Comprehensive bioinformatic analysis of Wnt1 and Wnt1-associated diseases

Peng, Chuanming; Li, Yanqin; Ren, Xiu Bao; Wang, Yanzhou; Zhang, Shie; Chen, Mei; Liu, Junlong; Fang, Fengling; Li, Tianyou; Han, Jinxiang

doi:10.5582/irdr.2020.01018

Cited by 6 publications

(5 citation statements)

References 45 publications

(54 reference statements)

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“…5 and Supplementary Table S10 that Wnt1 expression was significantly higher (Dunn’s Test p value < 0.01) in metastatic tissues over tumor tissues of lungs, colon and skin; and was significantly lower (Dunn’s Test p value < 0.01) in breast, esophagus and kidney metastatic tissues over tumor tissues. As deregulation of Wnt1 activity was associated with various cancers and other human diseases 8 , 9 , a meta-analysis was also carried out to assess the overall survival rate of breast, gastric, lungs and ovarian cancer patients with Wnt1 expression, using Kaplan–Meier plotter (Fig. 6 ); and we found a strong relation between Wnt1 deregulation and the overall survival rate 72 .…”

Section: Resultsmentioning

confidence: 85%

“…The genes exhibit comparable expression profiles between cancerous and normal tissues, can serve as either targets of treatment or molecular biomarkers of cancer progression 8 . Comparing the expression of Wnt1 gene in normal and tumor samples across 21 different tissues had revealed no statistically significant up or down regulation of this gene.…”

Section: Discussionmentioning

confidence: 99%

“…Impaired Wnt signaling due to p.C218G mutation in Wnt1, causes significant and progressive changes in the spine, present both in bony vertebrae and in cartilaginous tissues and become increasingly severe with age over 50 years 7 . Literature studies have also shown that the malfunction of Wnt1 is associated with various cancers, genetic type XV osteogenesis imperfecta, osteoporosis, and neurological diseases 8 , 9 . High levels of Wnt1 expression was found in patients with advanced metastasis and the overall survival rate is lower in patients with Wnt1 -positive cancer 10 .…”

Section: Introductionmentioning

confidence: 99%

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In silico analyses of Wnt1 nsSNPs reveal structurally destabilizing variants, altered interactions with Frizzled receptors and its deregulation in tumorigenesis

Mondal

Paul

Dastidar

et al. 2022

Sci Rep

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Wnt1 is the first mammalian Wnt gene, which is discovered as proto-oncogene and in human the gene is located on the chromosome 12q13. Mutations in Wnt1 are reported to be associated with various cancers and other human diseases. The structural and functional consequences of most of the non-synonymous SNPs (nsSNPs), present in the human Wnt1 gene, are not known. In the present work, extensive bioinformatics analyses are used to screen 292 nsSNPs of Wnt1 for predicting pathogenic and harmless polymorphisms. We have identified 10 highly deleterious nsSNPs among which 7 are located within the highly conserved areas. These 10 nsSNPs are also predicted to affect the post-translational modifications of Wnt1. Further, structure based stability analyses of these 10 highly deleterious nsSNPs revealed 8 variants as highly destabilizing. These 8 highly destabilizing variants were shown to have high BC score and high RMSIP score from normal mode analyses. Based on the deformation energies, obtained from the normal mode analyses, variants like G169A, G169S, G331R and G331S were found to be unstable. Molecular Dynamics (MD) simulations revealed structural stability and fluctuation of WT Wnt1 and its prioritized variants. RMSD remained fluctuating mostly between 4 and 5 Å and occasionally between 3.5 and 5.5 Å ranges. RMSF in the CTD region (residues 330–360) of the binding pocket were lower compared to that of WT. Studying the impacts of nsSNPs on the binding interface of Wnt1 and seven Frizzled receptors have predicted substitutions which can stabilize or destabilize the binding interface. We have found that Wnt1 and FZD8-CRD is the best docked complex in our study. MD simulation based analyses of wild type Wnt1-FZD8-CRD complex and the 8 prioritized variants revealed that RMSF was higher in the unstructured regions and RMSD remained fluctuating in the region of 5 Å ± 1 Å. We have also observed differential Wnt1 gene expression pattern in normal, tumor and metastatic conditions across different tissues. Wnt1 gene expression was significantly higher in metastatic tissues of lungs, colon and skin; and was significantly lower in metastatic tissues of breast, esophagus and kidney. We have also found that Wnt1 deregulation is associated with survival outcome in patients with gastric and breast cancer. Furthermore, these computationally screened highly deleterious nsSNPs of Wnt1 can be analyzed in population based genetic studies and may help understand the Wnt1 associated diseases.

