由于胆道癌（BTC）的患病率较低，发现和验证胆道癌（BTC）的诊断或治疗生物标志物具有挑战性。在此，我们鉴定并研究了 BTC 中由 1;14 染色体易位引起的融合基因 Pumilio1-肿瘤坏死因子受体相关因子 3 (PUM1-TRAF3) 的临床影响。 PUM1-TRAF3 最初是在 5 个 BTC 手术组织的 RNA 测序中鉴定出来的，并通过荧光原位杂交得到证实。融合基因的表达在扩大的队列中得到验证（5/55，9.1%）。表达 PUM1-TRAF3 的 BTC 细胞的建立和分子评估表明，PUM1-TRAF3 通过 NF-κB 诱导激酶 (NIK) 激活非经典 NF-κB 信号传导。由 PUM1-TRAF3 和 TRAF3 与 NIK 竞争性结合驱动的异常 TRAF3 活性导致 NIK 救援，随后发生 P52/RelB 核易位，所有这些都被 NIK 抑制剂逆转。在患者组织的 PUM1-TRAF3 表达区域中观察到 NIK 表达升高并激活 NF-κB 信号传导。 PUM1-TRAF3 融合蛋白的表达与 NIK 的强表达显着相关，这与 BTC 患者的较差预后相关。总体而言，我们的研究确定了一种新的融合基因 PUM1-TRAF3，它可以激活 NIK 和非典型 NF-κB 信号传导，这可能有利于制定 BTC 的精确治疗策略。© 2024。作者。

Discovery and verification of diagnostic or therapeutic biomarkers for biliary tract cancer (BTC) is challenging owing to the low prevalence of the disease. Here, we identified and investigated the clinical impact of a fusion gene, Pumilio1-tumor necrosis factor receptor-associated factor 3 (PUM1-TRAF3), caused by 1;14 chromosomal translocation in BTC. PUM1-TRAF3 was initially identified in the RNA-sequencing of five BTC surgical tissues and confirmed by fluorescence in situ hybridization. Expression of the fusion gene was validated in an expanded cohort (5/55, 9.1%). Establishment and molecular assessment of PUM1-TRAF3 expressing BTC cells revealed that PUM1-TRAF3 activates non-canonical NF-κB signaling via NF-κB-inducing kinase (NIK). Abnormal TRAF3 activity, driven by competitive binding of PUM1-TRAF3 and TRAF3 to NIK, led to NIK rescue followed by P52/RelB nuclear translocation, all of which were reverted by an NIK inhibitor. The elevated expression of NIK and activated NF-κB signaling was observed in the PUM1-TRAF3-expressing regions of patient tissues. Expression of the PUM1-TRAF3 fusion was significantly correlated with strong NIK expression, which is associated with a poorer prognosis for patients with BTC. Overall, our study identifies a new fusion gene, PUM1-TRAF3, that activates NIK and non-canonical NF-κB signaling, which may be beneficial for developing precise treatment strategies for BTC.© 2024. The Author(s).