GI Research Unit and Cancer Cell Biology Program, Mayo Clinic, Rochester, Minnesota 55905, USA.
J Clin Invest. 2013 Mar;123(3):1138-56. doi: 10.1172/JCI63836. Epub 2013 Feb 1.
In the tumor microenvironment, TGF-β induces transdifferentiation of quiescent pericytes and related stromal cells into myofibroblasts that promote tumor growth and metastasis. The mechanisms governing myofibroblastic activation remain poorly understood, and its role in the tumor microenvironment has not been explored. Here, we demonstrate that IQ motif containing GTPase activating protein 1 (IQGAP1) binds to TGF-β receptor II (TβRII) and suppresses TβRII-mediated signaling in pericytes to prevent myofibroblastic differentiation in the tumor microenvironment. We found that TGF-β1 recruited IQGAP1 to TβRII in hepatic stellate cells (HSCs), the resident liver pericytes. Iqgap1 knockdown inhibited the targeting of the E3 ubiquitin ligase SMAD ubiquitination regulatory factor 1 (SMURF1) to the plasma membrane and TβRII ubiquitination and degradation. Thus, Iqgap1 knockdown stabilized TβRII and potentiated TGF-β1 transdifferentiation of pericytes into myofibroblasts in vitro. Iqgap1 deficiency in HSCs promoted myofibroblast activation, tumor implantation, and metastatic growth in mice via upregulation of paracrine signaling molecules. Additionally, we found that IQGAP1 expression was downregulated in myofibroblasts associated with human colorectal liver metastases. Taken together, our studies demonstrate that IQGAP1 in the tumor microenvironment suppresses TβRII and TGF-β dependent myofibroblastic differentiation to constrain tumor growth.
在肿瘤微环境中，TGF-β诱导静止的周细胞和相关基质细胞向肌成纤维细胞转化，促进肿瘤生长和转移。调控肌成纤维细胞激活的机制尚不清楚，其在肿瘤微环境中的作用也尚未被探索。在这里，我们证明了含有 IQ 基序的 GTP 酶激活蛋白 1（IQGAP1）与 TGF-β 受体 II（TβRII）结合，并抑制周细胞中 TβRII 介导的信号转导，以防止肿瘤微环境中的肌成纤维细胞分化。我们发现 TGF-β1 在肝星状细胞（HSCs），即驻留的肝周细胞中，募集 IQGAP1 到 TβRII。Iqgap1 敲低抑制了 E3 泛素连接酶 SMAD 泛素化调节因子 1（SMURF1）到质膜和 TβRII 泛素化和降解的靶向。因此，Iqgap1 敲低稳定了 TβRII，并增强了 TGF-β1 体外诱导周细胞向肌成纤维细胞的转化。HSCs 中的 Iqgap1 缺失通过上调旁分泌信号分子促进肌成纤维细胞的激活、肿瘤植入和转移生长。此外，我们发现与人类结直肠肝转移相关的肌成纤维细胞中 IQGAP1 的表达下调。综上所述，我们的研究表明，肿瘤微环境中的 IQGAP1 抑制了 TβRII 和 TGF-β 依赖性肌成纤维细胞分化，从而限制了肿瘤生长。
