Abstract

Elevated activity of sterol regulatory element-binding protein 1 (SREBP1) has been implicated in the tumorigenesis of different cancer types. However, the functional roles of SREBP1 in esophageal cancer are not well appreciated. Here, we aimed to investigate the therapeutic potential of SREBP1 and associated signaling in esophageal cancer. Our initial bioinformatics analyses showed that SREBP1 expression was overexpressed in esophageal tumors and correlated with a significantly lower overall survival rate in patients. Additionally, tumor suppressor miR-142-5p was predicted to target SREBP1/ZEB1 and a lower miR-142-5p was correlated with poor prognosis. We then performed in vitro experiments and showed that overexpressing SREBP1 in OE33 cell line led to increased abilities of colony formation, migration, and invasion; the opposite was observed in SREBP1-silenced OE21cells and SREBP1-silencing was accompanied by the reduced mesenchymal markers, including vimentin (Vim) and ZEB1, while E-cadherin and tumor suppressor miR-142-5p were increased. Subsequently, we first demonstrated that both SREBP1 and ZEB1 were potential targets of miR-142-5p, followed by the examination of the regulatory circuit of miR-142-5p and SREBP1/ZEB1. We observed that increased miR-142-5p level led to the reduced tumorigenic properties, such as migration and tumor sphere formation, and both observations were accompanied by the reduction of ZEB1 and SREBP1, and increase of E-cadherin. We then explored the potential therapeutic agent targeting SREBP1-associated signaling by testing fatostatin (4-hydroxytamoxifen, an active metabolite of tamoxifen). We found that fatostatin suppressed the cell viability of OE21 and OE33 cells and tumor spheres. Interestingly, fatostatin treatment reduced CD133+ population in both OE21 and OE33 cells in concert of increased miR-142-5p level. Finally, we evaluated the efficacy of fatostatin using a xenograft mouse model. Mice treated with fatostatin showed a significantly lower tumor burden and better survival rate as compared to their control counterparts. The treatment of fatostatin resulted in the reduced staining of SREBP1, ZEB1, and Vim, while E-cadherin and miR-142-5p were increased. In summary, we showed that increased SREBP1 and reduced miR-142-5p were associated with increased tumorigenic properties of esophageal cancer cells and poor prognosis. Preclinical tests showed that suppression of SREBP1 using fatostatin led to the reduced malignant phenotype of esophageal cancer via the reduction of EMT markers and increased tumor suppressor, miR-142-5p. Further investigation is warranted for the clinical use of fatostatin for the treatment of esophageal malignancy.

Highlights

  • Esophageal cancer (EC) represents a common and malignant type of gastrointestinal cancer worldwide, with approximately 572,000 new cases and more than half of million deaths in 2018 [1].Among all subtypes, approximately 90% cases are esophageal squamous cell carcinoma (ESCC) and ESCC is often diagnosed at the advanced stage [2,3]

  • To determine whether sterol regulatory element-binding protein 1 (SREBP1) is dysregulated in esophageal cancer, we first performed bioinformatics analysis using Oncomine to investigate the expression of SREBP1, and found that

  • An increased SREBP1 mRNA was significantly correlated to the shorter overall survival time of ESCC patients (Figure 1C) from the same TCGA ESCC

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Summary

Introduction

Esophageal cancer (EC) represents a common and malignant type of gastrointestinal cancer worldwide, with approximately 572,000 new cases and more than half of million deaths in 2018 [1]. Approximately 90% cases are esophageal squamous cell carcinoma (ESCC) and ESCC is often diagnosed at the advanced stage [2,3]. Treatment options become limited for patients with metastatic ESCC, and the five-year survival rate is estimated at only 15% [2,5]. Clinical evidence indicates that 90% of ESCC patients died from distant invasion and metastasis, and 36.8% patients show lymph node metastasis [4,5]. It is urgent to better understand the molecular mechanisms by which ESCC invasion and metastasis occur so that improved therapeutic and diagnostic agents can be developed

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