The Fibrosis-Targeted Collagen/Integrins Gene Profile Predicts Risk of Metastasis in Pulmonary Neuroendocrine Neoplasms

Prieto, Tabatha Gutierrez; Machado-Rugolo, Juliana; Baldavira, Camila Machado; Velosa, Ana Paula Pereira; Teodoro, Walcy Rosolia; Saber, Alexandre M Ab'; Capelozzi, Vera Luíza

doi:10.3389/fonc.2021.706141

Cited by 5 publications

(5 citation statements)

References 56 publications

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“…Because fibrosis plays a critical role in metastasis [38][39][40] which frequently accompanies recurrence, we compared the key regulators of fibrosis between the NR and R groups. We found that the collagens COL5A3 and COL12A1 and fibronectins 1 (FN1) were significantly increased in the R samples (Fig.…”

Section: Resultsmentioning

confidence: 99%

Proteome and phosphoproteome signatures of recurrence for HPV+ head and neck squamous cell carcinoma

et al. 2022

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Background Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and the human papillomavirus (HPV+)-driven subtype is the fastest rising cancer in North America. Although most cases of HPV+ HNSCC respond favorably to the treatment via surgery followed by radiochemotherapy, up to 20% recur with a poor prognosis. The molecular and cellular mechanisms of recurrence are not fully understood. Methods To gain insights into the mechanisms of recurrence and to inform patient stratification and personalized treatment, we compared the proteome and phosphoproteome of recurrent and non-recurrent tumors by quantitative mass spectrometry. Results We observe significant differences between the recurrent and non-recurrent tumors in cellular composition, function, and signaling. The recurrent tumors are characterized by a pro-fibrotic and immunosuppressive tumor microenvironment (TME) featuring markedly more abundant cancer-associated fibroblasts, extracellular matrix (ECM), neutrophils, and suppressive myeloid cells. Defective T cell function and increased epithelial-mesenchymal transition potential are also associated with recurrence. These cellular changes in the TME are accompanied by reprogramming of the kinome and the signaling networks that regulate the ECM, cytoskeletal reorganization, cell adhesion, neutrophil function, and coagulation. Conclusions In addition to providing systems-level insights into the molecular basis of recurrence, our work identifies numerous mechanism-based, candidate biomarkers and therapeutic targets that may aid future endeavors to develop prognostic biomarkers and precision-targeted treatment for recurrent HPV+ HNSCC.

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Section: Resultsmentioning

confidence: 99%

Proteome and phosphoproteome signatures of recurrence for HPV+ head and neck squamous cell carcinoma

et al. 2022

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“…AutoDock, which is open source and widely used, was selected for SBDD and virtual screening to obtain lead compounds with binding potential to the target. Previous studies have shown that drugs targeting multiple receptors may inhibit the development of IPF better than those targeting individual receptors ( Cheng et al, 2019 ; Prieto et al, 2021 ). To evaluate the feasibility of screening drugs against multiple targets, we first analyzed the spatial structural similarity, sequence similarity, and physiological pathway associations of ligand-binding domains in nine receptors.…”

Section: Resultsmentioning

confidence: 99%

Virtual screening and activity evaluation of multitargeting inhibitors for idiopathic pulmonary fibrosis

Wang

Yan

et al. 2022

Front. Pharmacol.

