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COUP-TFII regulates metastasis of colorectal adenocarcinoma cells by modulating Snail1.

Bao Y, Gu D, Feng W, Sun X, Wang X, Zhang X, Shi Q, Cui G, Yu H, Tang C, Deng A - Br. J. Cancer (2014)

Bottom Line: Overexpression of COUP-TFII was required for cancer cells to metastasise in vivo.Chicken ovalbumin upstream promoter-transcription factor II regulated the transcription and expression of Snail1 by directly targeting the Snail1 promoter and regulated associated genes.Chicken ovalbumin upstream promoter-transcription factor II was found to be a biomarker associated with patient survival and colorectal cancer metastasis.

View Article: PubMed Central - PubMed

Affiliation: First Affiliated Hospital, Huzhou Teachers College, the First People's Hospital of Huzhou, Huzhou 313000, China.

ABSTRACT

Background: Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII, also known as NR2F2) promotes metastasis by functioning in the tumour microenvironment; however, the role of COUP-TFII in colorectal cancer remains unknown.

Methods: Human colon adenocarcinoma tissues were collected to test COUP-TFII expression. Wound-healing and cell invasion assay were used to evaluate migration and invasion of cells. Chicken ovalbumin upstream promoter-transcription factor II and related protein expression was assessed by immunostaining, immunoblotting and real-time PCR assay. Tamoxifen-inducible COUP-TFII knockout mice were employed to test COUP-TFII functions on colon cancer metastasis in vivo.

Results: Elevated expression of COUP-TFII in colorectal adenocarcinoma tissue correlated with overexpression of the Snail1 transcription factor. High COUP-TFII expression correlated with metastasis and shorter patient survival. Chicken ovalbumin upstream promoter-transcription factor II regulated the migration and invasion of cancer cells. With Snail1, COUP-TFII inhibited expression of adherence molecules such as ZO-1, E-cadherin and β-catenin in colorectal cancer cells. Overexpression of COUP-TFII was required for cancer cells to metastasise in vivo. Chicken ovalbumin upstream promoter-transcription factor II regulated the transcription and expression of Snail1 by directly targeting the Snail1 promoter and regulated associated genes.

Conclusions: Chicken ovalbumin upstream promoter-transcription factor II was crucial for colorectal cancer metastasis and regulated cell migration and metastasis in conjunction with Snail1. Chicken ovalbumin upstream promoter-transcription factor II was found to be a biomarker associated with patient survival and colorectal cancer metastasis.

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Chicken ovalbumin upstream promoter-transcription factor II and Snail1 are overexpressed in colon adenocarcinoma tissue. (A) Expression of COUP-TFII and Snail-1 in human colorectal adenocarcinoma tissue. Western blots were used to determine expression of COUP-TFII and Snail1 in human colorectal adenocarcinoma tissue. Lanes contain equal amounts of nuclear protein from colorectal adenocarcinoma tissue (T) and paired normal tissue (N). (B) Quantification of image density from A. *P<0.01 compared to normal. (C) Representive images were shown for the expression of COUP-TFII and Snail1 in 326 human colorectal adenocarcinoma tissue samples, determined by western blot. (D) Survival curves for colorectal adenocarcinoma patients with either high or low COUP-TFII (P<0.01). (E) Human colon adenocarcinoma LOVO or HT29 cells stably expressing control vector (CON), shRNA against COUP-TFII (COUP-TFII KD), shRNA against Snail1 (Snail-1 KD), COUP-TFII KD + Snail-1 overexpressing (Snail-1 OV), COUP-TFII overexpressing (COUP-TFII OV), or COUP-TFII OV + Snail-1 KD were cultured. Expression of COUP-TFII and Snail1 by western blot. Tubulin was the loading control. Density of bands were quantified.
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fig1: Chicken ovalbumin upstream promoter-transcription factor II and Snail1 are overexpressed in colon adenocarcinoma tissue. (A) Expression of COUP-TFII and Snail-1 in human colorectal adenocarcinoma tissue. Western blots were used to determine expression of COUP-TFII and Snail1 in human colorectal adenocarcinoma tissue. Lanes contain equal amounts of nuclear protein from colorectal adenocarcinoma tissue (T) and paired normal tissue (N). (B) Quantification of image density from A. *P<0.01 compared to normal. (C) Representive images were shown for the expression of COUP-TFII and Snail1 in 326 human colorectal adenocarcinoma tissue samples, determined by western blot. (D) Survival curves for colorectal adenocarcinoma patients with either high or low COUP-TFII (P<0.01). (E) Human colon adenocarcinoma LOVO or HT29 cells stably expressing control vector (CON), shRNA against COUP-TFII (COUP-TFII KD), shRNA against Snail1 (Snail-1 KD), COUP-TFII KD + Snail-1 overexpressing (Snail-1 OV), COUP-TFII overexpressing (COUP-TFII OV), or COUP-TFII OV + Snail-1 KD were cultured. Expression of COUP-TFII and Snail1 by western blot. Tubulin was the loading control. Density of bands were quantified.

