Erratum: Atypical role of sprouty in colorectal cancer: sprouty repression inhibits epithelial–mesenchymal transition

Spinster homologue 2 (SPNS2), a transporter of S1P (sphingosine-1-phosphate), has been reported to mediate immune response, vascular development, and pathologic processes of diseases such as cancer via S1P signaling pathways. However, its biological functions and expression profile in colorectal cancer (CRC) is elusive. In this study, we disclosed that SPNS2 expression, which was regulated by copy number variation and DNA methylation of its promoter, was dramatically upregulated in colon adenoma and CRC compared to normal tissues. However, its expression was lower in CRC than in colon adenoma, and low expression of SPN2 correlated with advanced T/M/N stage and poor prognosis in CRC. Ectopic expression of SPNS2 inhibited cell proliferation, migration, epithelial–mesenchymal transition (EMT), invasion, and metastasis in CRC cell lines, while silencing SPNS2 had the opposite effects. Meanwhile, measuring the intracellular and extracellular level of S1P after overexpression of SPNS2 pinpointed a S1P-independent model of SPNS2. Mechanically, SPNS2 led to PTEN upregulation and inactivation of Akt. Moreover, AKT inhibitor (MK2206) abrogated SPNS2 knockdown-induced promoting effects on the migration and invasion, while AKT activator (SC79) reversed the repression of migration and invasion by SPNS2 overexpression in CRC cells, confirming the pivotal role of AKT for SPNS2’s function. Collectively, our study demonstrated the suppressor role of SPNS2 during CRC metastasis, providing new insights into the pathology and molecular mechanisms of CRC progression.

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Tu1982 Downregulation of Sprouty Is Associated With Inhibition of Epithelial-Mesenchymal Transition in Colorectal Cancer: An Unique Role of Sprouty Proteins

Gastroenterology ◽

10.1016/s0016-5085(15)33249-2 ◽

2015 ◽

Vol 148 (4) ◽

pp. S-952

Author(s):

Qiong Zhang ◽

Katherine Shim ◽

Kevin Wright ◽

Alexander Jurkevich ◽

Sharad Khare

Keyword(s):

Colorectal Cancer ◽

Epithelial Mesenchymal Transition ◽

Unique Role ◽

Mesenchymal Transition

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Atypical role of sprouty in colorectal cancer: sprouty repression inhibits epithelial–mesenchymal transition

Oncogene ◽

10.1038/onc.2015.365 ◽

2015 ◽

Vol 35 (24) ◽

pp. 3151-3162 ◽

Cited By ~ 16

Author(s):

Q Zhang ◽

T Wei ◽

K Shim ◽

K Wright ◽

K Xu ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Cell Migration ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Migration And Invasion ◽

Colon Cancer Cells ◽

Mesenchymal Transition ◽

E Cadherin

Abstract Sprouty (SPRY) appears to act as a tumor suppressor in cancer, whereas we demonstrated that SPRY2 functions as a putative oncogene in colorectal cancer (CRC) (Oncogene, 2010, 29: 5241–5253). We investigated the mechanisms by which SPRY regulates epithelial–mesenchymal transition (EMT) in CRC. SPRY1 and SPRY2 mRNA transcripts were significantly upregulated in human CRC. Suppression of SPRY2 repressed AKT2 and EMT-inducing transcription factors and significantly increased E-cadherin expression. Concurrent downregulation of SPRY1 and SPRY2 also increased E-cadherin and suppressed mesenchymal markers in colon cancer cells. An inverse expression pattern between AKT2 and E-cadherin was established in a human CRC tissue microarray. SPRY2 negatively regulated miR-194-5p that interacts with AKT2 3′ untranslated region. Mir-194 mimics increased E-cadherin expression and suppressed cancer cell migration and invasion. By confocal microscopy, we demonstrated redistribution of E-cadherin to plasma membrane in colon cancer cells transfected with miR-194. Spry1 −/− and Spry2 −/− double mutant mouse embryonic fibroblasts exhibited decreased cell migration while acquiring several epithelial markers. In CRC, SPRY drive EMT and may serve as a biomarker of poor prognosis.

