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Cancer Cell International

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Open Access 01-12-2021 | Biomarkers | Primary research

HOXB7 acts as an oncogenic biomarker in head and neck squamous cell carcinoma

Authors: Xiang Wu, Jin Li, Tingyuan Yan, Xueping Ke, Xin Li, Yumin Zhu, Jianrong Yang, Zhongwu Li

Published in: Cancer Cell International | Issue 1/2021

Abstract

Background

The homeobox gene Homeobox B7 (HOXB7) is overexpressed across a range of cancers and promotes tumorigenesis through varying effects on proliferation, survival, migration and invasion. However, its expression pattern and oncogenic role of HOXB7 in head and neck squamous cell carcinoma (HNSCC) remain largely unexplored. Here, we aimed to explore the expression pattern of HOXB7, its clinical significance as well as functional roles in HNSCC.

Methods

HOXB7 mRNA expression in HNSCC was determined by data mining and analyses from TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) datasets. The protein abundance of HOXB7 was measured by immunohistochemistry in 119 primary HNSCC samples and associations between its expression and clinicopathological parameters and patient survival were evaluated. The pro-tumorigenic roles of HOXB7 in HNSCC were further delineated in vitro by loss-of-function assay. And a xenograft tumor model was established in nude mice to assess the role of HOXB7 in tumor growth. Connectivity Map (CMap) analysis was performed to identify bioactive small molecules which might be potential inhibitors for HOXB7.

Results

Bioinformatics analyses showed that HOXB7 mRNA was significantly overexpressed in 8 independent HNSCC datasets from TCGA and GEO databases. HOXB7 protein was markedly upregulated in HNSCC samples as compared to normal counterparts and its overexpression significantly associated with high pathological grade, advanced clinical stage, cervical node metastasis (P = 0.0195, 0.0152, 0.0300) and reduced overall and disease-free survival (P = 0.0014, 0.0007). Univariate and multivariate Cox regression analyses further revealed HOXB7 as an independent prognostic factor for patients’ overall survival. Moreover, HOXB7 knockdown significantly inhibited cell proliferation, migration and invasion and induced cell apoptosis in HNSCC cells, and resulted in compromised tumour growth in vivo. Furthermore, CMap (Connectivity map) analysis has identified three potential bioactive small molecule inhibitors (NU-1025, thiamine, vinburnine) for HOXB7 targeted therapy in HNSCC.

Conclusions

Our findings revealed that overexpression of HOXB7 was associates with tumour aggressiveness and unfavourable prognosis by serving a novel prognostic biomarker in HNSCC. Moreover, HOXB7 might be involved in the development and progression of HNSCC as an oncogene, and thereby might be a potential therapeutic target for HNSCC.

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Siegel RL, Miller KD, Jemal A. Cancer statistics 2020. CA Cancer J Clin. 2020;70:7–30. https://doi.org/10.3322/caac.21590.CrossRef

Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nat Rev Dis Primers. 2020;6:92. https://doi.org/10.1038/s41572-020-00224-3.CrossRefPubMedPubMedCentral

Sacco AG, Cohen EE. Current treatment options for recurrent or metastatic head and neck squamous cell carcinoma. J Clin Oncol. 2015;33:3305–13. https://doi.org/10.1200/JCO.2015.62.0963.CrossRefPubMed

Lydiatt WM, Patel SG, O’Sullivan B, Brandwein MS, Ridge JA, Migliacci JC, et al. Head and Neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67:122–37. https://doi.org/10.3322/caac.21389.CrossRefPubMed

Denaro N, Russi EG, Merlano MC. Pros and cons of the new edition of TNM classification of head and neck squamous cell carcinoma. Oncology. 2018;95:202–10. https://doi.org/10.1159/000490415.CrossRefPubMed

Elalfy MM, Borlak J. Exon array analysis to identify diethyl-nitrosamine differentially regulated and alternately spliced genes in early liver carcinogenesis in the transgenic mouse ATT-myc model. SciMedicine Journal. 2021;3:138–52. https://doi.org/10.28991/SciMedJ-2021-0302-6.CrossRef

