Epigenetic DNA Modifications Upregulate SPRY2 in Human Colorectal Cancers

Stuckel, Alexei J.; Zeng, Shuai; Lyu, Zhen; Zhang, Wei; Zhang, Xu; Dougherty, Urszula; Mustafi, Reba; Zhang, Qiong; Joshi, Trupti; Bissonnette, Marc; Choudhury, Samrat Roy; Khare, Sharad

doi:10.3390/cells10102632

Cited by 8 publications

(9 citation statements)

References 54 publications

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“…The upregulation of IL-1 has been shown in other cancers, including breast, colon, head and neck, lung, pancreas, and melanomas, with patients with high levels of IL-1 having generally poor prognosis [ 25 ]. The downregulation of SPRY2 has been shown in chronic lymphocytic leukemia, non-small cell lung cancer, hepatocellular carcinoma, breast cancer, and prostate cancers [ 26 ], highlighting its tumor suppressor function.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic Aqueous Humor Proteome Predicts Metastatic Potential in Uveal Melanoma

Peng

Sirivolu

Pike

et al. 2023

IJMS

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Gene expression profiling (GEP) is clinically validated to stratify the risk of metastasis by assigning uveal melanoma (UM) patients to two highly prognostic molecular classes: class 1 (low metastatic risk) and class 2 (high metastatic risk). However, GEP requires intraocular tumor biopsy, which is limited by small tumor size and tumor heterogeneity; furthermore, there are small risks of retinal hemorrhage, bleeding, or tumor dissemination. Thus, ocular liquid biopsy has emerged as a less-invasive alternative. In this study, we seek to determine the aqueous humor (AH) proteome related to the advanced GEP class 2 using diagnostic AH liquid biopsy specimens. Twenty AH samples were collected from patients with UM, grouped by GEP classes. Protein expression levels of 1472 targets were analyzed, compared between GEP classes, and correlated with clinical features. Significant differentially expressed proteins (DEPs) were subjected to analysis for cellular pathway and upstream regulator identification. The results showed that 45 DEPs detected in the AH could differentiate GEP class 1 and 2 at diagnosis. IL1R and SPRY2 are potential upstream regulators for the 8/45 DEPs that contribute to metastasis-related pathways. AH liquid biopsy offers a new opportunity to determine metastatic potential for patients in the absence of tumor biopsy.

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Section: Discussionmentioning

confidence: 99%

Diagnostic Aqueous Humor Proteome Predicts Metastatic Potential in Uveal Melanoma

Peng

Sirivolu

Pike

et al. 2023

IJMS

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“…This disparity in methylation and gene expression levels between primary cancer cells and cell lines seems counterintuitive. Our past studies have made examples out of this phenomenon for genes CXCR4 and SPRY2 in CRC [ 42 , 43 ]. Both of these genes greatly differ in methylation and expression between various CRC cell lines, whereas promoter hypomethylation and increased gene expression was consistently observed in patient tumor samples.…”

Section: Discussionmentioning

confidence: 99%

“…Both of these genes greatly differ in methylation and expression between various CRC cell lines, whereas promoter hypomethylation and increased gene expression was consistently observed in patient tumor samples. For example, among the Sprouty genes aberrantly expressed in CRC, we have previously shown that SPRY2 is also methylated and downregulated in several CRC cell lines [ 43 ]. However, in human CRC samples, we have shown that both the Sprouty genes (SPRY2 and SPRY4) are hypomethylated in the distal promoter regions and upregulated.…”

