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Aberrant epithelial cell interaction promotes esophageal squamous-cell carcinoma development and progression.

ABSTRACT: Epithelial-mesenchymal transition (EMT) and proliferation play important roles in epithelial cancer formation and progression, but what molecules and how they trigger EMT is largely unknown. Here we performed spatial transcriptomic and functional analyses on samples of multistage esophageal squamous-cell carcinoma (ESCC) from mice and humans to decipher these critical issues. By investigating spatiotemporal gene expression patterns and cell-cell interactions, we demonstrated that the aberrant epithelial cell interaction via EFNB1-EPHB4 triggers EMT and cell cycle mediated by downstream SRC/ERK/AKT signaling. The aberrant epithelial cell interaction occurs within the basal layer at early precancerous lesions, which expands to the whole epithelial layer and strengthens along the cancer development and progression. Functional analysis revealed that the aberrant EFNB1-EPHB4 interaction is caused by overexpressed ΔNP63 due to TP53 mutation, the culprit in human ESCC tumorigenesis. Our results shed new light on the role of TP53-TP63/ΔNP63-EFNB1-EPHB4 axis in EMT and cell proliferation in epithelial cancer formation.

SUBMITTER: Chen L

PROVIDER: S-EPMC10721848 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Aberrant epithelial cell interaction promotes esophageal squamous-cell carcinoma development and progression.

Chen Liping L Zhu Shihao S Liu Tianyuan T Zhao Xuan X Xiang Tao T Hu Xiao X Wu Chen C Lin Dongxin D

Signal transduction and targeted therapy 20231215 1

Epithelial-mesenchymal transition (EMT) and proliferation play important roles in epithelial cancer formation and progression, but what molecules and how they trigger EMT is largely unknown. Here we performed spatial transcriptomic and functional analyses on samples of multistage esophageal squamous-cell carcinoma (ESCC) from mice and humans to decipher these critical issues. By investigating spatiotemporal gene expression patterns and cell-cell interactions, we demonstrated that the aberrant ep ...[more]

PMID: 38097539

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Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most prevalent cancers worldwide. Due to its high morbidity and mortality rates, it is urgent to find a molecular target that contributes to esophageal carcinogenesis and progression. In this research, we aimed to investigate the functions of Latent transforming growth factor β binding protein 1(LTBP1) in ESCC progression and elucidate the underlying mechanisms.MethodsThe tandem mass tag-based quantitative proteomic approach was applied to screen the differentially expressed proteins (DEPs) between 3 cases of ESCC tumor samples and paired normal tissues. Then the DEPs were validated in human ESCC tissues using western blot assays and GEPIA database respectively. The expression level of LTBP1 was detected in 152 cases of ESCC tissues and paired normal tissues. Loss-of-function assays were performed to detect the function of LTBP1 in vivo and in vitro. Immunofluorescence and Western blot assays were used to detect the expression of apoptosis, epithelial-mesenchymal transition (EMT) and cancer-associated fibroblasts (CAFs) markers.ResultsA total of 39 proteins were screened to be up-regulated (ratio > 2.0) in all three ESCC tissues. The results of immunohistochemistry assays indicated that the expression level of LTBP1 was higher in ESCC tissues than that in paired normal tissues (p < 0.001). Overexpression of LTBP1 was positively associated with lymphatic metastasis in ESCC (p = 0.002). Down-regulation of LTBP1 inhibited the invasion and migration as well as metastatic abilities in vitro and in vivo. It was also observed the down-regulation of LTBP1 not only decreased the mesenchymal phenotypes but also inhibited TGFβ-induced EMT in ESCC cells. We further found that down-regulation of LTBP1 enhanced ESCC cells' sensitivity to 5-FU treatment. Inhibition of LTBP1 expression could also attenuate induction of CAFs transformation and restrain fibroblast express fibronectin (FN1) in ESCC cells.ConclusionOverexpression of LTBP1 was associated with lymph node metastasis in ESCC. Our results indicated that LTBP1 not only increased the malignant behaviors of ESCC cells but also induced EMT and CAFs transformation. Our studies suggested an oncogenic role of LTBP1 in ESCC progression and it may serve as a potential therapeutic target for ESCC patients.

Project description:One‑carbon metabolism plays an important role in cancer progression. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a mitochondrial enzyme in one‑carbon metabolism, is dysregulated in several cancer types. However, the precise role and mechanisms of MTHFD2 in esophageal squamous cell carcinoma (ESCC) remain unclear. The present study unravels the multifaceted mechanisms by which MTHFD2 contributes to ESCC pathogenesis. Bioinformatics analyses revealed significant upregulation of MTHFD2 in ESCC tumor tissues, which was associated with advanced disease stage and poor patient prognosis. Validating these findings in clinical samples, MTHFD2 overexpression was confirmed through immunohistochemistry, Reverse transcription‑quantitative PCR and western blotting. Knockdown of MTHFD2 inhibited ESCC cell viability, colony formation, invasion, and tumor growth in vivo, indicating its oncogenic potential. Mechanistically, the present study elucidated a novel regulatory axis involving N6‑methyladenosine modification and MTHFD2 mRNA stability. Specifically, methyltransferase‑like 3 (METTL3) and insulin‑like growth factor 2 mRNA binding protein 2 (IGF2BP2) were identified as key mediators of m6A‑dependent stabilization of MTHFD2 mRNA, contributing to its elevated expression in ESCC. Furthermore, MTHFD2 was found to activate PI3K/AKT and ERK signaling pathways by modulating interaction between phosphatidylethanolamine‑binding protein 1 (PEBP1) and raf‑1 proto‑oncogene (RAF1). This modulation was achieved through direct binding of MTHFD2 to PEBP1, disrupting the inhibitory effect of PEBP1 on RAF1 and promoting downstream pathway activation. The oncogenic functions of MTHFD2 were attenuated upon PEBP1 knockdown, underscoring the role of the MTHFD2‑PEBP1 axis in ESCC progression. In summary, the present study uncovers a novel regulatory mechanism involving m6A modification and the MTHFD2‑PEBP1 axis, unveiling potential therapeutic avenues for targeting MTHFD2 in ESCC.

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Aberrant epithelial cell interaction promotes esophageal squamous-cell carcinoma development and progression.

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Aberrant epithelial cell interaction promotes esophageal squamous-cell carcinoma development and progression.

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