Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150081, China.
Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, Heilongjiang, 150081, China.
Cell Death Dis. 2021 Oct 11;12(10):929. doi: 10.1038/s41419-021-04179-5.
Cervical adenocarcinoma is an important disease that affects young women and it has a high mortality and poor prognosis. Denticleless E3 ubiquitin protein ligase homolog (DTL) gene with oncogenic function has been evaluated in several cancers. Through this study, we aimed to clarify the clinical and molecular characteristics of cervical adenocarcinoma involving overexpression of DTL and elucidate its molecular mechanism. Bioinformatics analysis was performed through multiple databases. RNA sequencing was used to obtain differentially expressed genes after DTL was overexpressed in cells. The role of DTL in cervical adenocarcinoma was explored through in vitro and in vivo experiments. We found that DTL has an unfavorable prognostic implication for patients with cervical adenocarcinoma. Overexpression of DTL induced the migration and invasion of tumor cells in vitro and promoted intra-pulmonary metastasis in vivo. In addition, DTL activated JNK through RAC1 and upregulated FOXO1 to induce epithelial-mesenchymal transition, and the migration and invasion of tumor cells. Therefore, we conclude that overexpression of DTL enhanced cell motility and promoted tumor metastasis of cervical adenocarcinoma by regulating the RAC1-JNK-FOXO1 axis. These results suggest that DTL may become a potential therapeutic target for antitumor metastasis of cervical adenocarcinoma.
宫颈腺癌是一种影响年轻女性的重要疾病，其死亡率高，预后差。具有致癌功能的无小牙 E3 泛素蛋白连接酶同源物（DTL）基因已在几种癌症中进行了评估。通过本研究，我们旨在阐明涉及 DTL 过表达的宫颈腺癌的临床和分子特征，并阐明其分子机制。通过多个数据库进行了生物信息学分析。通过细胞中转染 DTL 获得差异表达基因。通过体外和体内实验探索了 DTL 在宫颈腺癌中的作用。我们发现 DTL 对宫颈腺癌患者的预后有不利影响。DTL 的过表达可诱导肿瘤细胞的体外迁移和侵袭，并促进体内肺内转移。此外，DTL 通过 RAC1 激活 JNK 并上调 FOXO1 诱导上皮-间充质转化，从而促进肿瘤细胞的迁移和侵袭。因此，我们得出结论，过表达 DTL 通过调节 RAC1-JNK-FOXO1 轴增强了宫颈腺癌的细胞迁移能力并促进了肿瘤转移。这些结果表明，DTL 可能成为宫颈腺癌抗肿瘤转移的潜在治疗靶点。
