Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
Theranostics. 2018 Jun 13;8(14):3841-3855. doi: 10.7150/thno.25784. eCollection 2018.
Human tumorous imaginal disc (Tid1), a DnaJ co-chaperone protein, is classified as a tumor suppressor. Previously, we demonstrated that Tid1 reduces head and neck squamous cell carcinoma (HNSCC) malignancy. However, the molecular details of Tid1-mediated anti-metastasis remain elusive. We used affinity chromatography and systemic mass spectrometry to identify Tid1-interacting client proteins. Immunohistochemical staining of Tid1 in HNSCC patient tissues was examined to evaluate the association between the expression profile of Tid1-interacting client proteins with pathologic features and prognosis. The roles of Tid1-interacting client proteins in metastasis were validated both in and in . The interacting partner and downstream target of Tid1-interacting client protein were determined. Herein, we first revealed that Galectin-7 was one of the Tid1-interacting client proteins. An inverse association of protein expression profile between Tid1 and Galectin-7 was determined in HNSCC patients. Low Tid1 and high Galectin-7 expression predicted poor overall survival in HNSCC. Furthermore, Tid1 abolished the nuclear translocation of Galectin-7 and suppressed Galectin-7-induced tumorigenesis and metastasis. Keratinocyte-specific Tid1-deficient mice with 4-nitroquinoline-1-oxide (4NQO) treatment exhibited increased protein levels of Galectin-7 and had a poor survival rate. Tid1 interacted with Galectin-7 through its N-linked glycosylation to promote Tid1-mediated ubiquitination and proteasomal degradation of Galectin-7. Additionally, Galectin-7 played a critical role in promoting tumorigenesis and metastatic progression by enhancing the transcriptional activity of TCF3 transcription factor through elevating MMP-9 expression. Overall, future treatments through activating Tid1 expression or inversely repressing the oncogenic function of Galectin-7 may exhibit great potential in targeting HNSCC progression.
人类肿瘤 imaginal 盘（Tid1），一种 DnaJ 共伴侣蛋白，被归类为肿瘤抑制因子。以前，我们证明 Tid1 降低了头颈部鳞状细胞癌（HNSCC）的恶性程度。然而，Tid1 介导的抗转移的分子细节仍然难以捉摸。我们使用亲和层析和系统质谱法来鉴定 Tid1 相互作用的客户蛋白。通过免疫组织化学染色检测 Tid1 在 HNSCC 患者组织中的表达，以评估 Tid1 相互作用的客户蛋白的表达谱与病理特征和预后之间的关系。在体内和体外验证了 Tid1 相互作用的客户蛋白在转移中的作用。确定了 Tid1 相互作用的客户蛋白的相互作用伙伴和下游靶标。在这里，我们首次揭示了 Galectin-7 是 Tid1 相互作用的客户蛋白之一。在 HNSCC 患者中，Tid1 和 Galectin-7 的蛋白表达谱呈负相关。低 Tid1 和高 Galectin-7 表达预示着 HNSCC 患者总体生存率差。此外，Tid1 可消除 Galectin-7 的核转位，并抑制 Galectin-7 诱导的肿瘤发生和转移。用 4-硝基喹啉-1-氧化物（4NQO）处理的角质形成细胞特异性 Tid1 缺陷型小鼠表现出 Galectin-7 蛋白水平升高，生存率差。Tid1 通过其 N 连接糖基化与 Galectin-7 相互作用，促进 Tid1 介导的 Galectin-7 的泛素化和蛋白酶体降解。此外，Galectin-7 通过提高 MMP-9 的表达来增强 TCF3 转录因子的转录活性，从而在促进肿瘤发生和转移进展中发挥关键作用。总的来说，通过激活 Tid1 表达或反向抑制 Galectin-7 的致癌功能来进行的未来治疗可能在靶向 HNSCC 进展方面具有很大潜力。
