Downregulation of expression of mater genes SOX9, FOXA2, and GATA4 in pancreatic cancer cells stimulated with TGFβ1 epithelial–mesenchymal transition

Kondratyeva, L. G.; Sveshnikova, A. A.; Grankina, E. V.; Чернов, И. П.; Kopantseva, M. R.; Kopantzev, E. P.

doi:10.1134/s1607672916040062

Cited by 20 publications

(13 citation statements)

References 12 publications

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“…For example, Li et al report that miR-187 can target the expression of FOXA2 and promote the proliferation and metastasis of gastric cancer, suggesting that FOXA2 may be a tumor-suppressor gene in gastric cancer ( 34 ). Down-regulation of FOXA2 may promote EMT in pancreatic cancer, suggesting that FOXA2 may inhibit tumor EMT ( 35 ). Tu et al discover that miR-1291 inhibits proliferation and metastasis of pancreatic cancer by targeting FOXA2 ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

FOXA2 promotes the proliferation, migration and invasion, and epithelial mesenchymal transition in colon cancer

et al. 2018

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The present study determined the expression and biological functions of FOXA2 gene in colon cancer in tissues, cells and animals. A total of 66 patients with colon cancer were included in the present study. Using The Human Protein Atlas database, expression and distribution of FOXA2 in colon cancer tissues were analyzed. Using immunohistochemistry, the expression and distribution of FOXA2 in colon cancer cells were studied. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to determine the expression of FOXA2 mRNA in colon cancer tissues. Following in vitro transfection with FOXA2 interference sequence (siR-FOXA2), the proliferation, cell cycle, migration and invasion of colon cancer HCT116 and HT29 cells were investigated using Cell Counting Kit-8 assay, flow cytometry, and Transwell assay, respectively. Furthermore, flow cytometry was used to determine apoptosis of HCT116 and HT29 cells. Western blotting was used to determine the expression of epithelial mesenchymal transition (EMT) proteins, E-Cadherin and Vimentin. Laser scanning confocal microscopy was performed to observe the cytoskeleton in HCT116 and HT29 cells. Results indicated tumorigenesis of colon cancer cells in nude mice. In addition, the expression of FOXA2 in colon cancer tissues was elevated and associated with the metastasis and clinical staging of colon cancer. Notably, inhibition of FOXA2 reduced the proliferation of colon cancer cells in vitro and reduced expression of FOXA2 was able to decrease the migration and invasion abilities of colon cancer cells. Furthermore, FOXA2 promoted EMT, inhibited apoptosis and enhanced the invasion ability of colon cancer cells. Decreased expression of FOXA2 inhibited tumorigenesis of colon cancer cells in nude mice. To conclude, the present study demonstrated that the expression of FOXA2 in colon cancer tissues was elevated and associated with the metastasis and clinical staging of colon cancer. As an oncogene, FOXA2 may promote the proliferation, migration and invasion and EMT in colon cancer.

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Section: Discussionmentioning

confidence: 99%

FOXA2 promotes the proliferation, migration and invasion, and epithelial mesenchymal transition in colon cancer

et al. 2018

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“…For example, an in vitro CRISPR screen identified HNF4a (as well as its target HNF1a) as dependencies in two out of nine human PDAC cell lines tested (39). In this regard, dichotomous effects on PDAC growth have been reported for HNF1a (40)(41)(42), PDX1 (43), FoxA1/2 (44)(45)(46)(47) and GATA6 (34,48,49). It seems likely that even though the most malignant subset of PDAC downregulates the endodermal differentiation program, loss of this program may only confer a selective advantage in specific situations or stages of tumor progression.…”

Section: Discussionmentioning

confidence: 99%

Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4

Camolotto

Belova

Torre-Healy

et al. 2019

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a five-year survival of less than 5%. Transcriptomic analysis has identified two clinically relevant molecular subtypes of PDAC: Classical and Basal-like. The Classical subtype is characterized by a more favorable prognosis and better response to chemotherapy than the Basal-like subtype. The Classical subtype also expresses higher levels of lineage specifiers that regulate endodermal differentiation, including the nuclear receptor HNF4a. Using in vitro and in vivo PDAC models, we show that HNF4a restrains tumor growth and drives tumor cells toward an epithelial identity.Gene expression analysis from murine models and human tumors shows that HNF4a activates expression of genes associated with the Classical subtype. Although HNF4a loss is not sufficient for complete conversion to the Basal-like subtype gene expression profile, HNF4a directly represses SIX4 and SIX1, mesodermal lineage specifiers expressed in the Basal-like subtype.Finally, HNF4a-negative PDAC cells rely on expression of SIX4 and SIX1 for proliferation in vitro and in vivo. Overall, our data show that HNF4a regulates the growth and molecular subtype of PDAC by multiple mechanisms, including activation of the Classical gene expression program and repression of SIX4 and SIX1, which may represent novel dependencies of the Basal-like subtype.

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“…The role of Snail in metastasis, tumor progression, and endowing a stem-like phenotype as part of its role in EMT and related processes has been well documented (3, 7, 8) and has broad impacts on tumor growth and invasiveness (9). Sox9 is a transcriptional regulator which recognizes a specific DNA sequence (GACAATG) and is part of the High Mobility Group (HMG) family of proteins (10), and has been directly implicated in EMT during both development and cancer progression (11, 12). Twist has been shown to inhibit the transcriptional regulatory functions of Sox9 (13), and it may impact the stabilization of Snail as well (14).…”

Section: Introductionmentioning

confidence: 99%

Twist, Snail, and Sox9 form an allosterically regulated complex, the EMTosome, on a bipartite E-box site

McCracken

2020

Preprint

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Epithelial-Mesenchymal transition (EMT) of primary tumor cells is a critical trans-differentiation event that contributes to dissemination and metastasis. The process of EMT is controlled by specific DNA-binding transcription factors (TFs) that reprogram the tumor transcriptome. In particular, the canonical EMT-TFs Twist and Snail can induce an EMT program when overexpressed in cancer cells, and both are found upregulated in metastatic cancers. Twist and Snail bind DNA directly, by recognition to variants of the E-Box sequence CANNTG. However, it is unclear how this binding is regulated. We have used a biochemical approach to dissect DNA binding and protein-protein interactions that occur amongst these proteins. We find that Twist preferentially recognizes a dyad repeat of E-boxes that are not directly bound by Snail. Our data suggest that Twist use its WR domain to recruit Snail into a binding complex through the Snail zinc-finger motifs. We analyzed Twist-Snail complexes in the breast carcinoma cell line SUM1315 and found evidence that it contains an additional protein partner, Sox9. Notably, we report that a native Twist complex can be displaced from its dyad binding site by consensus DNA binding sites for Snail and Sox9 even though these proteins do not contact the Twist dyad site. Taken together, our findings suggest that Snail and Sox9 interact with Twist to regulate its DNA binding ability via protein-protein interactions, thereby allosterically regulating Twist DNA binding. We designate this ternary complex EMTosome. These results may inform efforts to therapeutically target the EMT program in order to target cancer metastasis.

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Downregulation of expression of mater genes SOX9, FOXA2, and GATA4 in pancreatic cancer cells stimulated with TGFβ1 epithelial–mesenchymal transition

Cited by 20 publications

References 12 publications

FOXA2 promotes the proliferation, migration and invasion, and epithelial mesenchymal transition in colon cancer

FOXA2 promotes the proliferation, migration and invasion, and epithelial mesenchymal transition in colon cancer

Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4

Twist, Snail, and Sox9 form an allosterically regulated complex, the EMTosome, on a bipartite E-box site

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