Skip to main content
Top
Published in: Cancer Cell International 1/2019

Open Access 01-12-2019 | Metastasis | Primary research

HOXB8 enhances the proliferation and metastasis of colorectal cancer cells by promoting EMT via STAT3 activation

Authors: Tingting Wang, Feiyan Lin, Xuecheng Sun, Lei Jiang, Ruibo Mao, Shenyue Zhou, Wenjing Shang, Ruichun Bi, Fengying Lu, Shaotang Li

Published in: Cancer Cell International | Issue 1/2019

Login to get access

Abstract

Background

Previous studies have demonstrated that the expression of homeobox8 (HOXB8) is higher in colorectal cancer (CRC) tissues than in normal tissues; however, the precise role of HOXB8 in human CRC cells remains to be elucidated.

Methods

We generated lentiviral constructs to overexpress and silence HOXB8 in CRC cell lines, and examined their biological functions through MTT, wound healing, colony and transwell, expression of signal transducer and activator of transcription 3 (STAT3) and epithelial–mesenchymal transition (EMT) related factors through western-blot.

Results

HOXB8 knockdown inhibited cellular proliferation and invasion in vitro as well as carcinogenesis and metastasis in vivo. HOXB8 also induced EMT, which is characterized by the down-regulation of E-cadherin and the up-regulation of Vimentin, N-cadherin, Twist, Zeb1 and Zeb2. Moreover, HOXB8 activated STAT3, which is known to play an oncogenic role in diverse human malignancies.

