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HPV-positive human cervical cancer. [166] Evidence in favor with Notch1 receptor stimulation, and it did not lead to
of an oncogenic role for Notch in cervical cancer comes growth arrest, increased p21 (Waf1/CIP1), or decreased
from the observation that activated Notch1 synergizes proliferative factor Ki67. [173]
with HPV16 E6 and E7 proteins in conferring apoptosis
protection through the activation of the prosurvival PI3K- Notch signaling pathway is a key determinant of
protein kinase B/AKT (PI3K-PKB/AKT) pathway and in keratinocyte growth arrest and differentiation. [174] and it
the transformation of the immortalized human keratinocytes has been recently shown that it promotes expression of
HaCaT cell line. [167] Furthermore, in HaCat cells active differentiation markers acting together with the TAp63β
Notch1, through the PI3K-PKB/AKT-dependent pathway, isoform of the p63 transcription factor. [175] This evidence
inhibits p53-induced apoptosis and sustains transformation supports a role for Notch as putative tumor suppressor in
by HPV 16 E6 and E7. [168] Consistently with the findings HPV-associated tumorigenesis rather than an oncogene, as
of high level of Jagged1 in cervical cancer, Jagged1 but discussed so far. It is well established that Notch activity
not Dll1 expression correlates with the rapid induction of regulates tumor biology in a context-dependent manner and
PI3K-mediated epithelial-mesenchymal transition both in may act as an oncogene or a tumor-suppressor gene within
HaCaT cells and in a human cervical tumor-derived cell the same tumor type. In human, esophageal keratinocytes
line. [169] Microarray studies by the same authors show that overexpression of Notch1 induces senescence (induction
Notch-PI3K oncogenic functions can be independent of of G0/G1 cell-cycle arrest, Rb dephosphorylation, flat
CSL activation and rely instead on Deltex 1, an alternative and enlarged cell morphology, and senescence-associated
Notch effector. [169] The anti-apoptotic role played by Notch beta-galactosidase activity) requiring both canonical CSL-
in cervical cancer progression has also been revealed dependent transcriptional activity and the p16INK4A-Rb
by immunohistochemistry conducted in cervical cancer pathway. Loss of p16INK4A or the presence of HPVE6/E7
specimens in which high levels of Jagged1, Hes1, and Cdk9 oncogene products (which inactivate both the p53 and pRB)
were paralleled by nuclear translocation of both NF-κB p50 in these cells have been shown not only to prevent intra-
and p65 and NF-κB target genes expression (IκB-α, B-cell cellular Notch1 (N1IC) from inducing senescence, but also
lymphoma 2 and cyclin D1). [170] An active Notch pathway to facilitate N1IC-mediated anchorage-independent colony
is necessary for the survival and the maintenance of the formation and xenograft tumor growth with increased cell
neoplastic phenotype of HPV-positive cervical cancer proliferation and reduced squamous-cell differentiation. [176]
cell lines as demonstrated by experiments in which Notch These observations provide a possible molecular mechanism
signaling was inhibited by anti-sense Notch1 oligo, [46,171] to explain and support the hypothesis of the oncogenic role
by upregulation of Manic Fringe, [165] by small interfering on Notch in HPV-positive cervical cancer.
RNA against Jagged1 [165] or by inhibition of γ-secretase in
combination with dominant negative MAML1, a regulator In agreement with a protective role of Notch against
of crosstalk between the Notch and NF-κB pathways. [166] HPV-induced transformation, Talora et al. have reported
that the expression of the endogenous Notch1 gene
Experimental evidence shows that as with SV40, HPV is markedly reduced in a panel of cervical carcinoma
proteins have a direct effect on the activation of Notch cells, whereas expression of Notch2 remains elevated,
signaling. Weijzen et al. have reported that transfection and Notch1 expression is reduced or absent in invasive
of mouse primary embryonic cells and human primary cervical cancers. [177] The authors show that increased
fibroblasts with HPV16 E6 and E7 upregulates Notch1 Notch1 signaling, but not Notch2, causes a dramatic down-
not only transcriptionally but also post-translationally modulation of HPV-driven transcription of the E6/E7
by upregulating presenilin-1, a protein involved in Notch viral genes, through suppression of AP-1 activity by up-
processing. Microarray analyses have revealed enhanced regulation of the Fra-1 family member and decreased c-Fos
[46]
expression of Notch1 mRNA in HPV16 E6-expressing expression. According to the authors, the downmodulation
keratinocytes when NFX1-123 (a protein involved, together of Notch1 expression would play an important role in late
with E6, in binding and stabilization of mRNA coding for stages of HPV-induced carcinogenesis. [177] In agreement
human telomerase reverse transcriptase, the catalytic sub- with these observations, E6 protein from cutaneous HPVs
unit of telomerase) was overexpressed. A moderate increase of the β-genus, such as bovine papillomavirus Type 1 and
in Notch1 mRNA was seen with overexpression of NFX1- β-HPV5 and 8, induces a repression of Notch transcriptional
123 alone, but with 16E6 coexpression the increase in activation, which is dependent on an interaction with
Notch1 was enhanced. [172] A recent study by the same group MAML1 [178-180] and it has been shown to inhibit keratinocyte
has shown that the Notch canonical pathway genes Hes1 differentiation. [181]
and Hes5 were increased with overexpression of NFX1-123
in 16E6 - expressing keratinocytes, and their expression Technical approaches (type of anti-body used) for Notch
was directly linked to the activation or blockade of the detection have been invoked to explain the differences in
Notch1 receptor. Of interest, keratin 1 and keratin 10 were expression levels of Notch in HPV-positive cervical tumors
also increased in this model, but in contrast to Notch target linked to the different roles of Notch as an oncogene or tumor
genes, their upregulation was only indirectly associated suppressor gene. [182] As previously discussed, the opposite

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ Issue 1 ¦ January 15, 2016 ¦ 17