Yue Changli, Bai Yuping, Piao Yingshi, Liu Honggang
Department of Pathology, Beijing Tongren Hospital, Capital Medical University, Beijing Key Laboratory of Head and Neck Molecular Diagnostic Pathology, Beijing 100730, China.
J Oncol. 2021 Jan 22;2021:4035257. doi: 10.1155/2021/4035257. eCollection 2021.
Recently, increasing attention has been paid to the correlation between the expression of downstream of kinase 7 (DOK7) and the occurrence and development of various tumors. In this study, we clarified the effects of DOK7 in breast cancer. First, we showed that DOK7 expression was obviously reduced in the breast cancer tissues and lower levels of DOK7 linked to more aggressive behaviors and worse prognosis of patients. Furthermore, DOK7 expression of various breast cancer cell lines was lower than that of human noncancerous MCF-10A cells. Overexpression of DOK7 inhibited proliferation, migration, and invasion, while silencing DOK7 expression promoted the malignancy of breast cancer. In addition, overexpression of DOK7 suppressed tumor proliferation and lung metastasis in animal models. Finally, to investigate the possible signaling mechanism, we first found that the level of p-AKT protein was extremely downregulated and the level of PTEN protein was remarkably upregulated after overexpressing DOK7 in breast cancer cells. Repression of PTEN expression using PTEN siRNA or SF1670 (PTEN inhibitor) rescued the tumor-inhibiting effect induced by DOK7 overexpression, suggesting that DOK7 inhibits proliferation, migration, and invasion of breast cancer cells though the PI3K/PTEN/AKT pathway. These results suggest that the downregulation of DOK7 may become a novel breast cancer therapeutic target.
近年来，激酶7下游（DOK7）的表达与各种肿瘤的发生发展之间的相关性受到了越来越多的关注。在本研究中，我们阐明了DOK7在乳腺癌中的作用。首先，我们发现乳腺癌组织中DOK7表达明显降低，且DOK7水平较低与患者更具侵袭性的行为和更差的预后相关。此外，各种乳腺癌细胞系的DOK7表达均低于人非癌性MCF-10A细胞。DOK7的过表达抑制了增殖、迁移和侵袭，而沉默DOK7表达则促进了乳腺癌的恶性程度。此外，DOK7的过表达在动物模型中抑制了肿瘤增殖和肺转移。最后，为了研究可能的信号传导机制，我们首先发现，在乳腺癌细胞中过表达DOK7后，p-AKT蛋白水平极度下调，PTEN蛋白水平显著上调。使用PTEN siRNA或SF1670（PTEN抑制剂）抑制PTEN表达可挽救DOK7过表达诱导的肿瘤抑制作用，这表明DOK7通过PI3K/PTEN/AKT途径抑制乳腺癌细胞的增殖、迁移和侵袭。这些结果表明，DOK7的下调可能成为一种新的乳腺癌治疗靶点。
