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International Journal of Clinical and Experimental Pathology logoLink to International Journal of Clinical and Experimental Pathology
. 2018 Jun 1;11(6):3091–3096.

Expression and clinical significance of HOXA5, E-cadherin, and β-catenin in cervical squamous cell carcinoma

Lei Pei 1,2,*, Zhi-Qiang Wang 1,2,*, Jian Shen 1,*, Yu-Zhong Yang 1, Jia Tian 1, Xuan He 1,2, Jing Lin 1, Qiao-Yan Hou 1, Wen-Fa Mo 1, Hai-Lu Zhao 2, Ying-Qiong Zhou 1
PMCID: PMC6958071  PMID: 31938436

Abstract

Objectives: HOXA5 has been identified as a biomarker in pathogenesis of several cancers, such as non-small cell lung cancer (NSCLC) and breast cancer cells. The role has not been explored in cervical squamous cell carcinoma (CSCC). Methods: Tissues of 120 cases with CSCC and 30 controls with chronic cervicitis were constructed from our archived surgical pathology files and staining with HOXA5. Additional antibodies to E-cadherin and β-catenin were stained for comparison. For each marker, low expression was defined as staining score 0 to 3 points, whereas high expression referred to 4 points and above. Fifty-four patients in this research with cervical cancer were followed up for prognostic assessment. Result: HOXA5 had high expression in chronic cervicitis and low in CSCC (P=0.004). The positivity rates of HOXA5 in patients without muscular layer invasion (MLI) and lymphatic invasion (LI) was higher than that in metastasis (113 vs. 17; 117 vs. 3). Consistently, low expression of HOXA5 was more common in poorly differentiated carcinoma, CSCC subjects without MLI and LI. Expression of E-cadherin and β-catenin was parallel with the expression of HOXA5. Additionally, patients with higher expression of HOXA5 had much more favorable prognosis than those with lower expression among follow up of the 54 patients. Conclusion: In parallel with E-cadherin and β-catenin, low expression of HOXA5 was more common in CSCC patients with poor differentiation, without MLI and LI, among those which showed poor prognosis.

Keywords: HOXA5, E-cadherin, β-catenin, cervical squamous cell carcinoma

Introduction

Cervical cancer is the third most common malignancy in women worldwide, and the second leading cause of cancer deaths among females aged 20 to 39 years in less developed countries [1,2]. Among the two types of cervical cancers, cervical squamous cell carcinoma comprises more than 90% of primary cervical cancers [3,4]. Despite recent advances in cervical cancer prevention cervical squamous cell carcinoma remains a major cause of morbidity and mortality. Early detection and diagnosis of cervical squamous cell carcinoma greatly increases the chances for successful treatment. Therefore, it is important to find new biomarkers for early diagnosis and treatment of patients with cervical cancer.

Homeobox (HOX) genes, a subset of the HOX genes that contain a common 183-nucleotide sequence (homeobox) and encode a high conserved 60 amino-acid (homeoproteins) [5-7]. HOX genes constitute a family of regulatory genes that control embryonic development, and contribute to a variety of biological pathways [8-10]. HOX genes are found in clusters called A, B, C and D on four different chromosomes [11-13]. HOXA5 is a member of the HOX gene family, has been shown to play an important role in tumor development and progression [14-17]. Moreover, accumulating evidence suggests that misregulated expression of HOXA5 gene is associated with multiple cancers including non-small cell lung cancer, breast cancer, and acute myeloid leukemia [18-22]. However, the role of HOXA5 in cervical squamous cell carcinoma is still unclear. Therefore, we conducted this study to investigate the expression and clinical significance of HOXA5 in cervical squamous cell carcinoma development and progression.

Materials and methods

Patients and tissue samples

Cervical squamous cell carcinoma tissues were obtained from surgical specimens resected from 120 patients who underwent surgery without any preoperative chemotherapy or radiotherapy, and 30 non-cancerous tissues from patients of chronic cervicitis at Affiliated Hospital of Guilin Medical University between April 2007 and October 2014. Histopathological diagnosis was performed according to the World Health Organization (WHO) criteria [23]. According to WHO classification, cervical squamous cell carcinoma tissues that belonged to well-moderately differentiated (n=61) and poorly differentiated (n=59) were taken. Clinicopathological staging was determined by the international TNM classification [24]. This investigation was approved by the Ethics Committee of Guilin Medical University. Written informed consent was obtained from all patients.