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Effect of neuropilin-2 expression on TGF-β1-epithelial-mesenchymal transition in colorectal cancer cells.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.414 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 414-414

Author(s):

C. Grandclement ◽

R. Bedel ◽

B. Kantelip ◽

E. Viel ◽

J. Remy Martin ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Epithelial Mesenchymal Transition ◽

Human Colon ◽

Mesenchymal Transition ◽

Colorectal Cancer Cells ◽

Tgf Β1

414 Background: Initially characterized as neuronal receptors, Neuropilins (NRPs) were also found to be expressed in endothelial cells and subsequently were shown to play a role in the development of the vascular system. NRP family consists of two genes, neuropilin-1 (NRP1) and neuropilin-2 (NRP2).The multiple functions of NRPs were recently highlighted by the identification of NRP role in oncogenesis. In this study, we first confirmed the role of NRP2 in tumor progression. We also extended the understanding of NRP2 oncogenic functions by investigating the ability of NRP2 to orchestrate epithelial-mesenchymal transition (EMT) in colorectal cancer cells. Methods: We have generated human colon cancer cell lines transfected with NRP2 transgene or siRNA to investigate NRP2 involvement in EMT. First, the oncogenic functions of NRP2 were studied in vitro by MTT, soft agar, invasion assays and in vivo using xenografts experiments. Ability of NRP2 to orchestrate EMT was then investigated by flow cytometry, immunohistochemical (IHC) staining, western-blotting and quantitative real-time PCR. Results: IHC staining revealed that NRP2 is expressed in human colon and breast carcinomas while it is not expressed in healthy tissues. Then, we confirmed that NRP2 increases tumor proliferation, colony formation, invasion and xenograft formation. Moreover, NRP2-expressing cells displayed an immunohistochemical phenotype of EMT characterized by the loss of E-Cadherin and an increase of vimentin. Furthermore, NRP2 expression promotes transforming-growth factor-β1 (TGF- β1) signaling, leading to an increased phosphorylation of the Smad2/3 complex in colorectal cancer cell lines. Specific inhibition of NRP2 using siRNA or treatment with specific TGFβRI kinase inhibitors prevented this phosphorylation and the EMT, suggesting that NRP2 cooperates with TGFRI to promote EMT in colorectal carcinoma. Conclusions: Our findings have reinforced the essential role of NRP2 in cancer progression and demonstrated that NRP2 expression confers to tumor cell lines the hallmarks of EMT. Moreover, in the current work, we present evidence for the therapeutic value of NRP2 targeting. No significant financial relationships to disclose.

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The role of hERG1 ion channels in epithelial-mesenchymal transition and the capacity of riluzole to reduce cisplatin resistance in colorectal cancer cells

Cellular Oncology ◽

10.1007/s13402-017-0328-6 ◽

2017 ◽

Vol 40 (4) ◽

pp. 367-378 ◽

Cited By ~ 12

Author(s):

Angelo Fortunato

Keyword(s):

Colorectal Cancer ◽

Ion Channels ◽

Cancer Cells ◽

Cisplatin Resistance ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Colorectal Cancer Cells

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The FOXK1-CCDC43 Axis Promotes the Invasion and Metastasis of Colorectal Cancer Cells

Cellular Physiology and Biochemistry ◽

10.1159/000495924 ◽

2018 ◽

Vol 51 (6) ◽

pp. 2547-2563 ◽

Cited By ~ 4

Author(s):

Jing Wang ◽

Guangnan Liu ◽

Mengwei Liu ◽

Li Xiang ◽

Yizhi Xiao ◽

...

Keyword(s):

Colorectal Cancer ◽

Epithelial Mesenchymal Transition ◽

Expression Patterns ◽

Gene Promoter ◽

Mesenchymal Transition ◽

Colorectal Cancer Cells ◽

Invasion Assays ◽

Transcriptional Target

Background/Aims: The CCDC43 gene is conserved in human, rhesus monkey, mouse and zebrafish. Bioinformatics studies have demonstrated the abnormal expression of CCDC43 gene in colorectal cancer (CRC). However, the role and molecular mechanism of CCDC43 in CRC remain unknown. Methods: The functional role of CCDC43 and FOXK1 in epithelial-mesenchymal transition (EMT) was determined using immunohistochemistry, flow cytometry, western blot, EdU incorporation, luciferase, chromatin Immunoprecipitation (ChIP) and cell invasion assays. Results: The CCDC43 gene was overexpressed in human CRC. High expression of CCDC43 protein was associated with tumor progression and poor prognosis in patients with CRC. Moreover, the induction of EMT by CCDC43 occurred through TGF-β signaling. Furthermore, a positive correlation between the expression patterns of CCDC43 and FOXK1 was observed in CRC cells. Promoter assays demonstrated that FOXK1 directly bound and activated the human CCDC43 gene promoter. In addition, CCDC43 was necessary for FOXK1- mediated EMT and metastasis in vitro and vivo. Taken together, this work identified that CCDC43 promoted EMT and was a direct transcriptional target of FOXK1 in CRC cells. Conclusion: FOXK1-CCDC43 axis might be helpful to develop the drugs for the treatment of CRC.

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