Mentions: Expression of COUP-TFII and Snail1 was measured in tumour samples and adjacent normal tissues from 326 colon adenocarcinoma patients. The average patient age was 57.2 years. Chicken ovalbumin upstream promoter-transcription factor II levels were significantly increased in carcinoma tissue samples compared to adjacent normal controls in 58.6% (191 out of 326) of analysed patients (Figure 1A and B). Snail1 expression was elevated in 54% (177 out of 326) of carcinoma samples. In 66.7% (118 out of 177) of patient samples in which Snail1 overexpressed, COUP-TFII was also overexpressed (Figure 1C). Chicken ovalbumin upstream promoter-transcription factor II showed a positive correlation with Snail1 expression during different clinical stages of colon adenocarcinoma development (R=0.606). In total, 64.5% (118 out of 183) patients who showed vessel invasion were COUP-TFII overexpression. Meanwhile, 68% (113 out of 166) patients of metastasis at T3,4 stage showed COUP-TFII overexpression (Table 1). These results suggested that both COUP-TFII and Snail1 either might be important in colon adenocarcinoma development, or might be a prognostic marker. Expression level of COUP-TFII might relate to metastasis of tumours. Moreover, COUP-TFII overexpression might be correlated to Snail1 overexpression. Five-year follow-up after surgery and/or chemotherapy suggested that patients with high tumour expression of COUP-TFII had a shorter survival than patients whose tumours had low COUP-TFII levels (Figure 1D). In the investigation on the regulation of COUP-TFII on Snail1 in colon cancer cells in vitro, we found that repression of COUP-TFII decreased Snail1 expression. However, overexpression of COUP-TFII increased Snail1 expression. However, neither overexpression nor repression of Snail1 affected COUP-TFII expression, indicating that COUP-TFII is an upstream effector of Snail1 (Figure 1E).


COUP-TFII regulates metastasis of colorectal adenocarcinoma cells by modulating Snail1.

Bao Y, Gu D, Feng W, Sun X, Wang X, Zhang X, Shi Q, Cui G, Yu H, Tang C, Deng A - Br. J. Cancer (2014)

Chicken ovalbumin upstream promoter-transcription factor II and Snail1 are overexpressed in colon adenocarcinoma tissue. (A) Expression of COUP-TFII and Snail-1 in human colorectal adenocarcinoma tissue. Western blots were used to determine expression of COUP-TFII and Snail1 in human colorectal adenocarcinoma tissue. Lanes contain equal amounts of nuclear protein from colorectal adenocarcinoma tissue (T) and paired normal tissue (N). (B) Quantification of image density from A. *P<0.01 compared to normal. (C) Representive images were shown for the expression of COUP-TFII and Snail1 in 326 human colorectal adenocarcinoma tissue samples, determined by western blot. (D) Survival curves for colorectal adenocarcinoma patients with either high or low COUP-TFII (P<0.01). (E) Human colon adenocarcinoma LOVO or HT29 cells stably expressing control vector (CON), shRNA against COUP-TFII (COUP-TFII KD), shRNA against Snail1 (Snail-1 KD), COUP-TFII KD + Snail-1 overexpressing (Snail-1 OV), COUP-TFII overexpressing (COUP-TFII OV), or COUP-TFII OV + Snail-1 KD were cultured. Expression of COUP-TFII and Snail1 by western blot. Tubulin was the loading control. Density of bands were quantified.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4150277&req=5

