Dihydropyrimidinase‐like protein 3 expression is negatively regulated by <scp>MYCN</scp> and associated with clinical outcome in neuroblastoma

Tan, Fei; Wahdan-Alaswad, Reema S.; Yan, Shuang; Thiele, Carol J.; Li, Zhijie

doi:10.1111/cas.12278

Cited by 22 publications

(19 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Dihydropyrimidinase-like proteins (DPYSLs) are a family of proteins developmentally regulated during maturation of the nervous system. It has been previously established that DPYSLs are negatively regulated by N-Myc and reduced expression levels correlate with poor clinical outcomes [ 36 ]. In accordance with this observation, DPYSL1, 2, 4 and 5 were less abundant in SK-N-BE2 secretome.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of cathepsin proteases attenuates migration and sensitizes aggressive N-Myc amplified human neuroblastoma cells to doxorubicin

et al. 2015

View full text Add to dashboard Cite

Neuroblastoma arises from the sympathetic nervous system and accounts for 15% of childhood cancer mortality. Amplification of the oncogene N-Myc is reported to occur in more than 20% of patients. While N-Myc amplification status strongly correlates with higher tumour aggression and resistance to treatment, the role of N-Myc in the aggressive progression of the disease is poorly understood. N-Myc being a transcription factor can modulate the secretion of key proteins that may play a pivotal role in tumorigenesis. Characterising the soluble secreted proteins or secretome will aid in understanding their role in the tumour microenvironment, such as promoting cancer cell invasion and resistance to treatment. The aim of this study is to characterise the secretome of human malignant neuroblastoma SK-N-BE2 (N-Myc amplified, more aggressive) and SH-SY5Y (N-Myc non-amplified, less aggressive) cells. Conditioned media from SK-N-BE2 and SH-SY5Y cell lines were subjected to proteomics analysis. We report a catalogue of 894 proteins identified in the secretome isolated from the two neuroblastoma cell lines, SK-N-BE2 and SH-SY5Y. Functional enrichment analysis using FunRich software identified enhanced secretion of proteins implicated in cysteine peptidase activity in the aggressive N-Myc amplified SK-N-BE2 secretome compared to the less tumorigenic SH-SY5Y cells. Protein-protein interaction-based network analysis highlighted the enrichment of cathepsin and epithelial-to-mesenchymal transition sub-networks. For the first time, inhibition of cathepsins by inhibitors sensitized the resistant SK-N-BE2 cells to doxorubicin as well as decreased its migratory potential. The dataset of secretome proteins of N-Myc amplified (more aggressive) and non-amplified (less aggressive) neuroblastoma cells represent the first inventory of neuroblastoma secretome. The study also highlights the prominent role of cathepsins in the N-Myc amplified neuroblastoma pathogenesis. As N-Myc amplification correlates with aggressive neuroblastoma and chemotherapy-based treatment failure, co-treatment with cathepsin inhibitors might be a better avenue for disease management.

show abstract

Section: Resultsmentioning

confidence: 99%

Inhibition of cathepsin proteases attenuates migration and sensitizes aggressive N-Myc amplified human neuroblastoma cells to doxorubicin

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Conflicting roles of DPYSL3 have been described in different types of cancer, implying that it has a diversity of functions in different malignancies. Previous studies indicated that DPYSL3 inhibits cell migration by regulating the actin cytoskeleton in neuroblastoma cells [29]. DPYSL3 is also reported to play a role in cell migration and metastasis suppression in liver and prostate cancer [31][32][33].…”

Section: Discussionmentioning

confidence: 97%

“…DPYSL3, also referred to as the collapsing response mediator protein 4, is a member of the DPYSL gene family that is highly expressed in both normal tissues and tumors derived from the lung, colon and prostate [29]. The functions of DPYSL3 involves in various cellular processes, including cell differentiation, migration, neurogenesis and neurodegeneration [30].…”

Section: Discussionmentioning

confidence: 99%

Upregulation of Thr/Tyr kinase Increases the Cancer Progression by Neurotensin and Dihydropyrimidinase-Like 3 in Lung Cancer

