Krug Sebastian, Weissbach Julia, Blank Annika, Perren Aurel, Haybaeck Johannes, Fendrich Volker, Rinke Anja, Gress Thomas Mathias, Rosendahl Jonas, Michl Patrick
Department of Internal Medicine I, Martin Luther University, 06120 Halle (Saale), Germany.
Institute of Pathology, University of Bern, 3008 Bern, Switzerland.
Cancers (Basel). 2020 Jul 19;12(7):1957. doi: 10.3390/cancers12071957.
Recently, we identified the homeodomain transcription factor Cut homeobox 1 (CUX1) as mediator of tumour de-differentiation and metastatic behaviour in human insulinoma patients. In insulinomas, CUX1 enhanced tumour progression by stimulating proliferation and angiogenesis in vitro and in vivo. In patients with non-functional pancreatic neuroendocrine tumours (PanNET), however, the impact of CUX1 remains to be elucidated. Here, we analysed CUX1 expression in two large independent cohorts ( = 43 and = 141 tissues) of non-functional treatment-naïve and pre-treated PanNET patients, as well as in the RIP1Tag2 mouse model of pancreatic neuroendocrine tumours. To further assess the functional role of CUX1, expression profiling of DNA damage-, proliferation- and apoptosis-associated genes was performed in CUX1-overexpressing Bon-1 cells. Validation of differentially regulated genes was performed in Bon-1 and QGP1 cells with knock-down and overexpression strategies. CUX1 expression assessed by a predefined immunoreactivity score (IRS) was significantly associated with shorter progression-free survival (PFS) of pre-treated PanNET patients (23 vs. 8 months; = 0.005). In treatment-naïve patients, CUX1 was negatively correlated with grading and recurrence-free survival (mRFS of 39 versus 8 months; = 0.022). In both groups, high CUX1 levels indicated a metastatic phenotype. Functionally, CUX1 upregulated expression of caspases and death associated protein kinase 1 (DAPK1), known as mediators of tumour progression and resistance to cytotoxic drugs. This was also confirmed in both cell lines and human tissues. In the RIP1Tag2 mouse model, CUX1 expression was associated with advanced tumour stage and resistance to apoptosis. In summary, we identified the transcription factor CUX1 as mediator of tumour progression in non-functional PanNET in vitro and in vivo, indicating that the CUX1-dependent signalling network is a promising target for future therapeutic intervention.
最近，我们确定同源异型域转录因子切割同源框1（CUX1）是人类胰岛素瘤患者肿瘤去分化和转移行为的介导因子。在胰岛素瘤中，CUX1通过在体外和体内刺激增殖和血管生成来促进肿瘤进展。然而，在无功能性胰腺神经内分泌肿瘤（PanNET）患者中，CUX1的影响仍有待阐明。在此，我们分析了两个大型独立队列（分别为43例和141例组织）中未经治疗和经预处理的无功能性PanNET患者以及胰腺神经内分泌肿瘤的RIP1Tag2小鼠模型中CUX1的表达。为了进一步评估CUX1的功能作用，在过表达CUX1的Bon-1细胞中进行了DNA损伤、增殖和凋亡相关基因的表达谱分析。采用敲低和过表达策略在Bon-1和QGP1细胞中对差异调节基因进行验证。通过预定义的免疫反应性评分（IRS）评估的CUX1表达与经预处理的PanNET患者较短的无进展生存期（PFS）显著相关（23个月对8个月；P = 0.005）。在未经治疗的患者中，CUX1与分级和无复发生存期呈负相关（无复发生存期分别为39个月和8个月；P = 0.022）。在两组中，高CUX1水平均表明为转移表型。在功能上，CUX1上调了胱天蛋白酶和死亡相关蛋白激酶1（DAPK1）的表达，这两种蛋白是肿瘤进展和对细胞毒性药物耐药的介导因子。这在细胞系和人体组织中也得到了证实。在RIP1Tag2小鼠模型中，CUX1表达与肿瘤晚期和抗凋亡相关。总之，我们确定转录因子CUX1是无功能性PanNET体外和体内肿瘤进展的介导因子，表明CUX1依赖性信号网络是未来治疗干预的一个有前景的靶点。
