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Elevated HOXB9 expression promotes differentiation and predicts a favourable outcome in colon adenocarcinoma patients.

Zhan J, Niu M, Wang P, Zhu X, Li S, Song J, He H, Wang Y, Xue L, Fang W, Zhang H - Br. J. Cancer (2014)

Bottom Line: Elevated HOXB9 expression was identified in well-differentiated colon adenocarcinoma patients and was associated with a better overall patients' survival.Overexpression of HOXB9 inhibited colon adenocarcinoma cell growth, migration, invasion in vitro and tumour growth, liver as well as lung metastases in nude mice; whereas silencing HOXB9 promoted these functions.Elevated expression of HOXB9 predicts a longer survival in colon adenocarcinoma patients.

View Article: PubMed Central - PubMed

Affiliation: 1] Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Health Science Center, Beijing 100191, China [2] State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China [3] Laboratory of Molecular Cell Biology and Tumor Biology, Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing 100191, China.

ABSTRACT

Background: Little is known about the tumour suppressive proteins and the underlying mechanisms that suppress colon cancer progression. Homeodomain-containing transcription factor HOXB9 plays an important role in embryogenesis and cancer development. We here aim to uncover the potential role of HOXB9 in the regulation of colon adenocarcinoma progression including epithelial-to-mesenchymal transition.

Methods: HOXB9 expression in colon adenocarcinoma cells and patients was analysed by western blot and immunohistochemistry separately. Correlation between HOXB9 expressions with patients' survival was assessed by Kaplan-Meier analysis. HOXB9-regulated target gene expression was determined by RNA sequencing in HOXB9-overexpressing colon adenocarcinoma cells.

Results: Elevated HOXB9 expression was identified in well-differentiated colon adenocarcinoma patients and was associated with a better overall patients' survival. Overexpression of HOXB9 inhibited colon adenocarcinoma cell growth, migration, invasion in vitro and tumour growth, liver as well as lung metastases in nude mice; whereas silencing HOXB9 promoted these functions. HOXB9 promoted colon adenocarcinoma differentiation via a mechanism that stimulates mesenchymal-to-epithelial transition, involving downregulation of EMT-promoting transcriptional factors including Snail, Twist, FOXC2 and ZEB1 and upregulation of epithelial proteins including E-cadherin, claudins-1, -4, -7, occludin and ZO-1.

Conclusions: HOXB9 is a novel tumour suppressor that inhibits colon adenocarcinoma progression by inducing differentiation. Elevated expression of HOXB9 predicts a longer survival in colon adenocarcinoma patients.

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Elevated expression of HOXB9 predicts longer overall survival for patients with colon adenocarcinoma. (A) HOXB9 differentially expressed in colon adenocarcinoma patients with different degree of differentiation. For patient samples: (a) well differentiated; (b) moderate differentiated; (c) poorly differentiated. (B) Semi-quantitative analysis of HOXB9 levels in colon adenocarcinoma patients with different degree of differentiation, in which HOXB9 expressed higher in well-differentiated adenocarcinoma than the moderate- or poorly differentiated ones. Statistical analysis was performed and the difference between well- and poorly differentiated is significant (P=0.026), whereas the differences between well- and moderate-differentiated tumours as well as moderate- and poorly differentiated tumours were not significant (Figure 2B, P=0.2108 and 0.0570 separately). (C) Two groups of colon adenocarcinoma patients with HOXB9 high or low expression were determined by Kaplan–Meier analysis with a log-rank at P<0.05, showing that elevated expression of HOXB9 correlates to a better overall survival for colon adenocarcinoma patients.
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fig2: Elevated expression of HOXB9 predicts longer overall survival for patients with colon adenocarcinoma. (A) HOXB9 differentially expressed in colon adenocarcinoma patients with different degree of differentiation. For patient samples: (a) well differentiated; (b) moderate differentiated; (c) poorly differentiated. (B) Semi-quantitative analysis of HOXB9 levels in colon adenocarcinoma patients with different degree of differentiation, in which HOXB9 expressed higher in well-differentiated adenocarcinoma than the moderate- or poorly differentiated ones. Statistical analysis was performed and the difference between well- and poorly differentiated is significant (P=0.026), whereas the differences between well- and moderate-differentiated tumours as well as moderate- and poorly differentiated tumours were not significant (Figure 2B, P=0.2108 and 0.0570 separately). (C) Two groups of colon adenocarcinoma patients with HOXB9 high or low expression were determined by Kaplan–Meier analysis with a log-rank at P<0.05, showing that elevated expression of HOXB9 correlates to a better overall survival for colon adenocarcinoma patients.

Mentions: We continued to examine the HOXB9 expression profile in three typical differentiation types of colon adenocarcinoma that include well-, moderate- and poorly differentiated tumours. Interestingly, we found that HOXB9 expression is higher in well-differentiated tumours (Figure 2Aa) than in that of moderate- and poorly differentiated ones (Figure 2Ab and c). Furthermore, the well-differentiated types in the patients were significantly different from the poorly differentiated tumours in terms of HOXB9 expression (Figure 2B, P=0.026), whereas the other two pairs are not statistically significant. However, in Spearman's correlation coefficient test (Table 2), the expression level of HOXB9 correlated with the degree of differentiation in colon adenocarcinomas (Spearman's correlation test=0.26595; P=0.0436), providing further evidence that HOXB9 does play a role in colon adenocarcinoma differentiation.


