T beta RIII 作为一种新型肿瘤抑制基因，该基因在 NSCLC 中通常丢失，导致肺癌细胞的细胞迁移、侵袭和贴壁依赖性生长的功能增加。
The transforming growth factor-beta (TGF-beta) superfamily has essential roles in lung development, regulating cell proliferation, branching morphogenesis, differentiation and apoptosis. Although most lung cancers become resistant to the tumor suppressor effects of TGF-beta, and loss or mutation of one of the components of the TGF-beta signaling pathway, including T beta RII, Smad2 and Smad4 have been reported, mutations are not common in non-small cell lung cancer (NSCLC). Here we demonstrate that the TGF-beta superfamily co-receptor, the type III TGF-beta receptor (T beta RIII or betaglycan) is lost in the majority of NSCLC specimens at the mRNA and protein levels, with loss correlating with increased tumor grade and disease progression. Loss of heterozygosity at the TGFBR3 genomic locus occurs in 38.5% of NSCLC specimens and correlates with decreased T beta RIII expression, suggesting loss of heterozygosity as one mechanism for T beta RIII loss. In the H460 cell model of NSCLC, restoring T beta RIII expression decreased colony formation in soft agar. In the A549 cell model of NSCLC, restoring T beta RIII expression significantly decreased cellular migration and invasion through Matrigel, in the presence and absence of TGF-beta 1, and decreased tumorigenicity in vivo. In a reciprocal manner, shRNA-mediated silencing of endogenous T beta RIII expression enhanced invasion through Matrigel. Mechanistically, T beta RIII functions, at least in part, through undergoing ectodomain shedding, generating soluble T beta RIII, which is able to inhibit cellular invasiveness. Taken together, these results support T beta RIII as a novel tumor suppressor gene that is commonly lost in NSCLC resulting in a functional increase in cellular migration, invasion and anchorage-independent growth of lung cancer cells.