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HOXA1 is overexpressed in oral squamous cell carcinomas and its expression is correlated with poor prognosis.

Bitu CC, Destro MF, Carrera M, da Silva SD, Graner E, Kowalski LP, Soares FA, Coletta RD - BMC Cancer (2012)

Bottom Line: In particular, HOXA1, which has been described as one of the HOX members that plays an important role in tumorigenesis, was significantly more expressed in OSCCs compared to healthy oral mucosas.Further analysis demonstrated that overexpression of HOXA1 in HaCAT human epithelial cells promotes proliferation, whereas downregulation of HOXA1 in human OSCC cells (SCC9 cells) decreases it.A high number of HOXA1-positive cells was significantly associated with T stage, N stage, tumor differentiation and proliferative potential of the tumors, and was predictive of poor survival.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Oral Diagnosis, School of Dentistry, State University of Campinas, CP 52, CEP 13414-018 Piracicaba, São Paulo, Brazil. coletta@fop.unicamp.br

ABSTRACT

Background: HOX genes encode homeodomain-containing transcription factors involved in the regulation of cellular proliferation and differentiation during embryogenesis. However, members of this family demonstrated oncogenic properties in some malignancies. The present study investigated whether genes of the HOXA cluster play a role in oral cancer.

Methods: In order to identify differentially expressed HOXA genes, duplex RT-PCR in oral samples from healthy mucosa and squamous cell carcinoma was used. The effects of HOXA1 on proliferation, apoptosis, adhesion, invasion, epithelial-mesenchymal transition (EMT) and anchorage-independent growth were assessed in cells with up- and down-regulation of HOXA1. Immunohistochemical analysis using a tissue microarray (TMA) containing 127 oral squamous cell carcinomas (OSCC) was performed to determine the prognostic role of HOXA1 expression.

Results: We showed that transcripts of HOXA genes are more abundant in OSCC than in healthy oral mucosa. In particular, HOXA1, which has been described as one of the HOX members that plays an important role in tumorigenesis, was significantly more expressed in OSCCs compared to healthy oral mucosas. Further analysis demonstrated that overexpression of HOXA1 in HaCAT human epithelial cells promotes proliferation, whereas downregulation of HOXA1 in human OSCC cells (SCC9 cells) decreases it. Enforced HOXA1 expression in HaCAT cells was not capable of modulating other events related to tumorigenesis, including apoptosis, adhesion, invasion, EMT and anchorage-independent growth. A high number of HOXA1-positive cells was significantly associated with T stage, N stage, tumor differentiation and proliferative potential of the tumors, and was predictive of poor survival. In multivariate analysis, HOXA1 was an independent prognostic factor for OSCC patients (HR: 2.68; 95% CI: 1.59-2.97; p = 0.026).

Conclusion: Our findings indicate that HOXA1 may contribute to oral carcinogenesis by increasing tumor cell proliferation, and suggest that HOXA1 expression might be helpful as a prognostic marker for patients with OSCC.

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Expression of HOXA1 is associated with shortened overall survival of patients with OSCC. (A) The overall survival analysis according to the Kaplan-Meier method for HOXA1 immunoexpression revealed that high HOXA1 expression is associated with poor prognosis with a 5-year survival of 55.5% (p = 0.0073). (B) Disease-specific overall survival for patients with high expression of HOXA1 was even shorter (p = 0.0048). (C) Five-year disease-free survival was not associated with HOXA1 immunoexpression in OSCC tumors (p = 0.27).
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Figure 6: Expression of HOXA1 is associated with shortened overall survival of patients with OSCC. (A) The overall survival analysis according to the Kaplan-Meier method for HOXA1 immunoexpression revealed that high HOXA1 expression is associated with poor prognosis with a 5-year survival of 55.5% (p = 0.0073). (B) Disease-specific overall survival for patients with high expression of HOXA1 was even shorter (p = 0.0048). (C) Five-year disease-free survival was not associated with HOXA1 immunoexpression in OSCC tumors (p = 0.27).

Mentions: High HOXA1 immunoreactivity was a marker of reduced overall survival with a 5-year survival of 55.5% (95% CI 42.4-76.4) for the patients with strong positivity for HOXA1 compared with 76.8% (95% CI 60.7-88.1) for those with low HOXA1 expression (p = 0.007; Figure 6A). The 5-year disease-specific survival was even shortened. Patients with high HOXA1 expression showed a 5-year disease-specific survival of 49.2% (95% CI 32.3-61.7) compared with 72.8% (95% CI 62.3-91.3) for patients with low HOXA1 immunoreactivity (p = 0.0048; Figure 6B). No significant influence of HOXA1 immunoexpression in the disease-free survival was observed in this cohort (Figure 6C). Multivariate analysis was performed to assess the independent predictive value of HOXA1, including variables that demonstrated a statistical correlation with HOXA1. In this analysis, high HOXA1 immunopositivity with a hazard ratio (HR) of 2.68 (95% IC 1.59-2.97, p = 0,026) and regional metastasis at diagnosis (N stage) with a HR of 1.74 (95% IC 1.20-2.52, p = 0.017) remained as independent prognostic factors (Table 2).


