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. 2022 Nov 9;12(22):3082.
doi: 10.3390/ani12223082.

BUBR1 as a Prognostic Biomarker in Canine Oral Squamous Cell Carcinoma

Leonor Delgado  1   2 , Luís Monteiro  1   3 , Patrícia Silva  1   4 , Hassan Bousbaa  1 , Fernanda Garcez  1 , João Silva  1 , Paula Brilhante-Simões  2 , Isabel Pires  5   6 , Justina Prada  5   6
Affiliations

BUBR1 as a Prognostic Biomarker in Canine Oral Squamous Cell Carcinoma

Leonor Delgado et al. Animals (Basel). .

Abstract

Chromosomal instability (CIN) plays a key role in the carcinogenesis of several human cancers and can be related to the deregulation of core components of the spindle assembly checkpoint (SAC) including BUBR1 protein kinase. These proteins have been related to tumor development and poor survival rates in human patients with oral squamous cell carcinoma (OSCC). To investigate the expression of the SAC proteins BUBR1, BUB3 and SPINDLY and also Ki-67 in canine OSCC, we performed an immunohistochemical evaluation in 60 canine OSCCs and compared them with clinical and pathological variables. BUBR1, Ki-67, BUB3 and SPINDLY protein expressions were detected in all cases and classified as with a high-expression extent score in 31 (51.7%) cases for BUBR1, 33 (58.9%) cases for BUB3 and 28 (50.9%) cases for SPINDLY. Ki-67 high expression was observed in 14 (25%) cases. An independent prognostic value for BUBR1 was found, where high BUBR1 expression was associated with lower survival (p = 0.012). These results indicate that BUBR1 expression is an independent prognostic factor in these tumors, suggesting the potential use for clinical applications as a prognostic biomarker and also as a pharmacological target in canine OSCC.

Keywords: BUB3; BUBR1; Ki-67; SPINDLY; immunohistochemistry; oral cancer; prognostic markers; survival.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The Spindle assembly checkpoint mechanism. (A) In the presence of unattached or misattached kinetochores (red circle), the spindle assembly checkpoint is turned on (SAC ON) and the kinetochore proteins BUB3, BUBR1, MAD2 and CDC20 assemble at the cytosol to form the mitotic checkpoint complex (MCC). Once the MCC is generated, the CDC20 becomes unable to bind to the anaphase-promoting complex/cyclosome (APC/C), leading to mitotic arrest at the metaphase to anaphase transition. (B) Upon appropriate kinetochore microtubule attachments, the SAC is turned off (SAC OFF) through dynein/SPINDLY-mediated stripping of BUB3, BUBR1, MAD2 and CDC20 from attached kinetochores, which prevents the assembly of new MCC and through disassembly of existing MCC (not shown). Both mechanisms release CDC20 which, thus, binds to and activates the APC/C, promoting mitosis exit.
Figure 2
Figure 2
Immunohistochemical (IHC) staining of the BUBR1 in canine OSCC (a–d) showing high expression (extent and intensity) (a,b) and low expression (extent and intensity) (c,d) of the biomarker. Figures (b,d) correspond to a higher magnification of the white square indicated in cases (a,c), respectively.
Figure 3
Figure 3
Immunohistochemical (IHC) staining of the BUB3 in canine OSCC (a–d) showing high expression (extent and intensity) (a,b) and low expression (extent and intensity) (c,d) of the biomarker. Figures (b,d) correspond to a higher magnification of the white square indicated in cases (a,c), respectively.
Figure 4
Figure 4
Immunohistochemical (IHC) staining of the SPINDLY in canine OSCC (a–d) showing high expression (extent and intensity) (a,b) and low expression (extent and intensity) (c,d) of the biomarker. Figures (b,d) correspond to a higher magnification of the white square indicated in cases (a,c), respectively.
Figure 5
Figure 5
Immunohistochemical (IHC) staining of the Ki-67 in canine OSCC (a–d) showing high expression (a,b) and low expression (c,d) of the biomarker. Figures (b,d) correspond to a higher magnification of the white square indicated in cases (a,c), respectively.
Figure 6
Figure 6
Immunohistochemical (IHC) staining of the BUBR1 (a,b), SPINDLY (c,d) and Ki-67 (e,f) in the same case of canine OSCC, showing high expression of all biomarkers. Figures (b,d,f) correspond to a higher magnification of the white square indicated in cases (a,c,e), respectively.
Figure 7
Figure 7
Kaplan–Meier curves of CSS analysis according to BUBR1 extent score.
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References

    1. Vail D.M., Thamm D., Liptak J. Withrow and MacEwen’s Small Animal Clinical Oncology—E-Book. Elsevier Health Sciences; Amsterdam, The Netherlands: 2019.
    1. Munday J.S., French A., Harvey C.J. Molecular and immunohistochemical studies do not support a role for papillomaviruses in canine oral squamous cell carcinoma development. Vet. J. 2015;204:223–225. doi: 10.1016/j.tvjl.2015.03.002. - DOI - PubMed
    1. Thaiwong T., Sledge D.G., Wise A.G., Olstad K., Maes R.K., Kiupel M. Malignant transformation of canine oral papillomavirus (CPV1)-associated papillomas in dogs: An emerging concern? Papillomavirus Res. 2018;6:83–89. doi: 10.1016/j.pvr.2018.10.007. - DOI - PMC - PubMed
    1. Warnakulasuriya S. Causes of oral cancer—An appraisal of controversies. Br. Dent. J. 2009;207:471–475. doi: 10.1038/sj.bdj.2009.1009. - DOI - PubMed
    1. Fulton A.J., Nemec A., Murphy B.G., Kass P.H., Verstraete F.J.M. Risk factors associated with survival in dogs with nontonsillar oral squamous cell carcinoma 31 cases (1990–2010) J. Am. Vet. Med. Assoc. 2013;243:696–702. doi: 10.2460/javma.243.5.696. - DOI - PubMed

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