Tsai

Chang

et al. 2020

IJMS

View full text Add to dashboard Cite

Lung cancer is one of the leading causes of cancer-related death globally, thus elucidation of its molecular pathology is highly highlighted. Aberrant alterations of the spindle assembly checkpoint (SAC) are implicated in the development of cancer due to abnormal cell division. TTK (Thr/Tyr kinase), a dual serine/threonine kinase, is considered to act as a cancer promoter by controlling SAC. However, the mechanistic details of how TTK-mediated signaling network supports cancer development is still a mystery. Here, we found that TTK was upregulated in the tumor tissue of patients with lung cancer, and enhanced tumor growth and metastasis in vitro and in vivo. Mechanistically, TTK exerted a significant enhancement in cancer growth by neurotensin (NTS) upregulation, and subsequently increased the expression of cyclin A and cdk2, which was resulting in the increase of DNA synthesis. In contrast, TTK increased cell migration and epithelial-to-mesenchymal transition (EMT) by enhancing the expression of dihydropyrimidinase-like 3 (DPYSL3) followed by the increase of snail-regulated EMT, thus reinforce metastatic potential and ultimately tumor metastasis. TTK and DPYSL3 upregulation was positively correlated with a poor clinical outcome in patients with lung cancer. Together, our findings revealed a novel mechanism underlying the oncogenic potential effect of TTK and clarified its downstream factors NTS and DPYSL3 might represent a novel, promising candidate oncogenes with potential therapeutic vulnerabilities in lung cancer.

show abstract

“…S3; Supplementary Tables S12 and S13). Notably, protein expression of dihydropyrimidinase-like 3 (DPYSL3) was high in the fast-growing group 1; this has previously been implicated in neuroblastoma progression (25). Additional proteins with higher levels in group 1 included: Ras GTPase-activating protein-binding protein 2 (G3BP2), involved in Ras signal transduction; stathmin (STMN1), involved in neuroblastoma metastasis (26); cofilin-1 (CFL1) implicated in neuroblastoma susceptibility (27), and microtubule-associated protein (MAP2; ref.…”

Section: Proteomic and Phosphoproteomic Analysis Reveal Molecular Spamentioning

confidence: 99%

Patient-Derived Xenograft Models Reveal Intratumor Heterogeneity and Temporal Stability in Neuroblastoma

et al. 2018

View full text Add to dashboard Cite

Patient-derived xenografts (PDX) and the Avatar, a single PDX mirroring an individual patient, are emerging tools in preclinical cancer research. However, the consequences of intratumor heterogeneity for PDX modeling of biomarkers, target identification, and treatment decisions remain underexplored. In this study, we undertook serial passaging and comprehensive molecular analysis of neuroblastoma orthotopic PDXs, which revealed strong intrinsic genetic, transcriptional, and phenotypic stability for more than 2 years. The PDXs showed preserved neuroblastoma-associated gene signatures that correlated with poor clinical outcome in a large cohort of patients with neuroblastoma. Furthermore, we captured spatial intratumor heterogeneity using ten PDXs from a single high-risk patient tumor. We observed diverse growth rates, transcriptional, proteomic, and phosphoproteomic profiles. PDX-derived transcriptional profiles were associated with diverse clinical characteristics in patients with high-risk neuroblastoma. These data suggest that high-risk neuroblastoma contains elements of both temporal stability and spatial intratumor heterogeneity, the latter of which complicates clinical translation of personalized PDX-Avatar studies into preclinical cancer research. These findings underpin the complexity of PDX modeling as a means to advance translational applications against neuroblastoma. .

show abstract

Dihydropyrimidinase‐like protein 3 expression is negatively regulated by MYCN and associated with clinical outcome in neuroblastoma

Cited by 22 publications

References 42 publications

Inhibition of cathepsin proteases attenuates migration and sensitizes aggressive N-Myc amplified human neuroblastoma cells to doxorubicin

Inhibition of cathepsin proteases attenuates migration and sensitizes aggressive N-Myc amplified human neuroblastoma cells to doxorubicin

Upregulation of Thr/Tyr kinase Increases the Cancer Progression by Neurotensin and Dihydropyrimidinase-Like 3 in Lung Cancer

Patient-Derived Xenograft Models Reveal Intratumor Heterogeneity and Temporal Stability in Neuroblastoma

Contact Info

Product

Resources

About