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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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HOXB9 suppresses tumour growth and metastasis in a mouse xenograft model. (A) Design of mouse xenograft experiment. (B) Tumour growth curve. (C) Tumour formation at day 28, which were dissected and photographed. (D) Average of tumour weights at day 28. (E) For HCT116-Flag control cells: (a) liver metastasis; (b) histology of live metastasis; (c) histology of lung metastasis. Please refer to Table 3 for summary of tumour formation, recurrence in situ and metastasis to remote organs for Flag HCT116 or Flag-HOXB9 HCT116 cells in the nude mouse model.
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fig4: HOXB9 suppresses tumour growth and metastasis in a mouse xenograft model. (A) Design of mouse xenograft experiment. (B) Tumour growth curve. (C) Tumour formation at day 28, which were dissected and photographed. (D) Average of tumour weights at day 28. (E) For HCT116-Flag control cells: (a) liver metastasis; (b) histology of live metastasis; (c) histology of lung metastasis. Please refer to Table 3 for summary of tumour formation, recurrence in situ and metastasis to remote organs for Flag HCT116 or Flag-HOXB9 HCT116 cells in the nude mouse model.

Mentions: To answer the question that whether HOXB9 plays a similar inhibitory role in vivo as in vitro, we examined the potential blockade of HOXB9 on tumour growth and metastasis in a nude mouse xenograft experiment as designed in Figure 4A. Overexpression of HOXB9 was identified to inhibit tumour growth in xenograft nude mice (Figure 4B–D). When tumours grew with a size of approximately 1 cm in diameter, they were removed by surgery. Interestingly, tumours derived from the HOXB9-expressing HCT116 cells displayed a low or no capability to metastasise to the remote organs including liver and lung of the nude mouse; whereas tumours derived from the control HCT116 cells demonstrated a high capability to metastasise to the liver and lung (Figure 4E, left: liver metastasis for a gross view, middle: a histology for liver metastasis, and right: a histology for lung metastasis). In addition, the capability of HOXB9 in blockade of tumour formation, recurrence and metastasis in nude mice was summarised in Table 3 from a representative experiment. These data strongly suggested that HOXB9 inhibited colon adenocarcinoma cell growth and metastasis to remote organs in nude mice. Taken together, these data indicated that elevated expression of HOXB9 exerted a suppressive role for colon adenocarcinoma cell progression both in vitro and in vivo. Thus, these functional experiments well interpreted the fact that elevated expression of HOXB9 correlated with a better patients' overall survival in colon adenocarcinomas.


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)

HOXB9 suppresses tumour growth and metastasis in a mouse xenograft model. (A) Design of mouse xenograft experiment. (B) Tumour growth curve. (C) Tumour formation at day 28, which were dissected and photographed. (D) Average of tumour weights at day 28. (E) For HCT116-Flag control cells: (a) liver metastasis; (b) histology of live metastasis; (c) histology of lung metastasis. Please refer to Table 3 for summary of tumour formation, recurrence in situ and metastasis to remote organs for Flag HCT116 or Flag-HOXB9 HCT116 cells in the nude mouse model.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: HOXB9 suppresses tumour growth and metastasis in a mouse xenograft model. (A) Design of mouse xenograft experiment. (B) Tumour growth curve. (C) Tumour formation at day 28, which were dissected and photographed. (D) Average of tumour weights at day 28. (E) For HCT116-Flag control cells: (a) liver metastasis; (b) histology of live metastasis; (c) histology of lung metastasis. Please refer to Table 3 for summary of tumour formation, recurrence in situ and metastasis to remote organs for Flag HCT116 or Flag-HOXB9 HCT116 cells in the nude mouse model.
Mentions: To answer the question that whether HOXB9 plays a similar inhibitory role in vivo as in vitro, we examined the potential blockade of HOXB9 on tumour growth and metastasis in a nude mouse xenograft experiment as designed in Figure 4A. Overexpression of HOXB9 was identified to inhibit tumour growth in xenograft nude mice (Figure 4B–D). When tumours grew with a size of approximately 1 cm in diameter, they were removed by surgery. Interestingly, tumours derived from the HOXB9-expressing HCT116 cells displayed a low or no capability to metastasise to the remote organs including liver and lung of the nude mouse; whereas tumours derived from the control HCT116 cells demonstrated a high capability to metastasise to the liver and lung (Figure 4E, left: liver metastasis for a gross view, middle: a histology for liver metastasis, and right: a histology for lung metastasis). In addition, the capability of HOXB9 in blockade of tumour formation, recurrence and metastasis in nude mice was summarised in Table 3 from a representative experiment. These data strongly suggested that HOXB9 inhibited colon adenocarcinoma cell growth and metastasis to remote organs in nude mice. Taken together, these data indicated that elevated expression of HOXB9 exerted a suppressive role for colon adenocarcinoma cell progression both in vitro and in vivo. Thus, these functional experiments well interpreted the fact that elevated expression of HOXB9 correlated with a better patients' overall survival in colon adenocarcinomas.

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