fig1: Chicken ovalbumin upstream promoter-transcription factor II and Snail1 are overexpressed in colon adenocarcinoma tissue. (A) Expression of COUP-TFII and Snail-1 in human colorectal adenocarcinoma tissue. Western blots were used to determine expression of COUP-TFII and Snail1 in human colorectal adenocarcinoma tissue. Lanes contain equal amounts of nuclear protein from colorectal adenocarcinoma tissue (T) and paired normal tissue (N). (B) Quantification of image density from A. *P<0.01 compared to normal. (C) Representive images were shown for the expression of COUP-TFII and Snail1 in 326 human colorectal adenocarcinoma tissue samples, determined by western blot. (D) Survival curves for colorectal adenocarcinoma patients with either high or low COUP-TFII (P<0.01). (E) Human colon adenocarcinoma LOVO or HT29 cells stably expressing control vector (CON), shRNA against COUP-TFII (COUP-TFII KD), shRNA against Snail1 (Snail-1 KD), COUP-TFII KD + Snail-1 overexpressing (Snail-1 OV), COUP-TFII overexpressing (COUP-TFII OV), or COUP-TFII OV + Snail-1 KD were cultured. Expression of COUP-TFII and Snail1 by western blot. Tubulin was the loading control. Density of bands were quantified.
Mentions: Expression of COUP-TFII and Snail1 was measured in tumour samples and adjacent normal tissues from 326 colon adenocarcinoma patients. The average patient age was 57.2 years. Chicken ovalbumin upstream promoter-transcription factor II levels were significantly increased in carcinoma tissue samples compared to adjacent normal controls in 58.6% (191 out of 326) of analysed patients (Figure 1A and B). Snail1 expression was elevated in 54% (177 out of 326) of carcinoma samples. In 66.7% (118 out of 177) of patient samples in which Snail1 overexpressed, COUP-TFII was also overexpressed (Figure 1C). Chicken ovalbumin upstream promoter-transcription factor II showed a positive correlation with Snail1 expression during different clinical stages of colon adenocarcinoma development (R=0.606). In total, 64.5% (118 out of 183) patients who showed vessel invasion were COUP-TFII overexpression. Meanwhile, 68% (113 out of 166) patients of metastasis at T3,4 stage showed COUP-TFII overexpression (Table 1). These results suggested that both COUP-TFII and Snail1 either might be important in colon adenocarcinoma development, or might be a prognostic marker. Expression level of COUP-TFII might relate to metastasis of tumours. Moreover, COUP-TFII overexpression might be correlated to Snail1 overexpression. Five-year follow-up after surgery and/or chemotherapy suggested that patients with high tumour expression of COUP-TFII had a shorter survival than patients whose tumours had low COUP-TFII levels (Figure 1D). In the investigation on the regulation of COUP-TFII on Snail1 in colon cancer cells in vitro, we found that repression of COUP-TFII decreased Snail1 expression. However, overexpression of COUP-TFII increased Snail1 expression. However, neither overexpression nor repression of Snail1 affected COUP-TFII expression, indicating that COUP-TFII is an upstream effector of Snail1 (Figure 1E).

Bottom Line: Overexpression of COUP-TFII was required for cancer cells to metastasise in vivo.Chicken ovalbumin upstream promoter-transcription factor II regulated the transcription and expression of Snail1 by directly targeting the Snail1 promoter and regulated associated genes.Chicken ovalbumin upstream promoter-transcription factor II was found to be a biomarker associated with patient survival and colorectal cancer metastasis.

View Article: PubMed Central - PubMed

Affiliation: First Affiliated Hospital, Huzhou Teachers College, the First People's Hospital of Huzhou, Huzhou 313000, China.

ABSTRACT

Background: Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII, also known as NR2F2) promotes metastasis by functioning in the tumour microenvironment; however, the role of COUP-TFII in colorectal cancer remains unknown.

Methods: Human colon adenocarcinoma tissues were collected to test COUP-TFII expression. Wound-healing and cell invasion assay were used to evaluate migration and invasion of cells. Chicken ovalbumin upstream promoter-transcription factor II and related protein expression was assessed by immunostaining, immunoblotting and real-time PCR assay. Tamoxifen-inducible COUP-TFII knockout mice were employed to test COUP-TFII functions on colon cancer metastasis in vivo.

Results: Elevated expression of COUP-TFII in colorectal adenocarcinoma tissue correlated with overexpression of the Snail1 transcription factor. High COUP-TFII expression correlated with metastasis and shorter patient survival. Chicken ovalbumin upstream promoter-transcription factor II regulated the migration and invasion of cancer cells. With Snail1, COUP-TFII inhibited expression of adherence molecules such as ZO-1, E-cadherin and β-catenin in colorectal cancer cells. Overexpression of COUP-TFII was required for cancer cells to metastasise in vivo. Chicken ovalbumin upstream promoter-transcription factor II regulated the transcription and expression of Snail1 by directly targeting the Snail1 promoter and regulated associated genes.

Conclusions: Chicken ovalbumin upstream promoter-transcription factor II was crucial for colorectal cancer metastasis and regulated cell migration and metastasis in conjunction with Snail1. Chicken ovalbumin upstream promoter-transcription factor II was found to be a biomarker associated with patient survival and colorectal cancer metastasis.

Show MeSH
Related in: MedlinePlus