Elevated HOXB9 expression promotes differentiation and predicts a favourable outcome in colon adenocarcinoma patients.

Zhan J, Niu M, Wang P, Zhu X, Li S, Song J, He H, Wang Y, Xue L, Fang W, Zhang H - Br. J. Cancer (2014)

Elevated expression of HOXB9 predicts longer overall survival for patients with colon adenocarcinoma. (A) HOXB9 differentially expressed in colon adenocarcinoma patients with different degree of differentiation. For patient samples: (a) well differentiated; (b) moderate differentiated; (c) poorly differentiated. (B) Semi-quantitative analysis of HOXB9 levels in colon adenocarcinoma patients with different degree of differentiation, in which HOXB9 expressed higher in well-differentiated adenocarcinoma than the moderate- or poorly differentiated ones. Statistical analysis was performed and the difference between well- and poorly differentiated is significant (P=0.026), whereas the differences between well- and moderate-differentiated tumours as well as moderate- and poorly differentiated tumours were not significant (Figure 2B, P=0.2108 and 0.0570 separately). (C) Two groups of colon adenocarcinoma patients with HOXB9 high or low expression were determined by Kaplan–Meier analysis with a log-rank at P<0.05, showing that elevated expression of HOXB9 correlates to a better overall survival for colon adenocarcinoma patients.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150282&req=5

fig2: Elevated expression of HOXB9 predicts longer overall survival for patients with colon adenocarcinoma. (A) HOXB9 differentially expressed in colon adenocarcinoma patients with different degree of differentiation. For patient samples: (a) well differentiated; (b) moderate differentiated; (c) poorly differentiated. (B) Semi-quantitative analysis of HOXB9 levels in colon adenocarcinoma patients with different degree of differentiation, in which HOXB9 expressed higher in well-differentiated adenocarcinoma than the moderate- or poorly differentiated ones. Statistical analysis was performed and the difference between well- and poorly differentiated is significant (P=0.026), whereas the differences between well- and moderate-differentiated tumours as well as moderate- and poorly differentiated tumours were not significant (Figure 2B, P=0.2108 and 0.0570 separately). (C) Two groups of colon adenocarcinoma patients with HOXB9 high or low expression were determined by Kaplan–Meier analysis with a log-rank at P<0.05, showing that elevated expression of HOXB9 correlates to a better overall survival for colon adenocarcinoma patients.
Mentions: We continued to examine the HOXB9 expression profile in three typical differentiation types of colon adenocarcinoma that include well-, moderate- and poorly differentiated tumours. Interestingly, we found that HOXB9 expression is higher in well-differentiated tumours (Figure 2Aa) than in that of moderate- and poorly differentiated ones (Figure 2Ab and c). Furthermore, the well-differentiated types in the patients were significantly different from the poorly differentiated tumours in terms of HOXB9 expression (Figure 2B, P=0.026), whereas the other two pairs are not statistically significant. However, in Spearman's correlation coefficient test (Table 2), the expression level of HOXB9 correlated with the degree of differentiation in colon adenocarcinomas (Spearman's correlation test=0.26595; P=0.0436), providing further evidence that HOXB9 does play a role in colon adenocarcinoma differentiation.

Bottom Line: Elevated HOXB9 expression was identified in well-differentiated colon adenocarcinoma patients and was associated with a better overall patients' survival.Overexpression of HOXB9 inhibited colon adenocarcinoma cell growth, migration, invasion in vitro and tumour growth, liver as well as lung metastases in nude mice; whereas silencing HOXB9 promoted these functions.Elevated expression of HOXB9 predicts a longer survival in colon adenocarcinoma patients.

View Article: PubMed Central - PubMed

Affiliation: 1] Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Health Science Center, Beijing 100191, China [2] State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China [3] Laboratory of Molecular Cell Biology and Tumor Biology, Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing 100191, China.

ABSTRACT

Background: Little is known about the tumour suppressive proteins and the underlying mechanisms that suppress colon cancer progression. Homeodomain-containing transcription factor HOXB9 plays an important role in embryogenesis and cancer development. We here aim to uncover the potential role of HOXB9 in the regulation of colon adenocarcinoma progression including epithelial-to-mesenchymal transition.

Methods: HOXB9 expression in colon adenocarcinoma cells and patients was analysed by western blot and immunohistochemistry separately. Correlation between HOXB9 expressions with patients' survival was assessed by Kaplan-Meier analysis. HOXB9-regulated target gene expression was determined by RNA sequencing in HOXB9-overexpressing colon adenocarcinoma cells.

Results: Elevated HOXB9 expression was identified in well-differentiated colon adenocarcinoma patients and was associated with a better overall patients' survival. Overexpression of HOXB9 inhibited colon adenocarcinoma cell growth, migration, invasion in vitro and tumour growth, liver as well as lung metastases in nude mice; whereas silencing HOXB9 promoted these functions. HOXB9 promoted colon adenocarcinoma differentiation via a mechanism that stimulates mesenchymal-to-epithelial transition, involving downregulation of EMT-promoting transcriptional factors including Snail, Twist, FOXC2 and ZEB1 and upregulation of epithelial proteins including E-cadherin, claudins-1, -4, -7, occludin and ZO-1.

Conclusions: HOXB9 is a novel tumour suppressor that inhibits colon adenocarcinoma progression by inducing differentiation. Elevated expression of HOXB9 predicts a longer survival in colon adenocarcinoma patients.

Show MeSH
Related in: MedlinePlus