Tong Hanxing, Jia Ning, Li Wenyang, Xu Jingjing, Li Qiuyue, He Xiaomeng, Sun Huaqin, Corpe Christopher, Wang Jin
Central Laboratory, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, China.
Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China.
J Transl Med. 2025 May 30;23(1):601. doi: 10.1186/s12967-025-06598-w.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal sarcomas of the upper digestive tract. Imatinib is the first-line therapy for patients with metastatic or unresectable GISTs. However, the majority of GIST patients eventually develop imatinib resistance.
To identify the factors that are responsible for imatinib resistance, we investigated the differentially expressed mRNAs and circRNAs in imatinib-naïve and imatinib-resistant GISTs via ceRNA microarrays. The expression levels of circ-BRIP1, circ-EPHB4 and their host genes were validated via quantitative real-time PCR analyses and formalin-fixed and paraffin-embedded (FFPE) tissue microarrays (TMAs).
We found that 107 mRNAs and 521 circRNAs were differentially expressed between imatinib-resistant and imatinib-naïve GIST tissue samples. Among them, circ-BRIP1, circ-EPHB4 and their host genes were upregulated in imatinib-resistant GISTs and associated with imatinib resistance, tumor relapse and progression, and metastasis in GIST patients. The expression level of EPHB4 was significantly greater in high-grade GISTs than in low-grade GISTs and was correlated with imatinib resistance.
Our results demonstrated that the circRNA in situ hybridization-immunohistochemistry could not only be applied to FFPE-TMAs for high-throughput analysis of circRNA expression in tumors but also suggested a possible role for circ-BRIP1, circ-EPHB4, and their host genes in the progression of GISTs.
胃肠道间质瘤（GISTs）是上消化道最常见的间叶性肉瘤。伊马替尼是转移性或不可切除GIST患者的一线治疗药物。然而，大多数GIST患者最终会产生伊马替尼耐药性。
为了确定导致伊马替尼耐药的因素，我们通过ceRNA微阵列研究了初治伊马替尼和伊马替尼耐药GIST中差异表达的mRNA和circRNA。通过定量实时PCR分析以及福尔马林固定石蜡包埋（FFPE）组织微阵列（TMA）验证了circ-BRIP1、circ-EPHB4及其宿主基因的表达水平。
我们发现，在伊马替尼耐药和初治伊马替尼的GIST组织样本之间，有107种mRNA和521种circRNA差异表达。其中，circ-BRIP1、circ-EPHB4及其宿主基因在伊马替尼耐药的GIST中上调，并与GIST患者的伊马替尼耐药、肿瘤复发和进展以及转移相关。EPHB4在高级别GIST中的表达水平显著高于低级别GIST，且与伊马替尼耐药相关。
我们的结果表明，circRNA原位杂交免疫组化不仅可应用于FFPE-TMA，用于肿瘤中circRNA表达的高通量分析，还提示circ-BRIP1、circ-EPHB4及其宿主基因在GIST进展中可能发挥作用。
