HOXB7 Predicts Poor Clinical Outcome in Patients with Advanced Esophageal Squamous Cell Cancer

Long, Qingyun; Zhou, Jun; Zhang, Xiaolong; Cao, Jianghui

doi:10.7314/apjcp.2014.15.4.1563

Cited by 6 publications

(5 citation statements)

References 24 publications

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“…But the clinical significance of HOXB7 in ESCC are rarely reported. There were two articles exploring prognostic significance of HOXB7 expression at mRNA and protein level in ESCC recently, but the sample sizes were very limited, and they did not confirm their findings in an independent cohort [25, 26]. Compared to these studies, we not only verified the reliability of our findings in two independent cohorts including 280 cases, but also studied further to explore the possible function of HOXB7 in ESCC.…”

Section: Discussionsupporting

confidence: 50%

Deregulated HOXB7 Expression Predicts Poor Prognosis of Patients with Esophageal Squamous Cell Carcinoma and Regulates Cancer Cell Proliferation In Vitro and In Vivo

Shen

Yan

et al. 2015

PLoS ONE

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BackgroundWe observed abnormal HOXB7 expression in esophageal squamous cell carcinoma (ESCC) previously. This study was to evaluate the prognostic significance of HOXB7 and reveal the potential mechanism.MethodsImmunohistochemistry was used to confirm the abnormal expression of HOXB7 in ESCC. The prognostic significance of HOXB7 expression was analyzed in two independent cohorts. RNAi was used to establish two stable HOXB7-knockdown cell strains. CCK8 assay, cell growth curve assay, colony formation assay, flow cycle analysis and tumorigenicity assay in nude mice were employed to investigate the effect of HOXB7 on proliferation in vitro and in vivo.ResultsImmunohistochemistry confirmed the abnormal expression of HOXB7 in ESCC compared with paracancerous mucosa (18/23 vs. 9/23, p=0.039). HOXB7 expression was positively correlated with the T stage, lymph node metastasis and TNM stage. The median survival of patients with high HOXB7 expression was significantly shorter than that with low expression (45 months vs. 137 months, p = 0.007 for cohort 1; 19 months vs. 34 months, p = 0.001 for cohort 2). Multivariate survival analysis showed that HOXB7 expression was another independent prognostic factor (HR [95% CI] = 0.573 [0.341–0.963], p = 0.036 for cohort 1; HR [95%CI] = 0.543 [0.350–0.844], p = 0.024 for cohort 2). Experiments in vitro and in vivo showed that after knockdown of HOXB7, the proliferation rate dropped, growth rate descended, colony-formation ability reduced, G1-phase arrest occurred and the tumorigenicity reduced remarkably.ConclusionsHOXB7 could promote cancer cell proliferation and might be an independent prognostic factor for patients with ESCC.

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Section: Discussionsupporting

confidence: 50%

Deregulated HOXB7 Expression Predicts Poor Prognosis of Patients with Esophageal Squamous Cell Carcinoma and Regulates Cancer Cell Proliferation In Vitro and In Vivo

Shen

Yan

et al. 2015

PLoS ONE

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“…To elucidate their significance in ESCC, it is necessary to clarify the association between their expression patterns and patient prognosis. It was shown that the survival time of patients with high HOXB7 or HOXC6 or HOXC8 expression was significantly shorter than that of patients with low expression, which is similar to the results of other groups . As reported, the consequences of dysregulated HOX genes in carcinogenesis can be interpreted as an extension of their normal function .…”

Section: Discussionsupporting

confidence: 86%

“…It was shown that the survival time of patients with high HOXB7 or HOXC6 or HOXC8 expression was significantly shorter than that of patients with low expression, which is similar to the results of other groups. [27][28][29] As reported, the consequences of dysregulated HOX genes in carcinogenesis can be interpreted as an extension of their normal function. [30][31][32] Given that HOX genes can be viewed as global regulators of growth and differentiation, we investigated whether they could modulate the malignant phenotype in es- Consequently, it becomes difficult to interpret these data and determine the exact contribution of any of these individual genes to a malignant phenotype.…”

Section: Discussionmentioning

confidence: 83%

Targeting HOX/PBX dimer formation as a potential therapeutic option in esophageal squamous cell carcinoma

