Abstract
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.
Highlights
Invasive cervical cancer (ICC) is the fourth most common malignancy among women worldwide, with an estimated 528,000 new cases and 266,000 deaths in 2012 and with 87% of cervical cancer deaths occurring in less developed regions [1]
We found that nuclear NOTCH1 expression was more frequently found in cervical intraepithelial neoplasia (CIN) samples compared with invasive cervical cancer (ICC) (77.55% vs. 15.79%, p = 0.001)
We showed that ICC samples exhibited lower NOTCH1 expression than CIN samples and that this differential expression is related to higher NUMB expression
Summary
Invasive cervical cancer (ICC) is the fourth most common malignancy among women worldwide, with an estimated 528,000 new cases and 266,000 deaths in 2012 and with 87% of cervical cancer deaths occurring in less developed regions [1]. Infection with human papillomaviruses (HPVs) has been well documented as the main etiological factor for ICC since the viral genome is present in practically all cervical cancer tumors [3]. 13 HPV genotypes have been defined as carcinogenic or high-risk (HR) viral types for cervical cancer [4]. In the canonical Notch pathway, a transmembrane Notch receptor (NOTCH 1–4) interacts with Delta-Serrate-Lag-type (Dll, Dll, Dll, Jagged or Jagged2) ligands. This interaction triggers the sequential proteolytic cleavage of the Notch receptor, releasing the intracellular domain (NICD), which translocates to the nucleus and activates the transcription of target genes, including Hes, Hes, Hey, Cyclin D1 and Myc [7,8,9]
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