Amini Khorasgani M, Mohammady Nejad P, Moghani Bashi MM, Hedayati M. Evaluation of mir-377-3p expression in patients with multiple sclerosis. SciMedicine Journal. 2019;1:48–54. https://doi.org/10.28991/SciMedJ-2019-0102-2.CrossRef

Samuel S, Naora H. Homeobox gene expression in cancer: insights from developmental regulation and deregulation. Eur J Cancer. 2005;41:2428–37. https://doi.org/10.1016/j.ejca.2005.08.014.CrossRefPubMed

Shah N, Sukumar S. The Hox genes and their roles in oncogenesis. Nat Rev Cancer. 2010;10:361–71. https://doi.org/10.1038/nrc2826.CrossRefPubMed

10.

Li B, Huang Q, Wei GH. The role of HOX transcription factors in cancer predisposition and progression. Cancers (Basel). 2019;11. https://doi.org/10.3390/cancers11040528.

11.

Sun M, Song CX, Huang H, Frankenberger CA, Sankarasharma D, Gomes S, et al. HMGA2/TET1/HOXA9 signaling pathway regulates breast cancer growth and metastasis. Proc Natl Acad Sci USA. 2013;110:9920–5. https://doi.org/10.1073/pnas.1305172110.CrossRefPubMedPubMedCentral

12.

Yoshida H, Broaddus R, Cheng W, Xie S, Naora H. Deregulation of the HOXA10 homeobox gene in endometrial carcinoma: role in epithelial–mesenchymal transition. Cancer Res. 2006;66:889–97. https://doi.org/10.1158/0008-5472.CAN-05-2828.CrossRefPubMed

13.

Stiegelbauer V, Vychytilova-Faltejskova P, Karbiener M, Pehserl AM, Reicher A, Resel M, et al. miR-196b-5p regulates colorectal cancer cell migration and metastases through interaction with HOXB7 and GALNT5. Clin Cancer Res. 2017;23:5255–66. https://doi.org/10.1158/1078-0432.CCR-17-0023.CrossRefPubMed

14.

De Souza Setubal Destro MF, Bitu CC, Zecchin KG, Graner E, Lopes MA, Kowalski LP, et al. Overexpression of HOXB7 homeobox gene in oral cancer induces cellular proliferation and is associated with poor prognosis. Int J Oncol. 2010;36:141–9.PubMed

15.

Chen H, Lee JS, Liang X, Zhang H, Zhu T, Zhang Z, et al. Hoxb7 inhibits transgenic HER-2/neu-induced mouse mammary tumor onset but promotes progression and lung metastasis. Cancer Res. 2008;68:3637–44. https://doi.org/10.1158/0008-5472.CAN-07-2926.CrossRefPubMedPubMedCentral

16.

Correction. HOXB7, a homeodomain protein, is overexpressed in breast cancer and confers epithelial–mesenchymal transition. Cancer Res. 2015;75:2401. https://doi.org/10.1158/0008-5472.CAN-15-0936.CrossRef

17.

Tu W, Zhu X, Han Y, Wen Y, Qiu G, Zhou C. Overexpression of HOXB7 is associated with a poor prognosis in patients with gastric cancer. Oncol Lett. 2015;10:2967–73. https://doi.org/10.3892/ol.2015.3630.CrossRefPubMedPubMedCentral

18.

Cai L, Wang Z, Zheng H, Xu L. The let-7c/HoxB7 axis regulates the cell proliferation, migration and apoptosis in hepatocellular carcinoma. Anticancer Drugs. 2020;31:6–18. https://doi.org/10.1097/CAD.0000000000000843.CrossRefPubMed

19.

Cheng W, Shi X, Lin M, Yao Q, Ma J, Li J. LncRNA MAGI2-AS3 overexpression sensitizes esophageal cancer cells to irradiation through down-regulation of HOXB7 via EZH2. Front Cell Dev Biol. 2020;8:552822. https://doi.org/10.3389/fcell.2020.552822.CrossRefPubMedPubMedCentral

20.

Li H, Shen LY, Yan WP, Dong B, Kang XZ, Dai L, et al. Deregulated HOXB7 expression predicts poor prognosis of patients with esophageal squamous cell carcinoma and regulates cancer cell proliferation in vitro and in vivo. PLoS One. 2015;10:e0130551. https://doi.org/10.1371/journal.pone.0130551.CrossRefPubMedPubMedCentral

21.