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Section: Resultsmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

In silico analyses of Wnt1 nsSNPs reveal structurally destabilizing variants, altered interactions with Frizzled receptors and its deregulation in tumorigenesis

Mondal

Paul

Dastidar

et al. 2022

Sci Rep

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“…Furthermore, our studies involved the Polish population. Importantly, WNT-1 has been demonstrated to be significantly associated with different cancer types, including head and neck squamous cell carcinoma, thyroid carcinoma, hepatocellular carcinoma, and uterine corpus endometrial carcinoma [25]. We decided to evaluate WNT-1 levels not only in the membrane, but also in the cytoplasm and nucleus.…”

Section: Discussionmentioning

confidence: 99%

Association of Membranous WNT-1 and Nuclear mTOR with Endometrial Cancer Grade

Pietrus

Pityński

Waligóra

et al. 2023

IJMS

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Endometrial cancer remains a common cancer affecting the female reproductive system. There is still a need for more efficient ways of determining the degree of malignancy and optimizing treatment. WNT and mTOR are components of signaling pathways within tumor cells, and dysfunction of either protein is associated with the pathogenesis of neoplasms. Therefore, the aim of our study was to assess the impact of subcellular WNT-1 and mTOR levels on the clinical course of endometrial cancer. WNT-1 and mTOR levels in the plasma membrane, nucleus, and cytoplasm were evaluated using immunohistochemical staining in a group of 64 patients with endometrial cancer of grades 1–3 and FIGO stages I–IV. We discovered that the levels of WNT-1 and mTOR expression in the cellular compartments were associated with tumor grade and staging. Membranous WNT-1 was negatively associated, whereas cytoplasmic WNT-1 and nuclear mTOR were positively associated with higher grading of endometrial cancer. Furthermore, nuclear mTOR was positively associated with FIGO stages IB–IV. To conclude, we found that the assessment of WNT-1 in the cell membrane may be useful for exclusion of grade 3 neoplasms, whereas cytoplasmic WNT-1 and nuclear mTOR may be used as indicators for confirmation of grade 3 neoplasms.

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“…In contrast, the loss of β-catenin has been correlated with poor prognosis for ampullary cancer patients 12 , 13 . Other mutations have been reported in gastrointestinal and colorectal cancer, such as mutation of APC , CTNNB1 , RNF43 (ring finger protein 43), WNT1 (WNT family member 1), and CDH1 (cadherin 1, E-cadherin) 14 – 16 . Thus, the aberrant or non-canonical regulation of WNT signalling possibly contributes to ampullary cancer development.…”

Section: Introductionmentioning

confidence: 99%

Increased expression of secreted frizzled related protein 1 (SFRP1) predicts ampullary adenocarcinoma recurrence

Chao

Overman

et al. 2020

Sci Rep

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Ampullary adenocarcinoma is a rare gastrointestinal cancer in which WNT signalling dysregulation has been previously reported. Secreted frizzled related protein 1 (SFRP1) is one of the extracellular ligands of WNT signalling. We performed bioinformatics analyses of SFRP1 expression in human cancer. Microarray analysis of SFRP1 in periampullary adenocarcinoma was obtained from the Gene Expression Omnibus GSE39409 dataset. SFRP1 expression in ampullary adenocarcinoma was detected by immunohistochemistry staining and correlated with patients' clinical outcomes. Our results showed that SFRP1 expression had different clinical applications in all types of human cancer. no detected alteration of SFPR1 gene and SFRP1 expression in ampullary adenocarcinoma was lower than that in other periampullary adenocarcinomas. However, high expression levels of SFRP1 protein were correlated with cancer recurrence, peritoneal carcinomatosis and poor patient prognosis. Gene set enrichment analysis showed downregulation of multiple WNT-related genes in primary culture cells from ampullary adenocarcinoma, but SFRP1 expression was increased. We found an interaction between WNT, bone morphogenetic protein and hedgehog signalling with SFRP1. Furthermore, a high expression of SFRP1 predicted poor prognosis for ampullary adenocarcinoma patients. Because it is a multifunctional protein, SFRP1 targeting serves as a potential therapy for ampullary adenocarcinoma patients.

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Comprehensive bioinformatic analysis of Wnt1 and Wnt1-associated diseases

Cited by 6 publications

References 45 publications

In silico analyses of Wnt1 nsSNPs reveal structurally destabilizing variants, altered interactions with Frizzled receptors and its deregulation in tumorigenesis

In silico analyses of Wnt1 nsSNPs reveal structurally destabilizing variants, altered interactions with Frizzled receptors and its deregulation in tumorigenesis

Association of Membranous WNT-1 and Nuclear mTOR with Endometrial Cancer Grade

Increased expression of secreted frizzled related protein 1 (SFRP1) predicts ampullary adenocarcinoma recurrence

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