Upregulated Expression of CUX1 Correlates with Poor Prognosis in Glioma Patients: a Bioinformatic Analysis

Wu, Xiujie; Fěng, Fang; Yang, Chuanchao; Zhang, Moxuan; Cheng, Yanhao; Zhao, Yayun; Wang, Yayu; Che, Fengyuan; Zhang, Jian; Heng, Xueyuan

doi:10.1007/s12031-019-01355-3

Cited by 5 publications

(3 citation statements)

References 42 publications

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“…Our data are in line with several reports in the literature describing CUX1 as important trigger of carcinogenesis in various solid tumor entities including glioma [ 41 ], neuroblastoma [ 42 ] and breast cancer [ 38 ]. In contrast to solid tumors and for reasons not entirely understood, CUX1 may act as tumor suppressor in myeloid malignancies in which it is frequently inactivated [ 43 ].…”

Section: Discussionsupporting

confidence: 92%

CUX1 Enhances Pancreatic Cancer Formation by Synergizing with KRAS and Inducing MEK/ERK-Dependent Proliferation

Griesmann

Mühl

Riedel

et al. 2021

Cancers

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The transcription factor CUX1 has been implicated in either tumor suppression or progression, depending on the cancer entity and the prevalent CUX1 isoform. Previously, we could show that CUX1 acts as an important mediator of tumor cell proliferation and resistance to apoptosis in pancreatic cancer cell lines. However, in vivo evidence for its impact on pancreatic carcinogenesis, isoform-specific effects and downstream signaling cascades are missing. We crossbred two different CUX1 isoform mouse models (p200 CUX1 and p110 CUX1) with KC (KrasLSL-G12D/+;Ptf1aCre/+) mice, a genetic model for pancreatic precursor lesions (PanIN). In the context of oncogenic KRASs, both mice KCCux1p200 and KCCux1p110 led to increased PanIN formation and development of invasive pancreatic ductal adenocarcinomata (PDAC). In KCCux1p110 mice, tumor development was dramatically more accelerated, leading to formation of invasive PDAC within 4 weeks. In vitro and in vivo, we could show that CUX1 enhanced proliferation by activating MEK-ERK signaling via an upstream increase of ADAM17 protein, which in turn led to an activation of EGFR. Additionally, CUX1 further enhanced MEK-ERK activation through upregulation of the serine/threonine kinase MOS, phosphorylating MEK in a KRAS-independent manner. We identified p110 CUX1 as major driver of pancreatic cancer formation in the context of mutant KRAS. These results provide the first in vivo evidence for the importance of CUX1 in the development of pancreatic cancer, and highlight the importance of CUX1-dependent signaling pathways as potential therapeutic targets.

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Section: Discussionsupporting

confidence: 92%

CUX1 Enhances Pancreatic Cancer Formation by Synergizing with KRAS and Inducing MEK/ERK-Dependent Proliferation

Griesmann

Mühl

Riedel

et al. 2021

Cancers

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“…In the present study we observed a strong correlation of CUX1 expression with grading, the presence of a metastatic phenotype and worsened prognosis. These data are in line with our own previous data that identified CUX1 as driver of tumour aggressiveness in malignant insulinomas and with findings of other groups confirming a negative prognostic impact of CUX1 in various solid tumours [31,32].…”

Section: Discussionsupporting

confidence: 93%

CUX1—Transcriptional Master Regulator of Tumor Progression in Pancreatic Neuroendocrine Tumors

Krug

Weißbach

Blank

et al. 2020

Cancers

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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 (n = 43 and n = 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; p = 0.005). In treatment-naïve patients, CUX1 was negatively correlated with grading and recurrence-free survival (mRFS of 39 versus 8 months; p = 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.

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“…There are several lines of evidence indicating the oncogenic role of CUX1. First, elevated expression of CUX1 has been observed in many types of cancers, including colorectal cancer (67), multiple myeloma (68), uterine leiomyomas (69), highgrade breast cancer (12), pancreatic cancer (70), melanoma 71, and glioma (72); second, CUX1 expression is positively associated with poor prognosis in glioma, glioblastoma, colorectal cancer, breast cancer, and pancreatic cancer (12,61,67,72); third, mouse mammary tumor virus (MMTV) p200, p110, and p75 CUX1 transgenic mice develop late-onset mammary carcinoma (64,73); fourth, active Kras mutations, such as KRAS G12D and KRAS Q61L , have been observed in mammary carcinomas from MMTV-p200 CUX1 transgenic mice, and CUX1 can cooperate with KRAS G12V , an active Kras mutant, to promote lung tumor formation in vivo (64); fifth, CUX1 is a transcriptional target downstream of the transforming growth factor β and/or PI3K-AKT signalings and contributes to enhanced proliferation, migration/invasion, and reduced apoptosis in tumor cells (12,70). More interestingly, a very recent study has demonstrated that CUX1 can generate a circular RNA (circ-CUX1) to promote tumor progression in neuroblastoma (NB) (74).…”

Section: Cux1 Serves As An Oncogenementioning

confidence: 99%

CUX1, A Controversial Player in Tumor Development

et al. 2020

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CUX1 belongs to the homeodomain transcription factor family and is evolutionarily and functionally conserved from Drosophila to humans. In addition to the involvement in various physiological events including tissue development, cell proliferation, differentiation and migration, and DNA damage response, CUX1 has been implicated in tumorigenesis. Interestingly, CUX1 has been recently recognized as a haploinsufficient tumor suppressor, which is paradoxically overexpressed in tumor cells. While loss of heterozygosity and/or mutations of CUX1 have been frequently detected in many types of cancers, genomic amplification, and overexpression of CUX1 have also been reported in cancer tissues and are correlated with higher tumor grade and poor prognosis. Therefore, deciphering the roles of different CUX1 isoforms and in different tumor stages is required to establish a CUX1-based therapeutic strategy for cancer treatment.

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Upregulated Expression of CUX1 Correlates with Poor Prognosis in Glioma Patients: a Bioinformatic Analysis

Cited by 5 publications

References 42 publications

CUX1 Enhances Pancreatic Cancer Formation by Synergizing with KRAS and Inducing MEK/ERK-Dependent Proliferation

CUX1 Enhances Pancreatic Cancer Formation by Synergizing with KRAS and Inducing MEK/ERK-Dependent Proliferation

CUX1—Transcriptional Master Regulator of Tumor Progression in Pancreatic Neuroendocrine Tumors

CUX1, A Controversial Player in Tumor Development

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