LTBP1 promotes esophageal squamous cell carcinoma progression through epithelial-mesenchymal transition and cancer-associated fibroblasts transformation

Abstract

Background: Esophageal 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. Methods: The 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. Results: A 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.

Mitochondrial calcium uniporter promotes cell proliferation and migration in esophageal cancer

“…There are two most common histological subtypes: Squamous cell carcinoma and adenocarcinoma. Despite marked improvements of therapies, the overall survival rate of patients with esophageal cancer remains unsatisfactory ( 2 ). The poor prognosis of esophageal cancer is attributed to early metastasis ( 3 ).…”

Identification of Key Genes and Pathways Associated With Paclitaxel Resistance in Esophageal Squamous Cell Carcinoma Based on Bioinformatics Analysis

“…In EC, the upregulation of FN1 expression is regulated by STAB1 (Song et al, 2017 ). A study also reported that the suppression of LTBP1 can attenuate cancer-associated fibroblast (CAF) transformation and inhibit FN1 in ESCC (Cai et al, 2020 ). The elevated FN1 expression may also promote the occurrence of cancer, including breast cancer (Dorman et al, 2016 ).…”

The Role of Tumor Microenvironment in Invasion and Metastasis of Esophageal Squamous Cell Carcinoma

“…The presence of CAFs in ESCC patients is associated with increased micro-vessel density, TAMs, and EMT, which are critical for ESCC invasion and metastasis ( 83 , 84 ). A number of genes have been shown to promote ESCC invasion and metastasis via the CAF transformation and EMT process ( 85 , 86 ). Also, it has been demonstrated that CAFs promote ESCC invasion by secreting hepatocyte growth factor (HGF) and infiltrating MDSCs ( 87 , 88 ).…”