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Dissecting the genetic and microenvironmental factors of gastric tumorigenesis in mice

ABSTRACT: Gastric cancer (GC) is one of the most frequent and lethal malignancies in the world. However, our understanding of the mechanisms underlying its initiation and progression is limited. Here, we applied genome-edited gastric organoids to establish a series of primary GC models in mice, which elucidated the genetic drivers for sequential transformation from dysplasia to well-differentiated and poorly differentiated GC. Further, we found that the orthotopic GC, but not the subcutaneous GC even with the same genetic drivers, displayed remote metastasis, suggesting critical roles of the microenvironment in GC metastasis. Through single-cell RNA-seq analyses and functional studies, we revealed that the molecular interaction between fibronectin 1 on stomach-specific macrophages and integrin α6β4 on GC cells promoted liver metastasis. Taken together, our studies proposed a new strategy to model GC and dissected the genetic and microenvironmental factors driving the full-range gastric tumorigenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE188761 | GEO | 2022/09/05

REPOSITORIES: GEO

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Project description:Cullin 4B (CUL4B), a scaffold protein that assembles CRL4B ubiquitin ligase complexes, has been reported to be overexpressed in several types of solid tumors and contributes to epigenetic silencing of tumor suppressor. However, its clinical significance and the molecular mechanisms underlying its regulation in gastric cancer (GC) remain largely unknown. Here, we showed that CUL4B was elevated in GC tissues and its overexpression was positively correlated with poor prognosis and lymph node metastasis. CUL4B knockdown in GC cells decreased proliferation, mesenchymal transition and invasion in vitro, as well as tumor growth and metastasis in nude mice, and CUL4B overexpression induced the opposite results. Further studies showed that miR-101 could inhibit CUL4B expression by directly targeting its 3’-UTR and they were inversely correlated in clinical GC specimens. Notably, a positive relationship between CUL4B and HER2 was found in GC clinical specimens, GC cells and GC xenograft tumors. Through bioinformatics analysis of miRNA-seq data and target prediction, we nominated miR-125a as a direct target of CUL4B. ChIP assays demonstrated that CUL4B directly repressed miR-125a expression by physically binding to its promoter. In addition, we confirmed miR-125a is the target of HER2. Consequently, we demonstrated that CUL4B can up-regulate HER2 expression through repressing miR-125a. Most importantly, silencing of HER2 by Herceptin or siRNA partially reversed CUL4B-induced epithelial-to-mesenchymal transition (EMT), cell invasion and metastasis in vitro and in vivo. These findings define a CUL4B-miR-125a-HER2 regulatory mechanism shed light on CUL4B oncogenic mechanisms and reveals promising therapeutic targets for progressive GC. CUL4B proteins are frequently upregulated in human cancer, yet little is known about the underlying molecular mechanisms of CUL4B induced gastric cancer(GC) carcigenesis.Here, we uncover the critical role of CUL4B in gastric cancer growth and metastasis through the regulation of HER2 expression.CUL4B contributes to GC invasion and metastasis by transcriptional repression of HER2 targeting miR-125a, which provide a new insight into how CUL4B regulates GC progression and metastasis.

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Dissecting the genetic and microenvironmental factors of gastric tumorigenesis in mice

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