Modulation of SRC by SNTB1 activates the Hippo-YAP pathway during colon adenocarcinoma metastasis.

Autor: Chang Z; Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China., Huang R; Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, People's Republic of China., Song J; Shanghai Jiao Tong University of Medicine, Shanghai, China., Li Z; Tongji University School of Medicine, Shanghai, China., Pi M; Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China., Xian S; Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, People's Republic of China., Zhang J; Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China., Huang J; Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China., Xie R; Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China., Ji G; Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China. chickapple@126.com., Han D; Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China. han_dongyan@163.com., Huang Q; Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China. hqiongyi2023@163.com.
Jazyk: angličtina
Zdroj: Journal of translational medicine [J Transl Med] 2024 Nov 15; Vol. 22 (1), pp. 1029. Date of Electronic Publication: 2024 Nov 15.
DOI: 10.1186/s12967-024-05548-2
Abstrakt: Background: Colon adenocarcinoma (COAD) ranks as the third most prevalent and lethal cancer in 2020, with metastasis being the primary cause of cancer-related mortality. A comprehensive understanding of the mechanism underlying distant metastasis is imperative for enhancing the prognosis and quality of life of patients with COAD.
Methods: This study employed gene set enrichment analysis (GSEA) on RNA-sequencing data from 408 patients with COAD in The Cancer Genome Atlas (TCGA) database. GSEA analysis was applied to find the significant hallmark gene set, and genes in the significant hallmark gene set was performed by univariate Cox regression to select the key gene. Then, multivariate Cox regression model was constructed. And various databases were utilized to validate and find the significant oncoprotein and hallmark gene set of the key gene. In addition, the expression of key regulators in para-carcinoma tissue, colon cancer and distant metastases samples were detected by real-time PCR, Immunohistochemistry and Western blot. Additionally, the biological functions were examined by in vitro and in vivo experiments. The scRNA-seq and CellphoneDB were performed to explore cell characters in COAD and the potential mechanism of metastasis.
Results: The regulatory network analysis revealed SRC/YAP1 as the most significant oncoprotein and signature gene set associated with SNTB1. Moreover, significant SNTB1 overexpression in COAD metastatic tissues was observed compared to para-carcinoma and primary COAD tissues. Co-immunoprecipitation assays demonstrated the formation of a complex between SNTB1 and SRC proteins. Furthermore, the overexpression of SNTB1 enhanced the proliferation, migration and invasion capacities of COAD cell lines. Caudal vein injection of COAD cells overexpressing SNTB1 in nude mice resulted in increased tumour growth and metastasis to the lung, liver and bone. Finally, single cell RNA-seq revealed alterations in the cellular subtypes of COAD, and CellphoneDB indicated that the interaction between cancer cells exhibiting high SNTB1 expression and enterocytes promoted EMT through cellular communications involving TGF-β, accelerating metastasis in COAD.
Conclusion: This study postulates that SNTB1 interacts with SRC to activate the Hippo-YAP pathway, thereby promoting COAD metastasis. Furthermore, cellular communication with enterocytes promotes EMT, facilitating metastasis. These findings propose novel therapeutic targets for preventing or treating metastatic COAD.
Competing Interests: Declarations Ethics approval and consent to participate Approval of the research protocol by an Institutional Reviewer Board: The study was approved by the Ethics Committee of Shanghai Tenth People’s Hospital. Consent for publication Not applicable. Informed consent N/A. Registry and the registration no. of the study N/A. Animal studies The study was approved by the Ethics Committee of Shanghai Tenth People’s Hospital. Competing interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(© 2024. The Author(s).)
Databáze: MEDLINE
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