Immunohistochemistry

The paraffin-embedded tissue sections (4 μm) were immunostained for HOXA5, β-catenin, and E-cadherin using a polyclonal anti-HOXA5 antibody (Santa Cruz Biotechnology, CA; diluted at 1:200), a polyclonal anti-β-catenin antibody (Boster, Wuhan; diluted at 1:200) and a monoclonal anti-E-cadherin antibody (MXB, Fuzhou; diluted at 1:200), respectively. Immunohistochemistry was carried out according to the streptavidin biotin peroxidase methods. The paraffin-fixed sections were deparaffinized, hydrated, and then microwaved in EDTA buffer (PH 8.0). Subsequently, endogenous peroxidase was blocked by incubating with 0.3% hydrogen peroxide methanol for 10 min. The goat nonimmune serum (Solarbio, Beijing; diluted at 1:10) was used to remove non-specific binding. After that, the slides of samples were incubated with primary antibody at 4°C overnight. Next, horse radish peroxidase labeled primary antibody was incubated and DAB (MXB, Fuzhou, China) kits were used to visualize tantibody binding, followed by counterstaining with hematoxylin. Using PBS instead of primary antibody as a negative control, and the corresponding positive expression was positive control.

Evaluation of immunohistochemical results

Staining results were diagnosed by two pathologists who were not informed about the clinical information of the patients. E-cadherin and β-catenin are normally expressed on the cell membrane in cervical squamous epithelium, and HOXA5 is cytoplasmic staining [25-27]. Staining score evaluation criteria were as follow: A total of five representative magnifying fields (200 ×) were analyzed. (1) The percentage of positive cells fell into five categories: negative for 0, 1%-25% for 1, 26%-50% for 2, 51%-75% for 3, 76%-100% for 4; (2) The staining intensity was scored as follows: negative for 0, weakly for 1, moderately for 2, strong for 3 [28]. The final score of each slice was defined as (1) × (2). To facilitate statistical analysis, for E-cadherin, β-catenin, and HOXA5 staining score, 0 to 3 points was used for low expression, and 4 points indicated high expression.

Statistical analysis

Statistical comparisons were carried out by either X2 test or Fisher’s exact test. The overall survival time of cervical squamous cell cancer patients was evaluated by using the Kaplan-Meier method and log-rank test. All the analyses were carried out using SPSS 19.0 statistical software package (IBM, IL, USA).

Result

Expression of HOXA5 in cervical cervicitis and cervical squamous cell carcinoma

Expression of HOXA5 was detected in all patients with cervical cervicitis and CSCC by immunohistochemistry. However, the intensity of immunoreactivity showed significant difference between these two tissues (Figure 1). Low expression of HOXA5 was more common in cases with CSCC whereas high expression of HOXA5 among patients with chronic cervicitis (62.5 vs. 66.7%, P=0.004) (Table 1).

Figure 1.

Figure 1

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HOXA5 expression in chronic cervicitis tissues and cervical squamous cell carcinoma tissues (200 ×).

Table 1.

Association of HOXA5, E-cadherin and β-catenin expression levels with cervical squamous cell carcinoma clinicopathological features

HOXA5 expression E-cadherin expression β-catenin expression
High Low P-value High Low P-value High Low P-value
Clinicopathological features Chronic cervicitis 20 10 P=0.004 28 2 P<0.0001 28 2 P<0.0001
Cervical squamous cell carcinoma 45 75 49 71 41 79
Age <50 years 25 42 27 40 26 41
≥50 years 20 33 22 31 15 38
Pathological grade Well-moderately differentiated 31 30 P=0.002 33 28 P=0.003 28 33 P=0.006
Poorly differentiated 14 45 16 43 13 46
Muscular layer invasion (MLI) MLI+ 7 10 6 11 6 11
MLI- 38 65 43 60 35 68
Lymphatic invasion (LI) LI+ 0 3 0 3 0 3
LI- 45 72 49 68 41 76
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Subgroups were further established to identify the intensity of immunoreactivity of HOXA5 in cervical squamous cell carcinoma. Based on tumor differentiation, the proportion of cases with HOXA5 positivity exhibited no difference in poorly differentiated and well-moderately differentiated carcinoma. Low expression of HOXA5 was more common in poorly differentiated carcinoma tissue. According to the condition of muscular layer invasion (MLI), we found more patients with CSCC without MLI showed HOXA5 positivity compared with those with MLI (113 vs. 17). A similar finding was also observed between patients with and without lymphatic invasion (LI). Consistently, both CSCC without MLI and without LI showed low expression level of HOXA5.