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Transforming growth factor β receptor (TGF-β1R) and receptor tyrosine kinases (RTKs), such as VEGFRs, PDGFRs and FGFRs are considered important therapeutic targets in blocking myofibroblast migration and activation of idiopathic pulmonary fibrosis (IPF). To screen and design innovative prodrug to simultaneously target these four classes of receptors, we proposed an approach based on network pharmacology combining virtual screening and machine learning activity prediction, followed by efficient in vitro and in vivo models to evaluate drug activity. We first constructed Collagen1A2-A549 cells with type I collagen as the main biomarker and evaluated the activity of compounds to inhibit collagen expression at the cellular level. The data from the first round of Collagen1A2-A549 cell screening were substituted into the machine learning model, and the model was optimized accordingly. As a result, the false positive rate of the model was reduced from 85.0% to 66.7%, and two prospective compounds, Z103080500 and Z104578368, were finally selected. Collagen levels were reduced effectively by both Z103080500 (67.88% reduction) and Z104578368 (69.54% reduction). Moreover, these two compounds showed low cellular cytotoxicity. Subsequently, the effect of Z103080500 and Z104578368 was evaluated in a bleomycin-induced C57BL/6 mouse IPF model. These results showed that 50 mg/kg Z103080500 and Z104578368 could effectively reduce the number of inflammatory cells and the expression level of α-SMA. Meanwhile, Z103080500 and Z104578368 reduced the expression of major markers and inflammatory factors of IPF, such as collagen, IFN-γ, IL-17 and HYP, indicating that these screened Z103080500 and Z104578368 effectively delayed lung tissue inflammation and had a potential therapeutic effect on IPF. Our findings demonstrate that a screening and evaluation model for prodrug against IPF has been successfully established. It is of great significance to further modify these compounds to enhance their potency and activity.

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“…Specific ECM alterations regulating tissue biochemical and biomechanical properties have been described in NETs [ 40 ], which may imply that several ECM glycoproteins may contribute to the tumorigenesis of NETs. In a recent study, the up-regulation of six fibrogenic genes ( COL5A2 , COL1A2 , COL3A1 , ITGA5 , ITGB1 , and ITGB1 ) in pulmonary neuroendocrine carcinoma and the down-regulation of pulmonary neuroendocrine neoplasms were strongly related to no metastasis and overall survival [ 41 ]. Only one study has shown that the activation of the lysine degradation pathway injures tumor cell proliferation [ 42 ], which is also related to miR-769-5p tumor suppression, as shown in subsequent studies.…”

Section: Discussionmentioning

confidence: 99%

Different miRNAs Related to FBXW7 Mutations or High Mitotic Indices Contribute to Rectal Neuroendocrine Tumors: A Pilot Study

Kang

Park

Lim

et al. 2023

IJMS

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Recent studies suggest that miRNA may be involved in the development of rectal neuroendocrine tumors (NETs). We explored the frequency of clinicopathologically relevant mutations and miRNA expression in rectal NETs to examine molecular profiles related to prognosis and behavior. Twenty-four eligible specimens with endoscopically excised rectal NETs were selected. Next-generation sequencing and an miRNA expression assay were used to evaluate the expression profile relevant to common genetic mutations in rectal NETs. Kyoto Encyclopedia of Genes and Genomes analysis predicted that the possible target signaling pathways were correlated with dysregulated miRNAs. Nineteen rectal NETs harbored more than one mutation in the 24 cancer-related genes. Seven miRNAs (hsa-miR-769-5p, hsa-miR-221-3p, hsa-miR-34a-5p, hsa-miR-181c-5p, hsa-miR-1246, hsa-miR-324-5p, and hsa-miR-361-3p) were significantly down-regulated in tumors harboring the FBWX7 mutation. Unsupervised hierarchical clustering analysis showed that up-regulation of these seven miRNAs may result in high mitotic indices, indicating the role of miRNAs in tumor progression. Among the down-regulated miRNAs, hsa-miR-769-5p was strongly correlated with extracellular matrix–receptor interaction and lysine degradation. Among the clinicopathological factors, up-regulated hsa-miR-3934-5p was linked to an increased mitotic count. No change in miRNA expression was associated with a tumor size >1 cm, lymphovascular invasion, or Ki-67 index. In summary, we identified different miRNA signatures involved in FBXW7 mutations or high mitotic indices in rectal NETs, which may play a critical role in tumor behavior.

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The Fibrosis-Targeted Collagen/Integrins Gene Profile Predicts Risk of Metastasis in Pulmonary Neuroendocrine Neoplasms

Cited by 5 publications

References 56 publications

Proteome and phosphoproteome signatures of recurrence for HPV+ head and neck squamous cell carcinoma

Proteome and phosphoproteome signatures of recurrence for HPV+ head and neck squamous cell carcinoma

Virtual screening and activity evaluation of multitargeting inhibitors for idiopathic pulmonary fibrosis

Different miRNAs Related to FBXW7 Mutations or High Mitotic Indices Contribute to Rectal Neuroendocrine Tumors: A Pilot Study

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