Page 21 - Read Online

Review

Roles of dysregulated Notch pathway and small DNA tumor viruses in
cancer initiation and progression

Anthony G. Clementz , Paola Rizzo , Fernanda Martini , Mauro Tognon 2
1
2
2
1 Department of Chemistry, College of Health and Sciences, DePaul University, Chicago, IL 60614, USA.
2 Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratories of Cell
Biology and Molecular Genetics, School of Medicine, University of Ferrara, 44121 Ferrara, Italy.
Correspondence to: Dr. Mauro Tognon, Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and
Experimental Biology, Laboratories of Cell Biology and Molecular Genetics, School of Medicine, University of Ferrara, 44121 Ferrara, Italy.
E-mail: tgm@unife.it

A B S T R AC T
Notch pathway is a major determinant of cell fate, and research within the last 30 years has shown dysfunctions within this
pathway in the majority of solid tumors and leukemias. The molecular mechanisms causing aberrant expression of Notch in cancer
are still partially known. Mesotheliomas, breast, and cervical cancers are among the cancer types for which the dysregulation of
Notch has been reported together with the association of simian virus 40 (SV40) or human papilloma virus (HPV) infections. In
mesotheliomas and cervical cancer, there is clear evidence that these viruses cause and rely on dysregulation of the Notch pathway
to promote and sustain cell transformation. The existence of a relationship in tumors between DNA viruses and Notch could have
an impact on cancer therapy by implementing Notch inhibition to interfere with the growth of SV40- and HPV-positive cancers. In
addition, since Notch links innate and acquired immunity and plays a key role in the regulation of the anti-viral response, targeting
Notch in the presence of oncogenic viruses infections may help prevent the onset and progression of cancers associated with the
exposure to these viruses.

Key words: Cancer; human papilloma virus; Notch; pathway; simian virus 40

INTRODUCTION Type 1 transmembrane receptor came after the identification
of a specific mutation in Drosophila melanogaster, which
Notch has been identified as a critical pathway aberrantly formed a Notch on the wing of the fly. This discovery
[1]
expressed in many types of solid tumors and leukemias. led to the naming of “Notch” to the mutated gene.
Dysregulation of Notch signaling is a result of many In Drosophila, the Notch receptor was found to encode
factors including interactions with viral proteins. In this a 300 kDa single-pass transmembrane receptor. Later,
short review, we took in consideration significant articles Notch-like molecules were identified from Caenorhabditis
dealing with the dysregulation of the Notch pathway and/ elegans (LIN-12) to humans, which are highly conserved
or presence of oncogenic viruses, mainly simian virus and play pivotal roles in development, stem cell renewal,
[2]
40 (SV40) and human papilloma viruses (HPVs), in and differentiation in postnatal tissues. In mammalians,
cancer. Indeed, the proteins encoded by Notch pathway there are four Notch Type I transmembrane receptors
genes and the viral oncoproteins of SV40 and HPV were (Notch 1, 2, 3, and 4) and five known ligands (delta-
found in some models of study, interconnected in the like 1, 3, and 4 and Jagged 1, 2). Notch signaling relies
cell transformation in vitro and tumor initiation and on cell-cell contact to initiate its eventual signaling
[3]
progression in vivo. activation. To be primed for mature Notch signaling
activation, the protein is processed first in the trans-Golgi
BASICS OF NOTCH SIGNALING apparatus by furin-like convertase creating a heterodimer,
which is shuttled to the cellular membrane and held
Beginning in the early 20th century, the discovery of a new
This is an open access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows
Access this article online others to remix, tweak, and build upon the work non-commercially, as long as
the author is credited and the new creations are licensed under the identical
Quick Response Code: terms.
Website:
www.jcmtjournal.com For reprints contact: service@oaepublish.com
How to cite this article: Clementz AG, Rizzo P, Martini F, Tognon M.
Roles of dysregulated Notch pathway and small DNA tumor viruses in
DOI: cancer initiation and progression. J Cancer Metastasis Treat 2016;2:11-23.
10.4103/2394-4722.171982
Received: 15-05-2015; Accepted: 26-11-2015

© 2016 Journal of Cancer Metastasis and Treatment ¦ Published by OAE Publishing Inc. 11