Relationship between expression of HOXA5 and E-cadherin or β-catenin

E-cadherin and β-catenin have been confirmed as biomarkers in identifying cervical cancer. Therefore, we also conducted E-cadherin and β-catenin staining and further compared the relationship between expression of E-cadherin and β-catenin, and HOXA5 in patients with chronic cervicitis and CSCC (Table 2).

Table 2.

Relationship between the expression of HOXA5 and E-cadherin, β-catenin in cervical squamous cell carcinoma

HOXA5 expression p-value r-value
High Low
46 74
E-cadherin expression High 25 24 P<0.05 0.217
Low 21 50
β-catenin expression High 27 14 P<0.01 0.408
Low 19 60
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Consistent with HOXA5 staining, high expression of E-cadherin and β-catenin was detected in patients with chronic cervicitis whereas low expression was detected in CSCC. In terms of subgroups within CSCC, cases showing HOXA5 expression revealed no significant difference in well-moderately differentiated carcinoma and poorly differentiated carcinoma in both E-cadherin and β-catenin (61 vs. 59). Low expression of E-cadherin and β-catenin were more common than high expression in poorly differentiated carcinoma tissue, while well-moderately differentiated carcinoma was on the contrary.

Follow-up study among 54 patients with cervical squamous cell carcinoma

Additionally, we followed up 54 patients with CSCC to estimate their survival rate for prognostic assessment. We found the survival rate for patients with higher expression of HOXA5 was more than 90%, contrasting to less than 50% in those with lower expression of HOXA5 (Figure 2).

Figure 2.

Figure 2

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Kaplan-Meier curves of overall survival in cervical squamous cell carcinoma patients by HOXA5 expression level.

Discussion

The occurrence of tumors, similar to early embryonic development, is an abnormal form of organogenesis. Whereas, HOX plays a key role in vertebrate embryonic development, research of HOX gene expression in tumors has become a hot spot in recent years. HOXA5, as a member of the HOX gene family, is an important transcriptional regulator which controls organismal morphogenesis [29-32]. HOXA5 have been found to have a critical role in tumorigenesis. For example, Strathdee G demonstrated that acute myeloid leukaemia (AML) samples often exhibited very high methylation levels, far greater than that seen in normal haematopoietic cells, which suggests that methylation of HOXA5 may play an important role in arrest of normal differentiation during the development of AML [33]. HOXA5 might act as a suppressor of metastasis during lung tumor progression, at least partly through inhibition of calcium-mediated actin cytoskeleton polymerization [34]. Lee pointed out that overexpression of HOXA5 alone induced very strong apoptotic response of human liposarcoma cells by caspase-dependent rather than p53-dependent [35]. Other research pointed out that during pathologic angiogenesis, sustained expression of HOXA5 regulated expression of several angiogenic effector molecules, notably increased expression of TSP-2, and reduced expression of VEGF. This leads to inhibition of pathological angiogenesis in tissues [36] and indicates that HOXA5 acts a complex role in regulating the occurrence and development of tumor.

To our knowledge, expression of HOXA5 in human cervical squamous cell carcinoma is poorly understood. Our study has, for the first time, contributed to unraveling the direct role of HOXA5 in development of cervical squamous cell carcinoma. Our results strongly indicate that HOXA5 plays an inhibitory role in cell differentiation, evidenced by immunohistochemical staining in chronic cervicitis and CSCC. In our study, HOXA5 had low expression in cervical squamous cell carcinoma, but high expression in squamous epithelium of chronic cervicitis. The expression level was related to the degree of tumor differentiation. Additionally, patients with high expression of HOXA5 had a better prognosis than those with low expression. So, we hypothesized that the low expression of HOXA5 plays a substantial role in the occurrence and development of cervical squamous cell carcinoma and it may become a new therapeutic target and diagnostic index. The relationship between HOXA5 low expression and CSCC may be related to abnormal DNA methylation at CpG island (small stretches of DNA with high frequencies of CpG sites), but the specific mechanism remains to be further studied.

