RHOJ 通过 IL-6/STAT3 诱导上皮间质转化促进胃癌侵袭转移。

RHOJ Induces Epithelial-to-Mesenchymal Transition by IL-6/STAT3 to Promote Invasion and Metastasis in Gastric Cancer.

机构信息

Zhongda Hospital, School of Medicine & Advanced Institute for Life and Health, Southeast University, Nanjing 210009, China.

Department of Pathology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing 210008, China.

出版信息

Int J Biol Sci. 2023 Aug 21;19(14):4411-4426. doi: 10.7150/ijbs.81972. eCollection 2023.

DOI:10.7150/ijbs.81972

PMID:37781036

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10535698/

Abstract

Recently, the molecular classification of gastric cancer (GC) promotes the advances of GC patients' precision therapy and prognosis prediction. According to the Asian Cancer Research Group (ACRG), GC is classified as microsatellite instable (MSI) subtype GC, microsatellite stable/epithelial-to-mesenchymal transition (MSS/EMT) subtype GC, MSS/TP53- subtype GC, and MSS/TP53+ subtype GC. Due to the easy metastasis of EMT-subtype GC, it has the worst prognosis, the highest recurrence rate, and the tendency to occur at a younger age. Therefore, it is curious and crucial for us to understand the molecular basis of EMT-subtype GC. The expression of RHOJ was detected by quantitative real-time PCR (qPCR) and immunohistochemistry (IHC) in GC cells and tissues. Western blotting and immunofluorescence (IF) were conducted to examine the effects of RHOJ on the EMT markers' expression of GC cells. The GC cells' migration and invasion were investigated by transwell assay. The tumor growth and metastasis were demonstrated correspondingly in different xenograft models. Firstly, it was noticed that RHOJ was significantly upregulated in EMT-subtype GC and RHOJ has close relationships with the EMT process of GC, based on the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases. Next, transwell assay and tail vein metastasis models were conducted to verify that RHOJ mediates the EMT to regulate the invasion and metastasis of GC and . In addition, weakened tumor angiogenesis was observed after RHOJ knockdown by the angiogenesis assay of HUVEC. RNA-seq and further study unveiled that RHOJ aggravates the malignant progression of GC by inducing EMT through IL-6/STAT3 to promote invasion and metastasis. Finally, blocking the IL-6/STAT3 signaling overcame RHOJ-mediated GC cells' growth and migration. These results indicate that the upregulation of RHOJ contributes to EMT-subtype GC invasion and metastasis via IL-6/STAT3 signaling, and RHOJ is expected to become a promising biomarker and therapeutic target for EMT-subtype GC patients.

摘要

最近，胃癌（GC）的分子分类促进了 GC 患者精准治疗和预后预测的进展。根据亚洲癌症研究组（ACRG）的分类，GC 分为微卫星不稳定（MSI）亚型 GC、微卫星稳定/上皮-间充质转化（MSS/EMT）亚型 GC、MSS/TP53- 亚型 GC 和 MSS/TP53+ 亚型 GC。由于 EMT 亚型 GC 易于转移，因此其预后最差、复发率最高、且发病年龄更年轻。因此，了解 EMT 亚型 GC 的分子基础对我们来说既好奇又至关重要。通过定量实时 PCR（qPCR）和免疫组织化学（IHC）检测 GC 细胞和组织中 RHOJ 的表达。通过 Western blot 和免疫荧光（IF）检测 RHOJ 对 GC 细胞 EMT 标志物表达的影响。通过 Transwell 测定法研究 GC 细胞的迁移和侵袭。相应地在不同的异种移植模型中证明了肿瘤的生长和转移。

首先，基于基因表达综合数据库（GEO）和癌症基因组图谱（TCGA）数据库，我们注意到 RHOJ 在 EMT 亚型 GC 中显著上调，并且 RHOJ 与 GC 的 EMT 过程密切相关。接下来，通过 Transwell 测定法和尾静脉转移模型验证了 RHOJ 通过调节 EMT 来调节 GC 的侵袭和转移。此外，通过 HUVEC 的血管生成测定法观察到 RHOJ 敲低后肿瘤血管生成减弱。RNA-seq 和进一步的研究表明，RHOJ 通过诱导 EMT 来加重 GC 的恶性进展，从而促进侵袭和转移，通过 IL-6/STAT3 促进侵袭和转移。最后，阻断 IL-6/STAT3 信号通路克服了 RHOJ 介导的 GC 细胞的生长和迁移。

这些结果表明，RHOJ 的上调通过 IL-6/STAT3 信号促进 EMT 亚型 GC 的侵袭和转移，并且 RHOJ 有望成为 EMT 亚型 GC 患者有前途的生物标志物和治疗靶点。