Conclusions

Our results indicate that HOXB8 may be an independent prognostic factor in CRC. Therefore, deserved a deeper research.
Appendix
Available only for authorised users
Literature
1.
go back to reference Weitz J, Koch M, Debus J, Hohler T, Galle PR, Buchler MW. Colorectal cancer. Lancet (London, England). 2005;365(9454):153–65.CrossRef Weitz J, Koch M, Debus J, Hohler T, Galle PR, Buchler MW. Colorectal cancer. Lancet (London, England). 2005;365(9454):153–65.CrossRef
2.
go back to reference Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759–67.CrossRef Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759–67.CrossRef
3.
go back to reference Jemal A, Center MM, DeSantis C, Ward EM. Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev. 2010;19(8):1893–907.CrossRef Jemal A, Center MM, DeSantis C, Ward EM. Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev. 2010;19(8):1893–907.CrossRef
4.
go back to reference Gehring WJ, Hiromi Y. Homeotic genes and the homeobox. Annu Rev Genet. 1986;20:147–73.CrossRef Gehring WJ, Hiromi Y. Homeotic genes and the homeobox. Annu Rev Genet. 1986;20:147–73.CrossRef
5.
go back to reference McGinnis W, Krumlauf R. Homeobox genes and axial patterning. Cell. 1992;68(2):283–302.CrossRef McGinnis W, Krumlauf R. Homeobox genes and axial patterning. Cell. 1992;68(2):283–302.CrossRef
6.
go back to reference Kanai M, Hamada J, Takada M, Asano T, Murakawa K, Takahashi Y, Murai T, Tada M, Miyamoto M, Kondo S, et al. Aberrant expressions of HOX genes in colorectal and hepatocellular carcinomas. Oncol Rep. 2010;23(3):843–51.PubMed Kanai M, Hamada J, Takada M, Asano T, Murakawa K, Takahashi Y, Murai T, Tada M, Miyamoto M, Kondo S, et al. Aberrant expressions of HOX genes in colorectal and hepatocellular carcinomas. Oncol Rep. 2010;23(3):843–51.PubMed
7.
go back to reference Ding WJ, Zhou M, Chen MM, Qu CY. HOXB8 promotes tumor metastasis and the epithelial–mesenchymal transition via ZEB2 targets in gastric cancer. J Cancer Res Clin Oncol. 2017;143(3):385–97.CrossRef Ding WJ, Zhou M, Chen MM, Qu CY. HOXB8 promotes tumor metastasis and the epithelial–mesenchymal transition via ZEB2 targets in gastric cancer. J Cancer Res Clin Oncol. 2017;143(3):385–97.CrossRef
8.
go back to reference Vider BZ, Zimber A, Chastre E, Gespach C, Halperin M, Mashiah P, Yaniv A, Gazit A. Deregulated expression of homeobox-containing genes, HOXB6, B8, C8, C9, and Cdx-1, in human colon cancer cell lines. Biochem Biophys Res Commun. 2000;272(2):513–8.CrossRef Vider BZ, Zimber A, Chastre E, Gespach C, Halperin M, Mashiah P, Yaniv A, Gazit A. Deregulated expression of homeobox-containing genes, HOXB6, B8, C8, C9, and Cdx-1, in human colon cancer cell lines. Biochem Biophys Res Commun. 2000;272(2):513–8.CrossRef
9.
go back to reference Vider BZ, Zimber A, Hirsch D, Estlein D, Chastre E, Prevot S, Gespach C, Yaniv A, Gazit A. Human colorectal carcinogenesis is associated with deregulation of homeobox gene expression. Biochem Biophys Res Commun. 1997;232(3):742–8.CrossRef Vider BZ, Zimber A, Hirsch D, Estlein D, Chastre E, Prevot S, Gespach C, Yaniv A, Gazit A. Human colorectal carcinogenesis is associated with deregulation of homeobox gene expression. Biochem Biophys Res Commun. 1997;232(3):742–8.CrossRef
10.
go back to reference Hur H, Lee JY, Yun HJ, Park BW, Kim MH. Analysis of HOX gene expression patterns in human breast cancer. Mol Biotechnol. 2014;56(1):64–71.CrossRef Hur H, Lee JY, Yun HJ, Park BW, Kim MH. Analysis of HOX gene expression patterns in human breast cancer. Mol Biotechnol. 2014;56(1):64–71.CrossRef
11.
go back to reference Cantile M, Scognamiglio G, La Sala L, La Mantia E, Scaramuzza V, Valentino E, Tatangelo F, Losito S, Pezzullo L, Chiofalo MG, et al. Aberrant expression of posterior HOX genes in well differentiated histotypes of thyroid cancers. Int J Mol Sci. 2013;14(11):21727–40.CrossRef Cantile M, Scognamiglio G, La Sala L, La Mantia E, Scaramuzza V, Valentino E, Tatangelo F, Losito S, Pezzullo L, Chiofalo MG, et al. Aberrant expression of posterior HOX genes in well differentiated histotypes of thyroid cancers. Int J Mol Sci. 2013;14(11):21727–40.CrossRef
12.
go back to reference Marra L, Cantile M, Scognamiglio G, Perdona S, La Mantia E, Cerrone M, Gigantino V, Cillo C, Caraglia M, Pignata S, et al. Deregulation of HOX B13 expression in urinary bladder cancer progression. Curr Med Chem. 2013;20(6):833–9.PubMed Marra L, Cantile M, Scognamiglio G, Perdona S, La Mantia E, Cerrone M, Gigantino V, Cillo C, Caraglia M, Pignata S, et al. Deregulation of HOX B13 expression in urinary bladder cancer progression. Curr Med Chem. 2013;20(6):833–9.PubMed
13.