Recently, Ordonez-Moran discovered that HOXA5 was suppressed by the Wnt pathway to maintain stemness and become active only outside the intestinal crypt where it inhibited Wnt signaling to enforce differentiation [37]. According to this, we proposed that HOXA5 may inhibit the occurrence and development of cervical cancer by regulating the Wnt/β-catenin signaling pathway. By immunohistochemical staining, we found that most cases with high HOXA5 expression were accompanied by E-cadherin and β-catenin membrane expression. Accordingly, cases with low HOXA5 expression, also exhibited low expression of E-cadherin and β-catenin. The possible mechanism is during the process in tumorigenesis, the expression of HOXA5 was inhibited which led to abnormal Wnt signaling. Then, β-catenin lost the capability in binding with E-cadherin, and free in the cytoplasm. However, the specific mechanism of HOXA5 to inhibit the occurrence and development of cervical cancer by Wnt/β-catenin pathway remains to be elucidated.

In conclusion, this study is the first to demonstrate that HOXA5 can promote CSCC differentiation in cervical squamous cell cancer patients. In addition, the tumorous morphological change induced by abnormal expression of HOXA5 may be related with regulation of βCatenin and E-cadherin expression. Furthermore, these results offer the possibility of using HOXA5 as a biomarker for CSCC diagnosis and treatment.

Acknowledgements

This work was supported by grants from the Guilin Medical University (KY2011002), Program for Innovative Research Team of Guilin Medical University (PIRTGMU) and National Natural Science Foundation of China (81270934).

Disclosure of conflict of interest

None.

