No associations of a set of SNPs in the Vascular Endothelial Growth Factor (VEGF) and Matrix Metalloproteinase (MMP) genes with survival of colorectal cancer patients

Dan, Lydia; Werdyani, Salem; Xu, Jingxiong; Shestopaloff, Konstantin; Hyde, Angela J.; Dicks, Elizabeth; Younghusband, Ban; Green, Jane; Parfrey, Patrick S.; Xu, Wei; Savas, Sevtap

doi:10.1002/cam4.796

Cited by 5 publications

(6 citation statements)

References 41 publications

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“…5,27 MMP-2 and MMP-9 have been proved to be upregulated and related to invasion and metastasis in CRC. 28,29 In this study, we noted decreased MMP-2 and MMP-9 mRNA and protein expression after MFG-E8 knockdown in HT-29 cells. We also found that pretreatment of HT-29 cells with rhMFG-E8 can upregulate MMP-2 and MMP-9 expression.…”

Section: Discussionmentioning

confidence: 50%

MFG-E8 overexpression promotes colorectal cancer progression via AKT/MMPs signalling

Zhao

Sun

et al. 2017

Tumour Biol.

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Several studies have revealed that MFG-E8 (milk fat globule-epidermal growth factor 8) is related to tumour development and progression. However, the relationship between MFG-E8 expression and metastasis in colorectal cancer patients and the role of MFG-E8 in colorectal cancer invasion and progression remain unknown. In this study, we performed immunohistochemistry and quantitative real-time polymerase chain reaction to assess MFG-E8 expression in colorectal cancer and adjacent non-cancerous tissues. Colorectal cancer RNAseq data from The Cancer Genome Atlas project were downloaded and MFG-E8 expression was analysed. Gene set enrichment analysis was performed for gene ontology and pathway analysis associated with MFG-E8 expression. For in vitro studies, we used lentivirus-mediated MFG-E8 RNA interference and commercialized recombinant human MFG-E8 to investigate its role in colorectal cancer cell growth, migration and invasion. It seems that MFG-E8 was overexpressed in advanced colorectal cancer tissues compared with early-stage colorectal cancer tissues and adjacent non-cancerous tissues. Correlation analysis revealed that MFG-E8 expression was significantly related to plasma membrane invasion, lymph node metastasis, distant metastasis and tumour-node-metastasis stage. Survival analysis revealed that high MFG-E8 expression predicted a poorer prognosis than low MFG-E8 expression group both in our colorectal cancer cohort and The Cancer Genome Atlas colorectal cancer cohort. In vitro study suggested that MFG-E8 knockdown can suppress the growth of colorectal cancer cells without affecting the expression of the proliferation-related gene Ki67. MFG-E8 knockdown also suppressed colorectal cancer cell migration and invasion, a change accompanied by MMP-2 and MMP-9 downregulation. Moreover, MFG-E8 knockdown induced a shift from mesenchymal makers to epithelial makers, while pretreatment with rhMFG-E8 had the opposite effect. The effect of MFG-E8 on colorectal cancer cell migration, invasion and epithelial-to-mesenchymal was partially dependent on the PI3K/AKT signalling pathway. These findings provide a better understanding of the molecular mechanism underlying colorectal cancer progression and suggest a predictive role for MFG-E8 in colorectal cancer metastasis and prognosis.

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Section: Discussionmentioning

confidence: 50%

MFG-E8 overexpression promotes colorectal cancer progression via AKT/MMPs signalling

Zhao

Sun

et al. 2017

Tumour Biol.

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“…8) Rhein has a wide range of bioactivities, such as inhibiting cell proliferation, 9) decreasing hypertrophy, 10) suppressing migration and invasion 11) and inducing tumor cell apoptosis. 12) Nevertheless, the effects of Rhein in resistance to ovarian cancer cell migration and its molecular mechanism are not clear.…”

Section: Introductionmentioning

confidence: 99%

Rhein Inhibits the Migration of Ovarian Cancer Cells through Down-Regulation of Matrix Metalloproteinases

