CUX1: a modulator of tumour aggressiveness in pancreatic neuroendocrine neoplasms

Abstract

Pancreatic neuroendocrine neoplasms (PNENs) constitute a rare tumour entity, and prognosis and treatment options depend on tumour-mediating hallmarks such as angiogenesis, proliferation rate and resistance to apoptosis. The molecular pathways that determine the malignant phenotype are still insufficiently understood and this has limited the use of effective combination therapies in the past. In this study, we aimed to characterise the effect of the oncogenic transcription factor Cut homeobox 1 (CUX1) on proliferation, resistance to apoptosis and angiogenesis in murine and human PNENs. The expression and function of CUX1 were analysed using knockdown and overexpression strategies in Ins-1 and Bon-1 cells, xenograft models and a genetically engineered mouse model of insulinoma (RIP1Tag2). Regulation of angiogenesis was assessed using RNA profiling and functional tube-formation assays in HMEC-1 cells. Finally, CUX1 expression was assessed in a tissue microarray of 59 human insulinomas and correlated with clinicopathological data. CUX1 expression was upregulated during tumour progression in a time-and stage-dependent manner in the RIP1Tag2 model, and associated with pro-invasive and metastatic features of human insulinomas. Endogenous and recombinant CUX1 expression increased tumour cell proliferation, tumour growth, resistance to apoptosis, and angiogenesis in vitro and in vivo. Mechanistically, the pro-angiogenic effect of CUX1 was mediated via upregulation of effectors such as HIF1a and MMP9. CUX1 mediates an invasive pro-angiogenic phenotype and is associated with malignant behaviour in human insulinomas. Key Words" CUX1 " pancreatic neuroendocrine neoplasms " angiogenesis " RIP1Tag2" insulinomas

Dipalmitoylphosphatidic acid inhibits breast cancer growth by suppressing angiogenesis via inhibition of the CUX1/FGF1/HGF signalling pathway

“…One study revealed that FGF1 is transcriptionally regulated by CUX1 in the Hs578T human breast cancer cell line and in the Bon-1 human pancreatic neuroendocrine tumour cell line. 15,21 In this study, Figure 5E). Meanwhile, CUX1 acted as a transcriptional activator, and the inhibition of CUX1 notably reduced the transcription and protein expression of FGF1, subsequently inhibiting HGF expression in HUVECs (Figure 5F,G).…”

“…The study of anti‐angiogenesis often focuses on the regulation of angiogenesis‐pathway gene. The overexpression of CUX1 in pancreatic neuroendocrine neoplasm cells upregulates hypoxia inducible factor‐1α (HIF‐1α) and matrix metalloprotein 9 (MMP9), and the paracrine stimulation of endothelial cells then leads to tumour angiogenesis 15. However, the biochemical role of CUX1 in vascular endothelial cells renains unclear.…”

“…The function of CUX1 is cell type‐dependent, and it acts as a transcriptional activator or transcriptional repressor in different types of cells. High CUX1 expression in pancreatic neuroendocrine tumour cells reportedly promotes angiogenesis via a paracrine pathway 15. However, the directly autocrine regulatory role and transcriptional regulatory mechanism of CUX1 in angiogenesis is still unknown.…”

Prognostic relevance of UCH-L1 and α-internexin in pancreatic neuroendocrine tumors

“…Both studies, however, did not identify applicable molecular markers for evaluating prognosis of insulinomas. Recently, a study showed that CUX1 mediates progression and angiogenesis in murine neuroendocrine tumors and is associated with malignant behaviors in human insulinomas 37 . Another interesting study revealed that TPD52 protein was associated with survival of patients with insulinomas using proteomic approach 27 .…”

The hypoglicemic syndrome (insulinoma): topical, pathomorphological, and genetic diagnostics and treatment (review, part 2)

“…В настоящее время активно проводятся ИГХ исследования по выявлению биомаркеров злокачественной инсулиномы. Такими кандидатами, по данным некоторых исследований, могут являться: молекула клеточной адгезии (EpCAM) [34], фактор транскрипции CUX1 [35], альдегиддегидрогеназа А1, потенциалзависимый анионселективный канал 1 [36]. В то же время экспрессия опухолевого белка D52 [36] и рецепторов ГПП1 [14] отмечена в большей степени в доброкачественных инсулиномах.…”