Kimura Motohiro, Hashimoto Naozumi, Kusunose Masaaki, Aoyama Daisuke, Sakamoto Koji, Miyazaki Shinichi, Ando Akira, Omote Norihiro, Imaizumi Kazuyoshi, Kawabe Tsutomu, Hasegawa Yoshinori
Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Respiratory Medicine and allergy, Fujita Health University, Toyoake, Japan.
Wound Repair Regen. 2017 Jan;25(1):86-97. doi: 10.1111/wrr.12506. Epub 2017 Jan 25.
Transforming growth factor β (TGFβ) plays an important role in regulating aberrant extracellular matrix (ECM) production from alveolar/epithelial cells (AECs) and fibroblasts in pulmonary fibrosis. Although the tumor suppressor gene phosphatase and tensin homologue deleted from chromosome 10 (PTEN) can negatively control many TGFβ-activated signaling pathways via the phosphatase activity, hyperactivation of the TGFβ-related signaling pathways is often observed in fibrosis. Loss of PTEN expression might cause TGFβ-induced ECM production. In addition, TGFβ was recently shown to induce loss of PTEN enzymatic activity by phosphorylating the PTEN C-terminus. Therefore, we hypothesized that exogenous transfer of unphosphorylated PTEN (PTEN4A) might lead to reduce TGFβ-induced ECM expression in not only epithelial cells but also fibroblasts. Adenovirus-based exogenous PTEN4A induction successfully reduced TGFβ-induced fibronectin expression and retained β-catenin at the cell membrane in human epithelial cells. Exogenous unphosphorylated PTEN also attenuated TGFβ-induced ECM production and inhibited TGFβ-induced β-catenin translocation in a human fibroblast cell line and in mouse primary isolated lung fibroblasts. Conversely, TGFβ-induced α-smooth muscle actin expression did not seem to be inhibited in these fibroblasts. Our data suggest that exogenous administration of unphosphorylated PTEN might be a promising strategy to restore TGFβ-induced loss of PTEN activity and reduce aberrant TGFβ-induced ECM production from epithelial cells and fibroblasts in lung fibrosis as compared with wild-type PTEN induction.
转化生长因子β（TGFβ）在调节肺纤维化中肺泡/上皮细胞（AECs）和成纤维细胞异常产生细胞外基质（ECM）方面发挥着重要作用。尽管肿瘤抑制基因10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）可通过磷酸酶活性对许多TGFβ激活的信号通路进行负调控，但在纤维化过程中常观察到TGFβ相关信号通路的过度激活。PTEN表达缺失可能导致TGFβ诱导的ECM产生。此外，最近发现TGFβ可通过磷酸化PTEN的C末端诱导PTEN酶活性丧失。因此，我们推测未磷酸化的PTEN（PTEN4A）的外源性转移可能不仅会导致上皮细胞中TGFβ诱导的ECM表达减少，还会使成纤维细胞中的表达减少。基于腺病毒的外源性PTEN4A诱导成功降低了人上皮细胞中TGFβ诱导的纤连蛋白表达，并使β-连环蛋白保留在细胞膜上。外源性未磷酸化的PTEN还减弱了人成纤维细胞系和小鼠原代分离肺成纤维细胞中TGFβ诱导的ECM产生，并抑制了TGFβ诱导的β-连环蛋白易位。相反，在这些成纤维细胞中，TGFβ诱导的α-平滑肌肌动蛋白表达似乎未受到抑制。我们的数据表明，与野生型PTEN诱导相比，外源性给予未磷酸化的PTEN可能是一种有前景的策略，可恢复TGFβ诱导的PTEN活性丧失，并减少肺纤维化中上皮细胞和成纤维细胞异常的TGFβ诱导的ECM产生。