References

  • 1.Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30. doi: 10.3322/caac.21387. [DOI] [PubMed] [Google Scholar]
  • 2.Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108. doi: 10.3322/caac.21262. [DOI] [PubMed] [Google Scholar]
  • 3.Hirschowitz L, Nucci M, Zaino RJ. Problematic issues in the staging of endometrial, cervical and vulval carcinomas. Histopathology. 2013;62:176–202. doi: 10.1111/his.12058. [DOI] [PubMed] [Google Scholar]
  • 4.Murillo R, Herrero R, Sierra MS, Forman D. Cervical cancer in Central and South America: Burden of disease and status of disease control. Cancer Epidemiol. 2016;44(Suppl 1):S121–S30. doi: 10.1016/j.canep.2016.07.015. [DOI] [PubMed] [Google Scholar]
  • 5.Johnston LA, Ostrow BD, Jasoni C, Blochlinger K. The homeobox gene cut interacts genetically with the homeotic genes proboscipedia and antennapedia. Genetics. 1998;149:131–42. doi: 10.1093/genetics/149.1.131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Gehring WJ, Hiromi Y. Homeotic genes and the homeobox. Annu Rev Genet. 1986;20:147–73. doi: 10.1146/annurev.ge.20.120186.001051. [DOI] [PubMed] [Google Scholar]
  • 7.Gehring WJ. Homeotic genes, the homeobox, and the spatial organization of the embryo. Harvey Lect. 1985;81:153–72. [PubMed] [Google Scholar]
  • 8.Spencer DH, Young MA, Lamprecht TL, Helton NM, Fulton R, O’Laughlin M, Fronick C, Magrini V, Demeter RT, Miller CA, Klco JM, Wilson RK, Ley TJ. Epigenomic analysis of the HOX gene loci reveals mechanisms that may control canonical expression patterns in AML and normal hematopoietic cells. Leukemia. 2015;29:1279–89. doi: 10.1038/leu.2015.6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Abramovich C, Humphries RK. Hox regulation of normal and leukemic hematopoietic stem cells. Curr Opin Hematol. 2005;12:210–6. doi: 10.1097/01.moh.0000160737.52349.aa. [DOI] [PubMed] [Google Scholar]
  • 10.McGinnis W, Krumlauf R. Homeobox genes and axial patterning. Cell. 1992;68:283–302. doi: 10.1016/0092-8674(92)90471-n. [DOI] [PubMed] [Google Scholar]
  • 11.Delval S, Taminiau A, Lamy J, Lallemand C, Gilles C, Noel A, Rezsohazy R. The Pbx interaction motif of Hoxa1 is essential for its oncogenic activity. PLoS One. 2011;6:e25247. doi: 10.1371/journal.pone.0025247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Hrycaj SM, Wellik DM. Hox genes and evolution. F1000Res. 2016;5 doi: 10.12688/f1000research.7663.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Krumlauf R. Evolution of the vertebrate Hox homeobox genes. Bioessays. 1992;14:245–52. doi: 10.1002/bies.950140408. [DOI] [PubMed] [Google Scholar]
  • 14.Stasinopoulos IA, Mironchik Y, Raman A, Wildes F, Winnard P Jr, Raman V. HOXA5-twist interaction alters p53 homeostasis in breast cancer cells. J Biol Chem. 2005;280:2294–9. doi: 10.1074/jbc.M411018200. [DOI] [PubMed] [Google Scholar]
  • 15.Raman V, Martensen SA, Reisman D, Evron E, Odenwald WF, Jaffee E, Marks J, Sukumar S. Compromised HOXA5 function can limit p53 expression in human breast tumours. Nature. 2000;405:974–8. doi: 10.1038/35016125. [DOI] [PubMed] [Google Scholar]
  • 16.Cillo C, Cantile M, Faiella A, Boncinelli E. Homeobox genes in normal and malignant cells. J Cell Physiol. 2001;188:161–9. doi: 10.1002/jcp.1115. [DOI] [PubMed] [Google Scholar]
  • 17.Bagadi SA, Prasad CP, Kaur J, Srivastava A, Prashad R, Gupta SD, Ralhan R. Clinical significance of promoter hypermethylation of RASSF1A, RARbeta2, BRCA1 and HOXA5 in breast cancers of Indian patients. Life Sci. 2008;82:1288–92. doi: 10.1016/j.lfs.2008.04.020. [DOI] [PubMed] [Google Scholar]
  • 18.Abe M, Hamada J, Takahashi O, Takahashi Y, Tada M, Miyamoto M, Morikawa T, Kondo S, Moriuchi T. Disordered expression of HOX genes in human non-small cell lung cancer. Oncol Rep. 2006;15:797–802. [PubMed] [Google Scholar]
  • 19.Nagai H, Kinoshita T, Suzuki H, Hatano S, Murate T, Saito H. Identification and mapping of novel tumor suppressor loci on 6p in diffuse large B-cell non-Hodgkin’s lymphoma. Genes Chromosomes Cancer. 1999;25:277–83. [PubMed] [Google Scholar]
  • 20.Nagai H, Li Y, Hatano S, Toshihito O, Yuge M, Ito E, Utsumi M, Saito H, Kinoshita T. Mutations and aberrant DNA methylation of the PROX1 gene in hematologic malignancies. Genes Chromosomes Cancer. 2003;38:13–21. doi: 10.1002/gcc.10248. [DOI] [PubMed] [Google Scholar]
  • 21.Furuta J, Nobeyama Y, Umebayashi Y, Otsuka F, Kikuchi K, Ushijima T. Silencing of peroxiredoxin 2 and aberrant methylation of 33 CpG islands in putative promoter regions in human malignant melanomas. Cancer Res. 2006;66:6080–6. doi: 10.1158/0008-5472.CAN-06-0157. [DOI] [PubMed] [Google Scholar]
