This review systematically synthesizes the current literature on the role of the RNA-binding motif single-stranded interacting protein 3 (RBMS3) in malignant tumourigenesis, focusing on its molecular mechanisms, tumour-suppressive roles across cancer types, and clinical translational potential. Since its identification in 2000, RBMS3 has emerged as a critical tumour suppressor gene (TSG) located in the chromosome 3p23-p24 region and belonging to the MSSP family.Mechanistically, RBMS3 modulates key signalling cascades, including the Wnt/β-catenin and LKB1/AMPK pathways, to regulate cellular processes such as proliferation, migration, and invasion. It also acts as a multifaceted regulator of the epithelial‒mesenchymal transition (EMT), a pivotal process driving cancer progression and metastasis.Preclinical evidence has demonstrated that RBMS3 expression is frequently downregulated in breast, lung, ovarian, bladder, oesophageal, and other solid tumours, with its loss correlating with enhanced tumour cell malignancy. For example, in triple-negative breast cancer, RBMS3 suppresses EMT by stabilizing PRRX1 mRNA, whereas in lung cancer, it inhibits metastasis via the LKB1/AMPK axis.Clinically, reduced RBMS3 levels are associated with advanced disease stages and poor prognosis, positioning it as a potential diagnostic biomarker and therapeutic target. However, the correlation between low RBMS3 expression and disease prognosis may be confounded by clinical variables (e.g., tumour stage and treatment regimens), thus requiring functional validation to clarify causality. Strategies to restore RBMS3 expression, such as epigenetic modulation or small-molecule induction, show promise in reversing drug resistance and enhancing antitumour immunity, as observed in ovarian cancer through ferroptosis induction.Notably, while RBMS3, a TSG, is well established, its context-dependent functional diversity across cancer types requires further elucidation. Gaps remain in understanding its precise molecular interactions and the heterogeneity of its expression in the tumour microenvironment (TME). Additionally, the clinical translation of RBMS3-based diagnostics (e.g., immunohistochemistry or gene expression profiling) necessitates the validation of specificity and sensitivity across patient cohorts. This review highlights the importance of RBMS3 in cancer biology and emphasizes the need for comprehensive studies to elucidate its full potential in precision oncology.

Function and Mechanism of the RNA-binding Protein RBMS3 in Malignant Tumours

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发表日期：

2025年8月1日

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Ziyun Xin,
Huaping Huang,
Yingjie Shao

摘要

This review systematically synthesizes the current literature on the role of the RNA-binding motif single-stranded interacting protein 3 (RBMS3) in malignant tumourigenesis, focusing on its molecular mechanisms, tumour-suppressive roles across cancer types, and clinical translational potential. Since its identification in 2000, RBMS3 has emerged as a critical tumour suppressor gene (TSG) located in the chromosome 3p23-p24 region and belonging to the MSSP family.

Mechanistically, RBMS3 modulates key signalling cascades, including the Wnt/β-catenin and LKB1/AMPK pathways, to regulate cellular processes such as proliferation, migration, and invasion. It also acts as a multifaceted regulator of the epithelial‒mesenchymal transition (EMT), a pivotal process driving cancer progression and metastasis.

Preclinical evidence has demonstrated that RBMS3 expression is frequently downregulated in breast, lung, ovarian, bladder, oesophageal, and other solid tumours, with its loss correlating with enhanced tumour cell malignancy. For example, in triple-negative breast cancer, RBMS3 suppresses EMT by stabilizing PRRX1 mRNA, whereas in lung cancer, it inhibits metastasis via the LKB1/AMPK axis.

Clinically, reduced RBMS3 levels are associated with advanced disease stages and poor prognosis, positioning it as a potential diagnostic biomarker and therapeutic target. However, the correlation between low RBMS3 expression and disease prognosis may be confounded by clinical variables (e.g., tumour stage and treatment regimens), thus requiring functional validation to clarify causality. Strategies to restore RBMS3 expression, such as epigenetic modulation or small-molecule induction, show promise in reversing drug resistance and enhancing antitumour immunity, as observed in ovarian cancer through ferroptosis induction.

Notably, while RBMS3, a TSG, is well established, its context-dependent functional diversity across cancer types requires further elucidation. Gaps remain in understanding its precise molecular interactions and the heterogeneity of its expression in the tumour microenvironment (TME). Additionally, the clinical translation of RBMS3-based diagnostics (e.g., immunohistochemistry or gene expression profiling) necessitates the validation of specificity and sensitivity across patient cohorts. This review highlights the importance of RBMS3 in cancer biology and emphasizes the need for comprehensive studies to elucidate its full potential in precision oncology.