Loss of nuclear NOTCH1, but not its negative regulator NUMB, is an independent predictor of cervical malignancy
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Elenaé Vázquez-Ulloa1, Ana Clara Ramos-Cruz2, Diddier Prada2,3, Alejandro Avilés-Salas4, Alma Delia Chávez-Blanco2, Luis A. Herrera2,5, Marcela Lizano2,5 and Adriana Contreras-Paredes2
1Programa de Maestría y Doctorado en Ciencias Bioquímicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City, México
2Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, México
3Departamento de Informática Biomédica, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, México
4Departamento de Patología Quirúrgica, Instituto Nacional de Cancerología, Mexico City, México
5Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, México
Adriana Contreras-Paredes, email: [email protected]
Marcela Lizano, email: [email protected]
Keywords: cervical cancer; cervical intraepithelial neoplasia; NOTCH1; NUMB; immunostaining
Received: June 20, 2017 Accepted: February 24, 2018 Published: April 10, 2018
The participation of NOTCH signaling in invasive cervical cancer (ICC) remains controversial since both tumor suppressive and oncogenic properties have been described. Additionally, the role of NUMB, a negative regulator of NOTCH, remains unclear in ICC. We aimed to investigate the role of NOTCH1 and NUMB expression and their localization in cervical intraepithelial neoplasia (CIN) and ICC samples. A total of 144 biopsies were obtained from the Instituto Nacional de Cancerología, México from 2004 to 2017, and were subjected to immunohistochemistry for NOTCH1 and NUMB. We found that nuclear NOTCH1 expression was more frequently found in CIN samples compared with ICC (77.55% vs. 15.79%, p = 0.001). NUMB was almost exclusively found in the nucleus of CIN samples (32.65% vs. 6.32%, p = 0.001). Cytoplasmic expression of NOTCH1 (44.21%) and NUMB (35.79%) was the most frequent localization in ICC. Multivariable-adjusted analysis showed that the loss of nuclear NOTCH1 expression was an independent predictor of malignancy (β = –3.428, 95% confidence interval [95% CI] = –5.127, –1.728, p = 0.001). In contrast, the association between cytoplasmic NUMB expression and cervical cancer was lost after adjusting for nuclear NOTCH1 expression (β = 2.074, 95% [CI] = –0.358, 4.506, P = 0.094). Additionally, patients with cytoplasmic NOTCH1 expression showed a borderline association with longer overall survival (OS) than those with nuclear NOTCH1 expression (P = 0.08). Our data suggest that the loss of nuclear NOTCH1 but not NUMB might be an independent predictor of malignancy in cervical cancer.
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