MSI2 regulates NLK-mediated EMT and PI3K/AKT/mTOR pathway to promote pancreatic cancer progression

IF 5.3 2区医学 Q1 ONCOLOGY Cancer Cell International Pub Date : 2024-08-03 DOI:10.1186/s12935-024-03444-9

Longping Huang, Jian Sun, Yuteng Ma, He Chen, Chen Tian, Ming Dong

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Abstract

The incidence of pancreatic cancer is increasing by years, and the 5-year survival rate is very low. Our team have revealed that Musashi2 (MSI2) could promote aggressive behaviors in pancreatic cancer by downregulating Numb and p53. MSI2 also facilitates EMT in pancreatic cancer induced by EGF through the ZEB1-ERK/MAPK signaling pathway. This study aims to further explore the molecular mechanisms of MSI2-regulated downstream pathways in pancreatic cancer. In vitro and in vivo experiments were conducted to investigate the role and mechanism of MSI2 in promoting malignant behaviors of pancreatic cancer through regulation of NLK. Genes closely related to MSI2 were screened from the GEPIA and TCGA databases. We found that NLK showed the most significant changes in mRNA levels with consistent changes following MSI2 interference and overexpression. The high correlation between MSI2 and NLK was also observed at the protein level. Multivariate analysis revealed that both MSI2 and NLK were independent adverse indicators of survival in pancreatic cancer patients, as well as join together. In vitro, silencing or overexpressing NLK altered cell invasion and migration, by regulating EMT and the PI3K-AKT-mTOR pathway. Silencing MSI2 reduced protein expression in the EMT and PI3K-AKT-mTOR pathways, leading to decreased cell invasion and migration abilities, while these effects could be reversed by overexpression of NLK. In vivo, MSI2 silencing inhibited liver metastasis, which could be reversed by overexpressing NLK. Mechanistically, MSI2 directly binds to the translation regulatory region of NLK mRNA at positions 79–87 nt, enhancing its transcriptional activity and exerting post-transcriptional regulatory roles. The analysis of molecular docking showed the close relationship between MSI2 and NLK in pancreatic cancer patients. Our findings elucidate the regulatory mechanisms of the MSI2-NLK axis in modulating aggressive behaviors of pancreatic cancer cells, which providing new evidence for therapeutic strategies in pancreatic cancer.

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MSI2 调控 NLK 介导的 EMT 和 PI3K/AKT/mTOR 通路，促进胰腺癌进展

胰腺癌的发病率逐年上升，5 年生存率非常低。我们的团队发现，Musashi2（MSI2）可通过下调Numb和p53促进胰腺癌的侵袭行为。MSI2 还可通过 ZEB1-ERK/MAPK 信号通路促进 EGF 诱导的胰腺癌 EMT。本研究旨在进一步探讨MSI2调控胰腺癌下游通路的分子机制。通过体外和体内实验，研究MSI2通过调控NLK促进胰腺癌恶性行为的作用和机制。我们从GEPIA和TCGA数据库中筛选了与MSI2密切相关的基因。我们发现，NLK在MSI2干扰和过表达后的mRNA水平变化最为显著，且变化一致。在蛋白质水平上也观察到了MSI2和NLK之间的高度相关性。多变量分析显示，MSI2和NLK是胰腺癌患者生存的独立不利指标，同时也是共同的不利指标。在体外，沉默或过表达NLK可通过调节EMT和PI3K-AKT-mTOR通路改变细胞的侵袭和迁移。沉默MSI2会降低EMT和PI3K-AKT-mTOR通路的蛋白表达，导致细胞侵袭和迁移能力下降，而过表达NLK则可逆转这些影响。在体内，沉默MSI2可抑制肝转移，而过表达NLK则可逆转这种效应。从机制上看，MSI2直接与NLK mRNA翻译调控区79-87 nt位结合，增强其转录活性并发挥转录后调控作用。分子对接分析表明，在胰腺癌患者中，MSI2与NLK关系密切。我们的研究结果阐明了MSI2-NLK轴在调节胰腺癌细胞侵袭行为中的调控机制，为胰腺癌的治疗策略提供了新的证据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell International ONCOLOGY-

CiteScore

10.90

自引率

1.70%

发文量

360

审稿时长

1 months

期刊介绍： Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques. The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors. Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.