Abstract
Deletions on chromosome 3p occur often in many solid tumors, including esophageal squamous cell carcinoma (ESCC), suggesting the existence at this location of one or more tumor suppressor genes (TSG). In this study, we characterized RBMS3 gene encoding an RNA-binding protein as a candidate TSG located at 3p24. Downregulation of RBMS3 mRNA and protein levels was documented in approximately 50% of the primary ESCCs examined. Clinical association studies determined that RBMS3 downregulation was associated with poor clinical outcomes. RBMS3 expression effectively suppressed the tumorigenicity of ESCC cells in vitro and in vivo, including by inhibition of cell growth rate, foci formation, soft agar colony formation, and tumor formation in nude mice. Molecular analyses revealed that RBMS3 downregulated c-Myc and CDK4, leading to subsequent inhibition of Rb phosphorylation. Together, our findings suggest a tumor suppression function for the human RBMS3 gene in ESCC, acting through c-Myc downregulation, with genetic loss of this gene in ESCC contributing to poor outcomes in this deadly disease.
Highlights
Esophageal cancer is one of the most common fatal cancers worldwide [1]
The result showed that downregulation of RBMS3 was detected in 18 of 40 (45%) of esophageal squamous cell carcinoma (ESCC) tissues compared with their paired nontumorous tissues (Fig. 1A)
The expression of RBMS3 in 6 ESCC cell lines was tested by RT-PCR, and the result showed that RBMS3 was downregulated in 3 cell lines (HKESC1, KYSE30, and KYSE140; Fig. 1B)
Summary
Esophageal cancer is one of the most common fatal cancers worldwide [1]. It ranks as the ninth most frequent cancer in the world, with a remarkable geographic distribution between and within countries. High-risk areas include northern Iran, South Africa, and northern China, where esophageal squamous cell carcinoma (ESCC) is still the main cancer burden and the fourth most common cause of death [2]. Epidemiologic studies indicate that tobacco and alcohol consumption are the major risk factors for squamous esophageal cancer in the low-risk regions of Europe and North America, the etiologic agents in high-risk regions have yet to be convincingly identified. Loss of 3p is one of the most frequent genetic alterations in ESCC detected by comparative
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