Liao WT, Jiang D, Yuan J, Cui YM, Shi XW, Chen CM, et al. HOXB7 as a prognostic factor and mediator of colorectal cancer progression. Clin Cancer Res. 2011;17:3569–78. https://doi.org/10.1158/1078-0432.CCR-10-2533.CrossRefPubMed

22.

Nguyen Kovochich A, Arensman M, Lay AR, Rao NP, Donahue T, Li X, et al. HOXB7 promotes invasion and predicts survival in pancreatic adenocarcinoma. Cancer. 2013;119:529–39. https://doi.org/10.1002/cncr.27725.CrossRefPubMed

23.

Huan HB, Yang DP, Wen XD, Chen XJ, Zhang L, Wu LL, et al. HOXB7 accelerates the malignant progression of hepatocellular carcinoma by promoting stemness and epithelial–mesenchymal transition. J Exp Clin Cancer Res. 2017;36:86. https://doi.org/10.1186/s13046-017-0559-4.CrossRefPubMedPubMedCentral

24.

Tsuboi M, Taniuchi K, Shimizu T, Saito M, Saibara T. The transcription factor HOXB7 regulates ERK kinase activity and thereby stimulates the motility and invasiveness of pancreatic cancer cells. J Biol Chem. 2017;292:17681–702. https://doi.org/10.1074/jbc.M116.772780.CrossRefPubMedPubMedCentral

25.

Jin K, Park S, Teo WW, Korangath P, Cho SS, Yoshida T, et al. HOXB7 Is an ERalpha cofactor in the activation of HER2 and multiple ER target genes leading to endocrine resistance. Cancer Discov. 2015;5:944–59. https://doi.org/10.1158/2159-8290.CD-15-0090.CrossRefPubMedPubMedCentral

26.

Care A, Valtieri M, Mattia G, Meccia E, Masella B, Luchetti L, et al. Enforced expression of HOXB7 promotes hematopoietic stem cell proliferation and myeloid-restricted progenitor differentiation. Oncogene. 1999;18:1993–2001. https://doi.org/10.1038/sj.onc.1202498.CrossRefPubMed

27.

Bostrom K, Tintut Y, Kao SC, Stanford WP, Demer LL. HOXB7 overexpression promotes differentiation of C3H10T1/2 cells to smooth muscle cells. J Cell Biochem. 2000;78:210–21. https://doi.org/10.1002/(sici)1097-4644(20000801)78:2%3c210::aid-jcb4%3e3.0.co;2-z.CrossRefPubMed

28.

Komatsu H, Iguchi T, Masuda T, Ueda M, Kidogami S, Ogawa Y, et al. HOXB7 expression is a novel biomarker for long-term prognosis after resection of hepatocellular carcinoma. Anticancer Res. 2016;36:2767–73.PubMed

29.

Gavrielatou N, Doumas S, Economopoulou P, Foukas PG, Psyrri A. Biomarkers for immunotherapy response in head and neck cancer. Cancer Treat Rev. 2020;84:101977. https://doi.org/10.1016/j.ctrv.2020.101977.CrossRefPubMed

30.

Birkeland AC, Owen JH, Prince ME. Targeting head and neck cancer stem cells: current advances and future challenges. J Dent Res. 2015;94:1516–23. https://doi.org/10.1177/0022034515601960.CrossRefPubMedPubMedCentral

31.

Monterisi S, Lo Riso P, Russo K, Bertalot G, Vecchi M, Testa G, et al. HOXB7 overexpression in lung cancer is a hallmark of acquired stem-like phenotype. Oncogene. 2018;37:3575–88. https://doi.org/10.1038/s41388-018-0229-9.CrossRefPubMed

32.

Huo XY, Zhang XY, Yuan F, Zhao XY, You BA. HOXB7 promotes proliferation and metastasis of glioma by regulating the Wnt/beta-catenin pathway. Eur Rev Med Pharmacol Sci. 2019;23:2476–85. https://doi.org/10.26355/eurrev_201903_17395.CrossRef

33.

