ISSN: 1449-2288International Journal of Biological Sciences
Global reach, higher impact
Int J Biol Sci 2023; 19(14):4411-4426. doi:10.7150/ijbs.81972 This issue Cite
Research Paper
RHOJ Induces Epithelial-to-Mesenchymal Transition by IL-6/STAT3 to Promote Invasion and Metastasis in Gastric Cancer
1. Zhongda Hospital, School of Medicine & Advanced Institute for Life and Health, Southeast University, Nanjing 210009, China.
2. Department of Pathology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing 210008, China.
3. School of Basic Medical Sciences & Key Laboratory of Antibody Technique of National Health Commission & Jiangsu Antibody Drug Engineering Research Center, Nanjing Medical University, Nanjing 211166, China.
4. Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China.
5. Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Nanjing 210009, China.
6. Department of Oncology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang, China.
# These authors contributed equally to this work.
Abstract
Background: 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.
Methods: 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.
Results: 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 in vitro and in vivo. 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.
Conclusions: 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.
Keywords: Gastric Cancer, RHOJ, EMT, IL-6/STAT3 signaling, Metastasis
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