SORBS2-Mediated inhibition of malignant behaviors in esophageal squamous cell carcinoma through TIMP3.

Zhang, Weiguang; Zhang, Peipei; Wang, Xiaoqing; Lin, Ye; Xu, Hui; Mao, Renyan; Zhu, Shujing; Lin, Tianxin; Cai, Junlan; Lin, Jihong; Kang, Mingqiang

Zhang, Weiguang; Zhang, Peipei; Wang, Xiaoqing; Lin, Ye; Xu, Hui; Mao, Renyan; Zhu, Shujing; Lin, Tianxin; Cai, Junlan; Lin, Jihong; Kang, Mingqiang.

Afiliación

Zhang W; Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
Zhang P; Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China. Electronic address: zhangpeipei0591@163.com.
Wang X; Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
Lin Y; Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
Xu H; Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
Mao R; The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
Zhu S; The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
Lin T; The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
Cai J; The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
Lin J; Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China; Clinical Research Center for Thoracic Tumors of Fujian Province, Fuzhou, China. Electronic address: jihong5625@163.com.
Kang M; Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China; Department of Cardiothoracic Surgery, Affiliated Hospital of Putian University, Putian, China; Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China; Fujia

Int Immunopharmacol ; 142(Pt B): 113096, 2024 Dec 05.

Article en En | MEDLINE | ID: mdl-39288625

ABSTRACT

ABSTRACT

BACKGROUND:

Esophageal squamous cell carcinoma (ESCC) is characterized by high invasiveness and poor prognosis. The role of Sorbin and SH3 domain-containing protein 2 (SORBS2) in ESCC remains largely unexplored.

METHODS:

The expression levels of SORBS2 in ESCC were detected using RNA-seq and proteomics data. The biological functions of SORBS2 in ESCC were investigated through in vivo and in vitro experiments. The mechanism of SORBS2 was explored using RIP-seq technology, which identified the key downstream molecule metalloproteinase-3 (TIMP3). The interaction between SORBS2 and TIMP3, including specific binding sites, was validated through RIP-qPCR and RNA pull-down assays. The impact of altered SORBS2 expression in ESCC on HUVECs was assessed using endothelial tube formation assays.

RESULTS:

SORBS2 expression was significantly downregulated in ESCC tissues, and its decreased expression was associated with poor prognosis. Overexpression of SORBS2 in ESCC cell lines inhibited cell proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, SORBS2 bound to the 3' UTR of TIMP3 mRNA, enhancing its stability and thereby regulating TIMP3 expression. Rescue experiments demonstrated that increased TIMP3 expression could reverse the promotive effects of SORBS2 knockdown on ESCC, confirming TIMP3 as a critical downstream molecule of SORBS2. Furthermore, downregulation of SORBS2 in ESCC cells was associated with activation of HUVEC functions, whereas upregulation of TIMP3 could reverse this effect. The SORBS2/TIMP3 axis may exert tumor suppressive effects by influencing extracellular matrix degradation.

CONCLUSION:

This study confirms that SORBS2 inhibits ESCC tumor progression by regulating extracellular matrix degradation through TIMP3, providing a potential therapeutic target for future treatment interventions.

Asunto(s)

Movimiento Celular; Proliferación Celular; Neoplasias Esofágicas; Carcinoma de Células Escamosas de Esófago; Regulación Neoplásica de la Expresión Génica; Inhibidor Tisular de Metaloproteinasa-3; Humanos; Inhibidor Tisular de Metaloproteinasa-3/genética; Inhibidor Tisular de Metaloproteinasa-3/metabolismo; Carcinoma de Células Escamosas de Esófago/genética; Carcinoma de Células Escamosas de Esófago/metabolismo; Carcinoma de Células Escamosas de Esófago/patología; Neoplasias Esofágicas/metabolismo; Neoplasias Esofágicas/genética; Neoplasias Esofágicas/patología; Animales; Línea Celular Tumoral; Masculino; Ratones Desnudos; Femenino; Ratones; Células Endoteliales de la Vena Umbilical Humana; Ratones Endogámicos BALB C; Proteínas Adaptadoras Transductoras de Señales/metabolismo; Proteínas Adaptadoras Transductoras de Señales/genética; Inhibidores de Serinpeptidasas Tipo Kazal

Palabras clave

Esophageal squamous cell carcinoma (ESCC); Extracellular Matrix (ECM); Malignant Behaviors; Metalloproteinase-3 (TIMP3); RNA-binding proteins (RBPs); Sorbin and SH3 domain-containing protein 2 (SORBS2)

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Esofágicas / Regulación Neoplásica de la Expresión Génica / Movimiento Celular / Inhibidor Tisular de Metaloproteinasa-3 / Proliferación Celular / Carcinoma de Células Escamosas de Esófago Límite: Animals / Female / Humans / Male Idioma: En Revista: Int Immunopharmacol Asunto de la revista: ALERGIA E IMUNOLOGIA / FARMACOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Países Bajos

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