  • 22.Carrio M, Arderiu G, Myers C, Boudreau NJ. Homeobox D10 induces phenotypic reversion of breast tumor cells in a three-dimensional culture model. Cancer Res. 2005;65:7177–85. doi: 10.1158/0008-5472.CAN-04-1717. [DOI] [PubMed] [Google Scholar]
  • 23.Lu Z, Chen J. [Introduction of WHO classification of tumours of female reproductive organs, 4th edition] . Zhonghua Bing Li Xue Za Zhi. 2014;43:649–50. [PubMed] [Google Scholar]
  • 24.Denny L, Quinn M. FIGO cancer report 2015. Int J Gynaecol Obstet. 2015;131(Suppl 2):S75. doi: 10.1016/j.ijgo.2015.06.024. [DOI] [PubMed] [Google Scholar]
  • 25.Ichikawa Y, Nagashima Y, Morioka K, Akimoto K, Kojima Y, Ishikawa T, Goto A, Kobayashi N, Watanabe K, Ota M, Fujii S, Kawamata M, Takagawa R, Kunizaki C, Takahashi H, Nakajima A, Maeda S, Shimada H, Inayama Y, Ohno S, Endo I. Colorectal laterally spreading tumors show characteristic expression of cell polarity factors, including atypical protein kinase C lambda/iota, E-cadherin, beta-catenin and basement membrane component. Oncol Lett. 2014;8:977–84. doi: 10.3892/ol.2014.2271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Rao Q, Xu ZF, Wang JY, Meng JH, Tang KJ, Tian Z, Xing HY, Wang M, Wang JX. [Leukemia cell surface expression of E-cadherin and its correlation with membrane localization of betacatenin] . Zhonghua Xue Ye Xue Za Zhi. 2008;29:592–4. [PubMed] [Google Scholar]
  • 27.Chen YT, Stewart DB, Nelson WJ. Coupling assembly of the E-cadherin/beta-catenin complex to efficient endoplasmic reticulum exit and basal-lateral membrane targeting of Ecadherin in polarized MDCK cells. J Cell Biol. 1999;144:687–99. doi: 10.1083/jcb.144.4.687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Zhang C, Liu LW, Sun WJ, Qin SH, Qin LZ, Wang X. Expressions of E-cadherin, p120ctn, betacatenin and NF-kappaB in ulcerative colitis. J Huazhong Univ Sci Technolog Med Sci. 2015;35:368–73. doi: 10.1007/s11596-015-1439-9. [DOI] [PubMed] [Google Scholar]
  • 29.Ford HL. Homeobox genes: a link between development, cell cycle, and cancer? Cell Biol Int. 1998;22:397–400. doi: 10.1006/cbir.1998.0329. [DOI] [PubMed] [Google Scholar]
  • 30.Hench J, Henriksson J, Abou-Zied AM, Luppert M, Dethlefsen J, Mukherjee K, Tong YG, Tang L, Gangishetti U, Baillie DL, Burglin TR. The homeobox genes of caenorhabditis elegans and Insights into their spatio-temporal expression dynamics during embryogenesis. PLoS One. 2015;10:e0126947. doi: 10.1371/journal.pone.0126947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Mark M, Rijli FM, Chambon P. Homeobox genes in embryogenesis and pathogenesis. Pediatr Res. 1997;42:421–9. doi: 10.1203/00006450-199710000-00001. [DOI] [PubMed] [Google Scholar]
  • 32.Sato Y, Sentoku N, Matsuoka M. [Expression patterns and functions of plant homeobox genes during embryogenesis] . Tanpakushitsu Kakusan Koso. 1997;42:1866–74. [PubMed] [Google Scholar]
  • 33.Rodini CO, Xavier FC, Paiva KB, De Souza Setubal Destro MF, Moyses RA, Michaluarte P, Carvalho MB, Fukuyama EE, Tajara EH, Okamoto OK, Nunes FD Head And Neck Genome Project Gencapo. Homeobox gene expression profile indicates HOXA5 as a candidate prognostic marker in oral squamous cell carcinoma. Int J Oncol. 2012;40:1180–8. doi: 10.3892/ijo.2011.1321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Wang CC, Su KY, Chen HY, Chang SY, Shen CF, Hsieh CH, Hong QS, Chiang CC, Chang GC, Yu SL, Chen JJ. HOXA5 inhibits metastasis via regulating cytoskeletal remodelling and associates with prolonged survival in non-smallcell lung carcinoma. PLoS One. 2015;10:e0124191. doi: 10.1371/journal.pone.0124191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Lee DH, Forscher C, Di Vizio D, Koeffler HP. Induction of p53-independent apoptosis by ectopic expression of HOXA5 in human liposarcomas. Sci Rep. 2015;5:12580. doi: 10.1038/srep12580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Rhoads K, Arderiu G, Charboneau A, Hansen SL, Hoffman W, Boudreau N. A role for Hox A5 in regulating angiogenesis and vascular patterning. Lymphat Res Biol. 2005;3:240–52. doi: 10.1089/lrb.2005.3.240. [DOI] [PubMed] [Google Scholar]
  • 37.Ordonez-Moran P, Dafflon C, Imajo M, Nishida E, Huelsken J. HOXA5 counteracts stem cell traits by inhibiting wnt signaling in colorectal cancer. Cancer Cell. 2015;28:815–29. doi: 10.1016/j.ccell.2015.11.001. [DOI] [PubMed] [Google Scholar]

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