SH3BGRL2 as a vital tumor suppressor and prognostic factor in human esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC), a highly aggressive malignancy associated with dismal prognosis, is a global healthcare threat. The molecular mechanisms underlying the carcinogenesis and progression of ESCC remain to be elucidated. This study aims to systematically dissect the pivotal genes and molecular mechanisms that orchestrate the progression of ESCC. METHODS: RNA-sequencing was performed to identify differentially expressed genes between resected ESCC tumor samples and paired adjacent normal tissues. The protein expression levels of SH3 domain binding glutamate rich protein-like 2 (SH3BGRL2) were assessed via immunohistochemistry (IHC) staining in a tissue microarray of 247 cases of ESCC tumor samples and paired normal tissues. Subsequent in vitro and in vivo assays were conducted to identify the functional role of SH3BGRL2 in ESCC. RESULTS: RNA-sequencing and IHC analyses both revealed significant downregulation of SH3BGRL2 in ESCC tissues (P<0.01). Patients with higher SH3BGRL2 expression exhibited significantly longer disease-free survival (DFS) and overall survival (OS) (DFS: 47.1 vs. 18.2 months, P=0.020; OS: 60.8 vs. 20.6 months, P=0.003). Moreover, SH3BGRL2 was identified as an independent prognostic factor for patients with resected ESCC in terms of DFS [hazard ratio (HR) =0.62, 95% confidence interval (CI): 0.43-0.91; P=0.02] and OS (HR =0.55, 95% CI: 0.37-0.81; P=0.002). In terms of mechanism, the proliferative capacity of ESCC patient-derived cell lines (PDCs) and in vivo xenograft models was enhanced upon SH3BGRL2 knockdown (P<0.05). Moreover, overexpression of SH3BGRL2 significantly inhibited cell proliferation. Notably, early growth response 1 (EGR1) expression was elevated in SH3BGRL2-silenced PDCs, suggesting that SH3BGRL2 may suppress ESCC proliferation by blocking the EGR1 pathway. CONCLUSIONS: SH3BGRL2 acts as a key tumor suppressor and prognostic determinant in ESCC, which represents a novel insight into the pathogenesis of this malignancy.