Shen

Zhou

et al. 2019

Cancer Science

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Homeobox genes are known to be classic examples of the intimate relationship between embryogenesis and tumorigenesis, which are a family of transcriptional factors involved in determining cell identity during early development, and also dysregulated in many malignancies. Previously, HOXB7 , HOXC6 and HOXC8 were found abnormally upregulated in esophageal squamous cell carcinoma (ESCC) tissues compared with normal mucosa and seen as poor prognostic predictors for ESCC patients, and were shown to promote cell proliferation and anti‐apoptosis in ESCC cells. These three HOX members have a high level of functional redundancy, making it difficult to target a single HOX gene. The aim of the present study was to explore whether ESCC cells are sensitive to HXR9 disrupting the interaction between multiple HOX proteins and their cofactor PBX, which is required for HOX functions. ESCC cell lines (KYSE70, KYSE150, KYSE450) were treated with HXR9 or CXR9, and coimmunoprecipitation and immunofluorescent colocalization were carried out to observe HOX/PBX dimer formation. To further investigate whether HXR9 disrupts the HOX pro‐oncogenic function, CCK‐8 assay and colony formation assay were carried out. Apoptosis was assessed by flow cytometry, and tumor growth in vivo was investigated in a xenograft model. RNA‐seq was used to study the transcriptome of HXR9‐treated cells. Results showed that HXR9 blocked HOX/PBX interaction, leading to subsequent transcription alteration of their potential target genes, which are involved in JAK‐signal transducer and activator of transcription (STAT) activation and apoptosis inducement. Meanwhile, HXR9 showed an antitumor phenotype, such as inhibiting cell proliferation, inducing cell apoptosis and significantly retarding tumor growth. Therefore, it is suggested that targeting HOX/PBX may be a novel effective treatment for ESCC.

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“…In our previous study, we demonstrated that HOXB7 was overexpressed in ESCC tissues to promote oncogenic properties and was predictive of a poor prognosis in ESCC 15 . Moreover, other studies have also confirmed this 31,32 . However, to our knowledge, whether HOXB7 is correlated with chemoresistance in ESCC has not previously been addressed.…”

Section: Discussionmentioning

confidence: 81%

“…15 Moreover, other studies have also confirmed this. 31,32 However, to our knowledge, whether HOXB7 is correlated with chemoresistance in ESCC has not previously been addressed. In the present study, high expression of HOXB7 was determined to be associated with cisplatin resistance in ESCC cells and chemotherapy efficacy of ESCC patients.…”

Section: Discussionmentioning

confidence: 98%

HOXB7 mediates cisplatin resistance in esophageal squamous cell carcinoma through involvement of DNA damage repair

Zhou

Dong

et al. 2019

Thoracic Cancer

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Background DNA damage repair is an important mechanism of platinum resistance. HOXB7 is one member of HOX family genes, which are essential developmental regulators and frequently dysregulated in cancer. Recently, its relevance in chemotherapy resistance and DNA damage repair has also been addressed. However, little is known regarding the association between HOXB7 and chemotherapy resistance in esophageal squamous cell carcinoma (ESCC). Methods The association between HOXB7 expression detected by immunohistochemisty and tumor regression grade (TRG) and long‐term survival was analyzed in 143 ESCC patients who underwent neoadjuvant chemotherapy. CCK8 assay was used to examine the effect of cisplatin in a panel of four ESCC cell lines. A stable cell strain with HOXB7 knockdown of KYSE150 and KYSE450 was established to explore the effect on cisplatin sensitivity. The interaction of HOXB7 with Ku70, Ku80 and DNA‐PKcs was determined by GST‐pull down, coimmunoprecipitation and immunofluorescent colocalization. Finally, we investigated whether disrupting HOXB7 function by a synthetic peptide HXR9 blocking the formation of HOXB7/PBX could enhance cisplatin sensitivity in vitro and in vivo. Results High expression of HOXB7 was associated with cisplatin resistance and worse chemotherapy efficacy. HOXB7 knockdown reinforced cisplatin sensitivity. It was identified that HOXB7 interacts with Ku70, Ku80 and DNA‐PKcs. HOXB7 knockdown was related to the downregulation of Ku70, Ku80 and DNA‐PKcs as well as arrested cell cycle in S phase. HOXB7 inhibition by HXR9 had a synergistic effect to improve cisplatin sensitivity. Conclusion HOXB7 may be a biomarker for the prediction of chemoresistance of ESCC and serves as a promising therapeutic target.

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HOXB7 Predicts Poor Clinical Outcome in Patients with Advanced Esophageal Squamous Cell Cancer

Cited by 6 publications

References 24 publications

Deregulated HOXB7 Expression Predicts Poor Prognosis of Patients with Esophageal Squamous Cell Carcinoma and Regulates Cancer Cell Proliferation In Vitro and In Vivo

Deregulated HOXB7 Expression Predicts Poor Prognosis of Patients with Esophageal Squamous Cell Carcinoma and Regulates Cancer Cell Proliferation In Vitro and In Vivo

Targeting HOX/PBX dimer formation as a potential therapeutic option in esophageal squamous cell carcinoma

HOXB7 mediates cisplatin resistance in esophageal squamous cell carcinoma through involvement of DNA damage repair

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