缺氧下调 miR-4521 通过调节 IGF2 和 FOXM1 抑制胃癌进展。
Hypoxia downregulated miR-4521 suppresses gastric carcinoma progression through regulation of IGF2 and FOXM1.
机构信息
Affiliated Cancer Hosipital & Institute of Guangzhou Medical University, Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", No.78, Hengzhigang Road, Guangzhou, 510095, China.
Department of Clinical Laboratory, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
出版信息
Mol Cancer. 2021 Jan 6;20(1):9. doi: 10.1186/s12943-020-01295-2.
BACKGROUND
MicroRNAs (miRNAs) show considerable promise as therapeutic agents to improve tumor treatment, as they have been revealed as crucial modulators in tumor progression. However, our understanding of their roles in gastric carcinoma (GC) metastasis is limited. Here, we aimed to identify novel miRNAs involved in GC metastasis and explored their regulatory mechanisms and therapeutic significance in GC.
METHODS
The microRNA expression profiles of GC tumors at different stages and at different metastasis statuses were compared respectively using the stomach adenocarcinoma (STAD) miRNASeq dataset in TCGA. Using the above method, miR-4521 was picked out for further study. miR-4521 expression in GC tissues was examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH). Highly and lowly invasive cell sublines were established using a repetitive transwell assay. Gain-of-function and loss-of-function analyses were performed to investigate the functions of miR-4521 and its upstream and downstream regulatory mechanisms in vitro and in vivo. Moreover, we investigated the therapeutic role of miR-4521 in a mouse xenograft model.
RESULTS
In this study, we found that miR-4521 expression was downregulated in GC tissues compared with adjacent normal tissues and that its downregulation was positively correlated with advanced clinical stage, metastasis status and poor patient prognosis. Functional experiments revealed that miR-4521 inhibited GC cell invasion and metastasis in vitro and in vivo. Further studies showed that hypoxia repressed miR-4521 expression via inducing ETS1 and miR-4521 mitigated hypoxia-mediated metastasis, while miR-4521 inactivated the AKT/GSK3β/Snai1 pathway by targeting IGF2 and FOXM1, thereby inhibiting the epithelial-mesenchymal transition (EMT) process and metastasis. In addition, we demonstrated that therapeutic delivery of synthetic miR-4521 suppressed gastric carcinoma progression in vivo.
CONCLUSIONS
Our results suggest an important role for miR-4521 in regulating GC metastasis and hypoxic response of tumor cells as well as the therapeutic significance of this miRNA in GC.
背景
MicroRNAs（miRNAs）作为改善肿瘤治疗的治疗剂具有很大的潜力，因为它们已被证明是肿瘤进展的关键调节剂。然而，我们对它们在胃癌（GC）转移中的作用的理解有限。在这里，我们旨在确定参与 GC 转移的新型 miRNA，并探索它们在 GC 中的调节机制和治疗意义。
方法
使用 TCGA 中的胃腺癌（STAD）miRNASeq 数据集，分别比较了不同阶段和不同转移状态的 GC 肿瘤的 miRNA 表达谱。使用上述方法，选择 miR-4521 进行进一步研究。通过定量逆转录聚合酶链反应（qRT-PCR）和原位杂交（ISH）检测 GC 组织中的 miR-4521 表达。使用重复 Transwell 测定法建立高侵袭性和低侵袭性细胞亚系。进行功能增益和功能丧失分析，以研究 miR-4521 及其上下游调节机制在体外和体内的功能。此外，我们在小鼠异种移植模型中研究了 miR-4521 的治疗作用。
结果
在这项研究中，我们发现与相邻正常组织相比，GC 组织中 miR-4521 的表达下调，其下调与晚期临床阶段、转移状态和患者预后不良呈正相关。功能实验表明，miR-4521 抑制 GC 细胞的体外和体内侵袭和转移。进一步的研究表明，缺氧通过诱导 ETS1 来抑制 miR-4521 的表达，而 miR-4521 通过靶向 IGF2 和 FOXM1 减轻缺氧介导的转移，从而抑制上皮-间质转化（EMT）过程和转移。此外，我们证明了合成 miR-4521 的治疗性递送至体内抑制了胃癌的进展。
结论
我们的研究结果表明，miR-4521 在调节 GC 转移和肿瘤细胞的缺氧反应以及该 miRNA 在 GC 中的治疗意义方面具有重要作用。
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