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inhibitors (GSI-I Z-Leu-Leu-Nle-CHO and LY-411, 575), Notch1. Suppression of miR-27a expression in HBERST
small molecules which block Notch activation, resulted cells leads to cell cycle arrest in the G0-G1 phase. [156]
in apoptosis in KS cells and established KS cell tumors in
mice, demonstrating the requirement for an active Notch Both SV40 Tag and tag have been shown to induce the
signaling in KS. [150] Notch pathway interactions have also immortalization of mammary gland epithelial cells. [157,158]
been shown with adenoviral oncoprotein 13S E1A, which SV40 tag expression inhibits mammary gland differentiation
binds to CSL, displaces associated corepressor complexes, during mid-pregnancy and about 10% of multiparous tag
and activates CSL-dependent gene expression. [151] transgenic animals develop breast tumors with latencies
ranging from 10 to 17 months, whereas expression of
In agreement with reports of an association between SV40 N-terminal truncated Tag molecules harboring the intact
infection and human mesothelioma, [152] SV40 infection p53 and pRB binding region does not have this effect. [158]
upregulates the expression of Notch1 in mesothelial Expression of SV40 Tag in the epithelium of the mammary
cells. [153] SV40-mediated Notch1 induction is achieved at glands results in cancers which resemble the human disease
the transcriptional level; it requires both SV40 Tag and tag and do not require hormone supplementation or pregnancy
and tag-induced activation of the mitogen-activated protein for insurgence. [157] Breast cancer has been associated
kinase-extracellular-signal-regulated kinase pathway. Notch to SV40 infection [159] and a specific gene signature in
activation is necessary for the growth of SV40-transformed transgenic models of breast cancer intrinsic to the functions
mesothelial cells, as treatment of these cells with a Notch of the SV40 T/t-antigens has been identified which is
inhibitor leads to G2/M cell cycle arrest. [153] Consistently, associated with poor prognosis. [160] It is not known whether
upregulation of Notch1 and ligands Jagged1 and 2 is SV40 is involved in the dysregulation of Notch signaling
maintained in SV40-transformed human mesothelial clones observed in breast cancer. [19,152] Of interest, the Notch target
and SV40-positive mesotheliomas and derived cell lines. [153] gene cyclin D1 is overexpressed in the SV40 tag-positive
mammary gland epithelial cells and in the breast tumor
Other than in mesothelial cells, Notch1 expression and cells from SV40 tag-expressing mice. [157]
signaling has been linked to SV40-mediated transformation
of primary astrocytes. [154] In both mesothelial cells and HPV is the most significant causative agent in the
astrocytes, SV40-mediated activation of Notch signaling development of cervical cancer. Despite its presence in
determines the survival of cells grown in suspension. Of almost all cervical cancers, it is widely recognized that
interest, the archetypal (1 copy of enhancer sequence in HPV by itself is unable to transform a normal cell to
the regulatory region) and the non-archetypal (2 copies of a cancerous one, and additional cellular mutations are
enhancer sequences in the regulatory region) SV40 strains required to supplement the HPV oncoproteins E6 and E7.
are both able to transform astrocytes whether only the non- The activation of the Notch signaling pathway induced by
archetypal strain can transform mesothelial cells. Differences HPV infection has been proposed as one of the cellular
in expression levels of Notch1 and its downstream effectors changes that cooperate with the E6 and E7 proteins to
(c-Myc, Hey1, Hes1 and HeyL) appear to explain these cause cervical cancers. [161] This proposition is based on
differences in SV40-mediated transformation of primary several studies showing overexpression of Notch signaling
astrocytes and mesothelial cells. [154] in HPV-cervical cancer or cell lines. Specifically, active
Notch1 expression has been shown in high-grade cervical
SV40 tag, which forms a complex and inhibits PP2A lesions and cancers [162,163] and progressively increasing up-
activity, plays a critical role in the malignant transformation regulation of Notch3 expression with severity of disease
of human cells. Microarray analyses on human embryonic as compared to normal cervix tissue has been reported
kidney cell lines overexpressing SV40 tag have identified in a set of 168 tissue biopsy samples comprising of
induction of Dll1 and Jagged1 suggesting a role for SV40 tumor specimens, precancer, and non-neoplastic cervical
tag in the activation of the Notch pathway. [155] Of interest, tissues. [164] Noteworthy, in the same specimens, Notch1
in these cells, Notch signaling was found to be upregulated was found to be downregulated thus suggesting the
in association with Hedgehog and Wnt pathways but existence of a complex interplay between Notch signaling
inhibition of Hedgehog and not of Notch interfered with and HPV in the context of the development of cervical
cell survival suggesting that Notch signaling is not essential carcinogenesis. [164] Upregulation of both Jagged1 and Hes1
for survival in cells expressing SV40 tag. [155] A link between and downregulation of Manic Fringe, a negative regulator of
SV40 tag and Notch has been observed also in human Jagged1-Notch1 signaling, have been shown in squamous
bronchial epithelial cells. Specifically, Wang et al. have cell carcinoma of cervix compared to high-grade lesions
shown that miR-27a is upregulated in SV40 tag-transformed and in late-passage, but not early-passage, HPV type
human bronchial epithelial cells (HBERST) following the 16-positive human cervical low-grade lesion-derived cell
interaction between tag and PP2A. In these cells, miR- line W12. [165] Overexpression of all Notch receptors, Hes1,
27a promotes cell cycle progression by downregulating and MAML1, the transcriptional co-activator originally
Fbxw7, a regulator of ubiquitin-dependent proteolysis of a identified by its role in Notch signaling, has been found in
set of protein involved in cell cycle progression, including HeLa, SiHa, and CaSki, three other cell lines derived from

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