Ren

Guo

Tang

et al. 2019

Biological & Pharmaceutical Bulletin

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The root of Rheum officinale BAILL as a traditional Chinese medicine, which main function is removing heat from the blood, promoting blood circulation and clearing toxins away. Rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid) is one of the most important active components in the root of Rheum officinale BAILL, which could inhibit the proliferation of tumor cells. However, the study on the mechanism of anti-cell migration capacity of Rhein on ovarian cancer is not yet clear. Here, we demonstrated that Rhein had dose-dependent effects of ovarian tumors on drugs and could inhibit the proliferations and migration of two typical ovarian cancer cell lines, A2780 and OV2008. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays showed that the survival rate of ovarian cancer cells was significantly decreased when treated with Rhein. Rhein inhibited the proliferation of ovarian cancer cells in dose-dependent manner. Moreover, the wound healing assay and transwell assay indicated that the cell migratory potential and expression of matrix metalloproteinases were markedly inhibited by Rhein. Our findings suggested that Rhein could be a potential candidate to be developed as a drug for the prevention of ovarian cancer cell migration.

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“…This may be initially attributed to the use of different scoring systems and response variables by these programs. However, Cox-MDR was the software which identified the MMP27 .rs11225388 variant, as well as the high-risk/low-genotype classification, that was previously identified to be associated with OS in a highly similar patient cohort ( Dan et al, 2016 ). Of note, this SNP had the strongest association in that dataset, so it is being identified by Cox-MDR and in all of the 20 1-way runs as the best SNP is quite striking ( Supplementary Table S6 ).…”

Section: Resultsmentioning

confidence: 99%

“…associated with the OS in the patient cohort under dominant genetic model ( MMP27 .rs11225388). This SNP was previously examined in our lab using a similar patient cohort and using Cox regression method and it had the strongest association in the SNP set ( Dan et al, 2016 ). This previous study had also shown the dominant genetic model as the best model explaining the relationship of the genotypes of this SNP with patient overall survival times.…”

Section: Discussionmentioning

confidence: 99%

“…Since one of our aims in Part 1 was to examine and compare the performance and functionality of the two MDR-based programs, we opted for a set of genes and SNPs that were previously examined in our lab ( Supplementary Table S2 ). Specifically, the best suited genetic model for SNPs from the MMP genes and their one-by-one associations with patient outcomes were previously examined ( Dan et al, 2016 ). This previous knowledge enabled us to assess the results of the 1-way interaction analyses obtained using the MDR methods during the current study.…”

Section: Methodsmentioning

confidence: 99%

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Examining SNP-SNP interactions and risk of clinical outcomes in colorectal cancer using multifactor dimensionality reduction based methods

Curtis

Carey

et al. 2022

Front. Genet.

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Background: SNP interactions may explain the variable outcome risk among colorectal cancer patients. Examining SNP interactions is challenging, especially with large datasets. Multifactor Dimensionality Reduction (MDR)-based programs may address this problem.Objectives: 1) To compare two MDR-based programs for their utility; and 2) to apply these programs to sets of MMP and VEGF-family gene SNPs in order to examine their interactions in relation to colorectal cancer survival outcomes.Methods: This study applied two data reduction methods, Cox-MDR and GMDR 0.9, to study one to three way SNP interactions. Both programs were run using a 5-fold cross validation step and the top models were verified by permutation testing. Prognostic associations of the SNP interactions were verified using multivariable regression methods. Eight datasets, including SNPs from MMP family genes (n = 201) and seven sets of VEGF-family interaction networks (n = 1,517 SNPs) were examined.Results: ∼90 million potential interactions were examined. Analyses in the MMP and VEGF gene family datasets found several novel 1- to 3-way SNP interactions. These interactions were able to distinguish between the patients with different outcome risks (regression p-values 0.03–2.2E-09). The strongest association was detected for a 3-way interaction including CHRM3.rs665159_EPN1.rs6509955_PTGER3.rs1327460 variants.Conclusion: Our work demonstrates the utility of data reduction methods while identifying potential prognostic markers in colorectal cancer.

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No associations of a set of SNPs in the Vascular Endothelial Growth Factor (VEGF) and Matrix Metalloproteinase (MMP) genes with survival of colorectal cancer patients

Cited by 5 publications

References 41 publications

MFG-E8 overexpression promotes colorectal cancer progression via AKT/MMPs signalling

MFG-E8 overexpression promotes colorectal cancer progression via AKT/MMPs signalling

Rhein Inhibits the Migration of Ovarian Cancer Cells through Down-Regulation of Matrix Metalloproteinases

Examining SNP-SNP interactions and risk of clinical outcomes in colorectal cancer using multifactor dimensionality reduction based methods

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