Section: Discussionmentioning

confidence: 99%

Sprouty4 is epigenetically upregulated in human colorectal cancer

et al. 2022

Self Cite

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Sprouty4 (SPRY4) has been frequently reported as a tumor suppressor and is therefore downregulated in various cancers. For the first time, we report that SPRY4 is epigenetically upregulated in colorectal cancer (CRC). In this study, we explored DNA methylation and hydroxymethylation levels of SPRY4 in CRC cells and patient samples and correlated these findings with mRNA and protein expression levels. Three loci within the promoter region of SPRY4 were evaluated for 5mC levels in CRC using the combined bisulfite restriction analysis. In addition, hydroxymethylation levels within SPRY4 were measured in CRC patients. Lastly, DNA methylation and mRNA expression data were extracted from CRC patients in multiple high-throughput data repositories like Gene Expression Omnibus and The Cancer Genome Atlas. Combined in vitro and in silico analysis of promoter methylation levels of SPRY4 clearly demonstrates that the distal promoter region undergoes hypomethylation in CRC patients and is associated with increased expression. Moreover, a decrease in gene body hydroxymethylation and an increase in gene body methylation within the coding region of SPRY4 were found in CRC patients and correlated with increased expression. SPRY4 is epigenetically upregulated in CRC by promoter hypomethylation and hypermethylation within the gene body that warrants future investigation of atypical roles of this established tumor suppressor.

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“…11 However, high expression of SPRY2 protein was reported to be associated with poor survival in CRC patients. 12,14,15 SPRY2 was demonstrated to enhance CRC invasion in vitro, 12,16 and is upregulated in the invasive front of primary CRCs. 17 Recently, SPRY2 was also shown to promote epithelial-to-mesenchymal transition of CRC cells through ZEB1 induction and miR-194-5p inhibition, [16][17][18] and enhance the transformed phenotype mediated in part by c-Met upregulation.…”

Section: Introductionmentioning

confidence: 96%

Dual role of sprouty2 as an inhibitor of RAS/ERK‐driven proliferation and a promoter of cancer invasion in KRAS wild‐type colorectal cancer

Lee

Chu

Wang

et al. 2023

Molecular Carcinogenesis

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Sprouty2 (SPRY2) is known to inhibit the RAS/MAPK/ERK pathway, and is a potential study target for cancer. The effect of SPRY2 in colorectal cancer (CRC) and whether it is influenced by KRAS mutation are not known. We manipulated SPRY2 gene expression and used an activating KRAS‐mutant plasmid to determine its effect on CRC cell function in vitro and/or in vivo. We performed SPRY2 immunohistochemical staining in 143 CRC specimens and analyzed the staining results with various clinicopathological characteristics in relation to KRAS mutation status. SPRY2 knockdown in Caco‐2 cells carrying the wild‐type (WT) KRAS gene upregulated phosphorylated ERK (p‐ERK) levels and increased cell proliferation in vitro, but inhibited cell invasion. However, SPRY2 knockdown in SW480 cells (activating KRAS mutant) or Caco‐2 cells transfected with KRAS‐mutant plasmid did not significantly alter p‐ERK levels, cell proliferation, or invasion. The xenografts of SPRY2‐knockdown Caco‐2 cells were larger with less deep muscle invasion than those of control cells. The clinical cohort study revealed a positive association of SPRY2 protein expression with pT status, lymphovascular invasion, and perineural invasion in KRAS‐WT CRCs. However, the associations were not observed in KRAS‐mutant CRCs. Interestingly, high SPRY2 expression was related to shorter cancer‐specific survival in both KRAS‐WT and KRAS‐mutant CRC patients. Our study demonstrated the dual role of SPRY2 as an inhibitor of RAS/ERK‐driven proliferation and as a promoter of cancer invasion in KRAS‐WT CRC. SPRY2 may promote the invasion and progression of KRAS‐WT CRC, and might also enhance KRAS‐mutant CRC progression through pathways other than invasion.

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Epigenetic DNA Modifications Upregulate SPRY2 in Human Colorectal Cancers

Cited by 8 publications

References 54 publications

Diagnostic Aqueous Humor Proteome Predicts Metastatic Potential in Uveal Melanoma

Diagnostic Aqueous Humor Proteome Predicts Metastatic Potential in Uveal Melanoma

Sprouty4 is epigenetically upregulated in human colorectal cancer

Dual role of sprouty2 as an inhibitor of RAS/ERK‐driven proliferation and a promoter of cancer invasion in KRAS wild‐type colorectal cancer

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