HOXA1 is overexpressed in oral squamous cell carcinomas and its expression is correlated with poor prognosis.

Bitu CC, Destro MF, Carrera M, da Silva SD, Graner E, Kowalski LP, Soares FA, Coletta RD - BMC Cancer (2012)

Expression of HOXA1 is associated with shortened overall survival of patients with OSCC. (A) The overall survival analysis according to the Kaplan-Meier method for HOXA1 immunoexpression revealed that high HOXA1 expression is associated with poor prognosis with a 5-year survival of 55.5% (p = 0.0073). (B) Disease-specific overall survival for patients with high expression of HOXA1 was even shorter (p = 0.0048). (C) Five-year disease-free survival was not associated with HOXA1 immunoexpression in OSCC tumors (p = 0.27).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3351375&req=5

Figure 6: Expression of HOXA1 is associated with shortened overall survival of patients with OSCC. (A) The overall survival analysis according to the Kaplan-Meier method for HOXA1 immunoexpression revealed that high HOXA1 expression is associated with poor prognosis with a 5-year survival of 55.5% (p = 0.0073). (B) Disease-specific overall survival for patients with high expression of HOXA1 was even shorter (p = 0.0048). (C) Five-year disease-free survival was not associated with HOXA1 immunoexpression in OSCC tumors (p = 0.27).
Mentions: High HOXA1 immunoreactivity was a marker of reduced overall survival with a 5-year survival of 55.5% (95% CI 42.4-76.4) for the patients with strong positivity for HOXA1 compared with 76.8% (95% CI 60.7-88.1) for those with low HOXA1 expression (p = 0.007; Figure 6A). The 5-year disease-specific survival was even shortened. Patients with high HOXA1 expression showed a 5-year disease-specific survival of 49.2% (95% CI 32.3-61.7) compared with 72.8% (95% CI 62.3-91.3) for patients with low HOXA1 immunoreactivity (p = 0.0048; Figure 6B). No significant influence of HOXA1 immunoexpression in the disease-free survival was observed in this cohort (Figure 6C). Multivariate analysis was performed to assess the independent predictive value of HOXA1, including variables that demonstrated a statistical correlation with HOXA1. In this analysis, high HOXA1 immunopositivity with a hazard ratio (HR) of 2.68 (95% IC 1.59-2.97, p = 0,026) and regional metastasis at diagnosis (N stage) with a HR of 1.74 (95% IC 1.20-2.52, p = 0.017) remained as independent prognostic factors (Table 2).

Bottom Line: In particular, HOXA1, which has been described as one of the HOX members that plays an important role in tumorigenesis, was significantly more expressed in OSCCs compared to healthy oral mucosas.Further analysis demonstrated that overexpression of HOXA1 in HaCAT human epithelial cells promotes proliferation, whereas downregulation of HOXA1 in human OSCC cells (SCC9 cells) decreases it.A high number of HOXA1-positive cells was significantly associated with T stage, N stage, tumor differentiation and proliferative potential of the tumors, and was predictive of poor survival.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Oral Diagnosis, School of Dentistry, State University of Campinas, CP 52, CEP 13414-018 Piracicaba, São Paulo, Brazil. coletta@fop.unicamp.br

ABSTRACT

Background: HOX genes encode homeodomain-containing transcription factors involved in the regulation of cellular proliferation and differentiation during embryogenesis. However, members of this family demonstrated oncogenic properties in some malignancies. The present study investigated whether genes of the HOXA cluster play a role in oral cancer.

Methods: In order to identify differentially expressed HOXA genes, duplex RT-PCR in oral samples from healthy mucosa and squamous cell carcinoma was used. The effects of HOXA1 on proliferation, apoptosis, adhesion, invasion, epithelial-mesenchymal transition (EMT) and anchorage-independent growth were assessed in cells with up- and down-regulation of HOXA1. Immunohistochemical analysis using a tissue microarray (TMA) containing 127 oral squamous cell carcinomas (OSCC) was performed to determine the prognostic role of HOXA1 expression.

Results: We showed that transcripts of HOXA genes are more abundant in OSCC than in healthy oral mucosa. In particular, HOXA1, which has been described as one of the HOX members that plays an important role in tumorigenesis, was significantly more expressed in OSCCs compared to healthy oral mucosas. Further analysis demonstrated that overexpression of HOXA1 in HaCAT human epithelial cells promotes proliferation, whereas downregulation of HOXA1 in human OSCC cells (SCC9 cells) decreases it. Enforced HOXA1 expression in HaCAT cells was not capable of modulating other events related to tumorigenesis, including apoptosis, adhesion, invasion, EMT and anchorage-independent growth. A high number of HOXA1-positive cells was significantly associated with T stage, N stage, tumor differentiation and proliferative potential of the tumors, and was predictive of poor survival. In multivariate analysis, HOXA1 was an independent prognostic factor for OSCC patients (HR: 2.68; 95% CI: 1.59-2.97; p = 0.026).

Conclusion: Our findings indicate that HOXA1 may contribute to oral carcinogenesis by increasing tumor cell proliferation, and suggest that HOXA1 expression might be helpful as a prognostic marker for patients with OSCC.

Show MeSH
Related in: MedlinePlus