Xie X, Zhang SS, Wen J, Yang H, Luo KJ, Yang F, et al. Prognostic value of HOXB7 mRNA expression in human oesophageal squamous cell cancer. Biomarkers. 2013;18:297–303. https://doi.org/10.3109/1354750X.2013.773380.CrossRefPubMed

34.

Wu X, Chen H, Parker B, Rubin E, Zhu T, Lee JS, et al. HOXB7, a homeodomain protein, is overexpressed in breast cancer and confers epithelial–mesenchymal transition. Cancer Res. 2006;66:9527–34. https://doi.org/10.1158/0008-5472.CAN-05-4470.CrossRefPubMed

35.

Song Z, Liao Z, Cui Y, Yang C. The relationship between homeobox B7 expression and the clinical characteristics of patient with prostate cancer. J Cell Biochem. 2019;120:6395–401. https://doi.org/10.1002/jcb.27926.CrossRefPubMed

36.

Yang L, Xie F, Li S. Downregulation of homeobox B7 inhibits the tumorigenesis and progression of osteosarcoma. Oncol Res. 2017;25:1089–95. https://doi.org/10.3727/096504016X14784668796788.CrossRefPubMedPubMedCentral

37.

Bakir B, Chiarella AM, Pitarresi JR, Rustgi AK. EMT, MET, plasticity, and tumor metastasis. Trends Cell Biol. 2020;30:764–76. https://doi.org/10.1016/j.tcb.2020.07.003.CrossRefPubMed

38.

Wu J, Long Z, Cai H, Yu S, Liu X. Homeobox B7 accelerates the cancer progression of gastric carcinoma cells by promoting epithelial–mesenchymal transition (EMT) and activating Src-FAK pathway. Onco Targets Ther. 2019;12:3743–51. https://doi.org/10.2147/OTT.S198115.CrossRefPubMedPubMedCentral

39.

LeBrun DP, Matthews BP, Feldman BJ, Cleary ML. The chimeric oncoproteins E2A-PBX1 and E2A-HLF are concentrated within spherical nuclear domains. Oncogene. 1997;15:2059–67. https://doi.org/10.1038/sj.onc.1201367.CrossRefPubMed

40.

Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A. 2007;104:973–8. https://doi.org/10.1073/pnas.0610117104.CrossRefPubMedPubMedCentral

41.

Boumahdi S, Driessens G, Lapouge G, Rorive S, Nassar D, Le Mercier M, et al. SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma. Nature. 2014;511:246–50. https://doi.org/10.1038/nature13305.CrossRefPubMed

42.

Chen D, Wu M, Li Y, Chang I, Yuan Q, Ekimyan-Salvo M, et al. Targeting BMI1(+) Cancer Stem Cells Overcomes Chemoresistance and Inhibits Metastases in Squamous Cell Carcinoma. Cell Stem Cell. 2017;20:621-34 e626. https://doi.org/10.1016/j.stem.2017.02.003.CrossRefPubMedPubMedCentral

43.

Jin K, Kong X, Shah T, Penet MF, Wildes F, Sgroi DC, et al. The HOXB7 protein renders breast cancer cells resistant to tamoxifen through activation of the EGFR pathway. Proc Natl Acad Sci U S A. 2012;109:2736–41. https://doi.org/10.1073/pnas.1018859108.CrossRefPubMed

44.

Jia L, Zhang W, Wang CY. BMI1 Inhibition Eliminates Residual Cancer Stem Cells after PD1 Blockade and Activates Antitumor Immunity to Prevent Metastasis and Relapse. Cell Stem Cell. 2020;27:238-53 e236. https://doi.org/10.1016/j.stem.2020.06.022.CrossRefPubMed

Title: HOXB7 acts as an oncogenic biomarker in head and neck squamous cell carcinoma
Authors: Xiang Wu
Jin Li
Tingyuan Yan
Xueping Ke
Xin Li
Yumin Zhu
Jianrong Yang
Zhongwu Li
Publication date: 01-12-2021
Publisher: BioMed Central
Keyword: Biomarkers
Published in: Cancer Cell International / Issue 1/2021
Electronic ISSN: 1475-2867
DOI: https://doi.org/10.1186/s12935-021-02093-6

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Abstract

Background

Methods

Results

Conclusions

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