Zhang Yunan, Chen Dayang, Zhang Guoqiang, Wu Xiongbo, Zhou Liangyun, Lin Yexin, Ding Junli, An Fangmei, Zhan Qiang
Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China.
Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China.
Oncol Lett. 2020 Nov;20(5):160. doi: 10.3892/ol.2020.12021. Epub 2020 Aug 26.
MicroRNA (miR)-23b-3p plays an important role in tumor growth, proliferation, invasion and migration in pancreatic cancer (PC). However, the function and mechanistic role of miR-23b-3p in the development of PC remains largely unknown. In the present study, the miR-23b-3p levels in the serum of patients with PC were found to be elevated, and the phosphorylation levels of Janus kinase (JAK)2, PI3K, Akt and NF-κВ were found to be upregulated. In addition, miR-23b-3p was induced in response to interleukin-6 (IL-6), which is known to be involved in the progression of PC. Overexpression of miR-23b-3p, on the other hand, activated the JAK/PI3K and Akt/NF-κB signaling pathways in PC cells, as evidenced by miR-23b-3p-induced upregulation of phosphorylated (p-)JAK2, p-PI3K, p-Akt and p-NF-κВ, as well as the downregulation of PTEN; and these effects were found to be reversible by miR-23b-3p inhibition. Furthermore, miR-23b-3p was found to downregulate PTEN by directly targeting the 3'-untranslated region of PTEN mRNA. Notably, in an xenograft mouse model, overexpression of miR-23b-3p accelerated PC cell-derived tumor growth, activated the JAK/Akt/NF-κВ signaling pathway and promoted liver metastasis. In contrast, knockdown of miR-23b-3p suppressed tumor growth and metastasis as well as JAK/Akt/NF-κВ signaling activity. imaging of the mice further confirmed the metastasis promoting role of miR-23b-3p in PC. These results suggested that miR-23b-3p enhances PC cell tumorigenesis and metastasis, at least, partially via the JAK/PI3K and Akt/NF-κB signaling pathways. Therefore, targeting miR-23b-3p or the JAK/PI3K and Akt/NF-κB signalings may be potential therapeutic strategy against PC.
微小RNA（miR）-23b-3p在胰腺癌（PC）的肿瘤生长、增殖、侵袭和迁移中起重要作用。然而，miR-23b-3p在PC发生发展中的功能和机制作用仍 largely未知。在本研究中，发现PC患者血清中的miR-23b-3p水平升高，且发现Janus激酶（JAK）2、PI3K、Akt和NF-κB的磷酸化水平上调。此外，miR-23b-3p是对白介素-6（IL-6）作出反应而被诱导产生的，已知IL-6参与PC的进展。另一方面，miR-23b-3p的过表达激活了PC细胞中的JAK/PI3K和Akt/NF-κB信号通路，这可通过miR-23b-3p诱导的磷酸化（p-）JAK2、p-PI3K、p-Akt和p-NF-κB的上调以及PTEN的下调得到证明；并且发现这些作用可通过miR-23b-3p抑制而逆转。此外，发现miR-23b-3p通过直接靶向PTEN mRNA的3'非翻译区来下调PTEN。值得注意的是，在异种移植小鼠模型中，miR-23b-3p的过表达加速了PC细胞来源的肿瘤生长，激活了JAK/Akt/NF-κB信号通路并促进了肝转移。相反，敲低miR-23b-3p可抑制肿瘤生长和转移以及JAK/Akt/NF-κB信号活性。对小鼠的成像进一步证实了miR-23b-3p在PC中的促转移作用。这些结果表明，miR-23b-3p至少部分地通过JAK/PI3K和Akt/NF-κB信号通路增强PC细胞的肿瘤发生和转移。因此，靶向miR-23b-3p或JAK/PI3K和Akt/NF-κB信号可能是针对PC的潜在治疗策略。