go back to reference Liao WT, Jiang D, Yuan J, Cui YM, Shi XW, Chen CM, Bian XW, Deng YJ, Ding YQ. HOXB7 as a prognostic factor and mediator of colorectal cancer progression. Clin Cancer Res. 2011;17(11):3569–78.CrossRef Liao WT, Jiang D, Yuan J, Cui YM, Shi XW, Chen CM, Bian XW, Deng YJ, Ding YQ. HOXB7 as a prognostic factor and mediator of colorectal cancer progression. Clin Cancer Res. 2011;17(11):3569–78.CrossRef
14.
go back to reference Antognelli C, Cecchetti R, Riuzzi F, Peirce MJ, Talesa VN. Glyoxalase 1 sustains the metastatic phenotype of prostate cancer cells via EMT control. J Cell Mol Med. 2018;22(5):2865–83.CrossRef Antognelli C, Cecchetti R, Riuzzi F, Peirce MJ, Talesa VN. Glyoxalase 1 sustains the metastatic phenotype of prostate cancer cells via EMT control. J Cell Mol Med. 2018;22(5):2865–83.CrossRef
15.
go back to reference Balanis N, Wendt MK, Schiemann BJ, Wang Z, Schiemann WP, Carlin CR. Epithelial to mesenchymal transition promotes breast cancer progression via a fibronectin-dependent STAT3 signaling pathway. J Biol Chem. 2013;288(25):17954–67.CrossRef Balanis N, Wendt MK, Schiemann BJ, Wang Z, Schiemann WP, Carlin CR. Epithelial to mesenchymal transition promotes breast cancer progression via a fibronectin-dependent STAT3 signaling pathway. J Biol Chem. 2013;288(25):17954–67.CrossRef
16.
go back to reference Zhang C, Guo F, Xu G, Ma J, Shao F. STAT3 cooperates with Twist to mediate epithelial–mesenchymal transition in human hepatocellular carcinoma cells. Oncol Rep. 2015;33(4):1872–82.CrossRef Zhang C, Guo F, Xu G, Ma J, Shao F. STAT3 cooperates with Twist to mediate epithelial–mesenchymal transition in human hepatocellular carcinoma cells. Oncol Rep. 2015;33(4):1872–82.CrossRef
17.
go back to reference Fu Q, Jiang Y, Zhang D, Liu X, Guo J, Zhao J. Valosin-containing protein (VCP) promotes the growth, invasion, and metastasis of colorectal cancer through activation of STAT3 signaling. Mol Cell Biochem. 2016;418(1–2):189–98.CrossRef Fu Q, Jiang Y, Zhang D, Liu X, Guo J, Zhao J. Valosin-containing protein (VCP) promotes the growth, invasion, and metastasis of colorectal cancer through activation of STAT3 signaling. Mol Cell Biochem. 2016;418(1–2):189–98.CrossRef
18.
go back to reference Lu X, Pan J, Li S, Shen S, Chi P, Lin H, Huang Y, Xu Z, Huang S. Establishment of a predictive genetic model for estimating chemotherapy sensitivity of colorectal cancer with synchronous liver metastasis. Cancer Biother Radiopharm. 2013;28(7):552–8.CrossRef Lu X, Pan J, Li S, Shen S, Chi P, Lin H, Huang Y, Xu Z, Huang S. Establishment of a predictive genetic model for estimating chemotherapy sensitivity of colorectal cancer with synchronous liver metastasis. Cancer Biother Radiopharm. 2013;28(7):552–8.CrossRef
19.
go back to reference Li S, Lu X, Chi P, Pan J. Identification of HOXB8 and KLK11 expression levels as potential biomarkers to predict the effects of FOLFOX4 chemotherapy. Future Oncol (London, England). 2013;9(5):727–36.CrossRef Li S, Lu X, Chi P, Pan J. Identification of HOXB8 and KLK11 expression levels as potential biomarkers to predict the effects of FOLFOX4 chemotherapy. Future Oncol (London, England). 2013;9(5):727–36.CrossRef
20.
go back to reference Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22(1):23–30.CrossRef Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22(1):23–30.CrossRef
21.
go back to reference Grothey A, Sargent D. Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single-agent therapy is used first line. J Clin Oncol. 2005;23(36):9441–2.CrossRef Grothey A, Sargent D. Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single-agent therapy is used first line. J Clin Oncol. 2005;23(36):9441–2.CrossRef
22.
go back to reference Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26(12):2013–9.CrossRef Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26(12):2013–9.CrossRef
23.
go back to reference Pullarkat ST, Stoehlmacher J, Ghaderi V, Xiong YP, Ingles SA, Sherrod A, Warren R, Tsao-Wei D, Groshen S, Lenz HJ. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J. 2001;1(1):65–70.CrossRef Pullarkat ST, Stoehlmacher J, Ghaderi V, Xiong YP, Ingles SA, Sherrod A, Warren R, Tsao-Wei D, Groshen S, Lenz HJ. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J. 2001;1(1):65–70.CrossRef
24.
go back to reference Meyer UA. Pharmacogenetics and adverse drug reactions. Lancet (London, England). 2000;356(9242):1667–71.CrossRef Meyer UA. Pharmacogenetics and adverse drug reactions. Lancet (London, England). 2000;356(9242):1667–71.CrossRef
Metadata
Title
HOXB8 enhances the proliferation and metastasis of colorectal cancer cells by promoting EMT via STAT3 activation
Authors
Tingting Wang
Feiyan Lin
Xuecheng Sun
Lei Jiang
Ruibo Mao
Shenyue Zhou
Wenjing Shang
Ruichun Bi
Fengying Lu
Shaotang Li
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2019
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-018-0717-6

Other articles of this Issue 1/2019

Cancer Cell International 1/2019 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine