Reversible and bidirectional signaling of notch ligands.

The Notch signaling pathway is a direct cell-cell communication system involved in a wide variety of biological processes, and its disruption is observed in several pathologies. The pathway is comprised of a ligand-expressing (sender) cell and a receptor-expressing (receiver) cell. The canonical ligands are members of the Delta/Serrate/Lag-1 (DSL) family of proteins. Their binding to a Notch receptor in a neighboring cell induces a conformational change in the receptor, which will undergo regulated intramembrane proteolysis (RIP), liberating the Notch intracellular domain (NICD). The NICD is translocated to the nucleus and promotes gene transcription. It has been demonstrated that the ligands can also undergo RIP and nuclear translocation, suggesting a function for the ligands in the sender cell and possible bidirectionality of the Notch pathway. Although the complete mechanism of ligand processing is not entirely understood, and its dependence on Notch receptors has not been ruled out. Also, ligands have autonomous functions beyond Notch activation. Here we review the concepts of reverse and bidirectional signalization of DSL proteins and discuss the characteristics that make them more than just ligands of the Notch pathway.

Deregulation of the Notch pathway as a common road in viral carcinogenesis.

The Notch pathway is a conserved signaling pathway and a form of direct cell-cell communication related to many biological processes during development and adulthood. Deregulation of the Notch pathway is involved in many diseases, including cancer. Almost 20% of all cancer cases have an infectious etiology, with viruses responsible for at least 1.5 million new cancer cases per year. Seven groups of viruses have been classified as oncogenic: hepatitis B and C viruses (HBV and HCV respectively), Epstein-Barr virus (EBV), Kaposi sarcoma-associated herpesvirus (KSHV), human T lymphotropic virus (HTLV-1), human papillomavirus (HPV), and Merkel cell polyomavirus (MCPyV). These viruses share the ability to manipulate a variety of cell pathways that are critical in proliferation and differentiation, leading to malignant transformation. Viral proteins interact directly or indirectly with different members of the Notch pathway, altering their normal function. This review focuses exclusively on the direct interactions of viral oncoproteins with Notch elements, providing a deeper understanding of the dual behavior of the Notch pathway as activator or suppressor of neoplasia in virus-related cancers.

Loss of nuclear NOTCH1, but not its negative regulator NUMB, is an independent predictor of cervical malignancy.

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 (ß = -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 (ß = 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.

The role of signaling pathways in cervical cancer and molecular therapeutic targets.

Cervical cancer is a public health issue in developing countries. Although the Pap smear and colposcopy remain the major strategies for detection, most cases are diagnosed in the late stages. Therefore, a major concern has been to develop early diagnostic approaches and more effective treatments. Molecular pathways that participate in cervical malignant transformation have emerged as promising directed therapeutic targets. In this review, we explore some of the major pathways implicated in cervical cancer development, including RAF/MEK/ERK, phosphatidylinositol-3 kinase (PI3K/AKT), Wnt/b-catenin, apoptosis and coupled membrane receptor signaling. We focus on the role of these pathways in cervical carcinogenesis, their alterations and the consequences of these abnormalities. In addition, the most recent preclinical and clinical data on the rationally designed target-based agents that are currently being tested against elements of these pathways are reviewed.

Abnormal distribution of hDlg and PTEN in premalignant lesions and invasive cervical cancer.

OBJECTIVE: The aim of the present study was to evaluate differences in expression levels and localization status of PTEN, p53 and hDlg suppressor proteins in premalignant lesions and cervical cancer, and to analyze the possible correlation between them. METHODS: Expression levels (positivity/intensity) and localization (nuclear, membrane or cytoplasmic) of PTEN, hDlg and p53 were analyzed by immunohistochemistry in 43 cases with different stages of cervical intraepithelial neoplasia (CIN) and 105 invasive cervical carcinomas (ICC) (91 squamous carcinoma, 14 adenocarcinoma). Differences between proportions were evaluated. RESULTS: We found a decreased expression of PTEN in ICC that correlated with a loss of hDlg from the cell membrane. In contrast, no changes were found in p53 protein levels or localization in CIN and ICC. CONCLUSIONS: These results suggest that the abnormal expression and localization of PTEN during cervical carcinogenesis may be a consequence of modifications in the expression patterns of hDlg.