Notch Signaling in CD66+ Cells Drives the Progression of Human Cervical Cancers

Bajaj, Jeevisha; Maliekal, Tessy Thomas; Vivien, Eric; Pattabiraman, Chitra; Srivastava, Sweta; Krishnamurthy, Hanumanthappa; Giri, Venkat G.; Subramanyam, Deepa; Krishna, Sudhir

doi:10.1158/0008-5472.can-11-0543

Cited by 32 publications

(44 citation statements)

References 47 publications

(54 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In cervical cancer specifically, investigators have found decreased Notch1 expression (27)(28)(29). Conversely, others have found increased Notch1 expression during cervical cancer development (30)(31)(32) and increased Notch1 expression and activation by the HR E6 and E7 oncogenes (33), which leads to improved cell growth (34,35). Our findings support the positive regulation of Notch1 by 16E6 and NFX1-123.…”

supporting

confidence: 74%

NFX1-123 and Human Papillomavirus 16E6 Increase Notch Expression in Keratinocytes

Vliet-Gregg¹,

Hamilton²,

Katzenellenbogen

2013

J Virol

View full text Add to dashboard Cite

The high-risk human papillomavirus (HR HPV) E6 oncoprotein binds host cell proteins to dysregulate multiple regulatory pathways, including apoptosis and senescence. HR HPV16 E6 (16E6) interacts with the cellular protein NFX1-123, and together they posttranscriptionally increase hTERT expression, the catalytic subunit of telomerase. NFX1-123 interacts with hTERT mRNA and stabilizes it, leading to greater telomerase activity and the avoidance of cellular senescence. Little is known regarding what other transcripts are dependent on or augmented by the association of NFX1-123 with 16E6. Microarray analysis revealed enhanced expression of Notch1 mRNA in 16E6-expressing keratinocytes when NFX1-123 was overexpressed. A moderate increase in Notch1 mRNA was seen with overexpression of NFX1-123 alone, but with 16E6 coexpression the increase in Notch1 was enhanced. The PAM2 motif and R3H protein domains in NFX1-123, which were important for increased hTERT expression, were also important in the augmentation of Notch1 expression by 16E6. These findings identify a second gene coregulated by 16E6 and NFX1-123 and the protein motifs in NFX1-123 that are important for this effect. Human papillomaviruses (HPVs) are nonenveloped doublestranded DNA viruses. Of the more than 150 HPVs that have been identified to date, over 30 types are capable of infecting the genital and oral mucosa. HPVs that infect mucosa are divided into low-risk (LR) and high-risk (HR) categories based on their associated risk for anogenital and, increasingly, head and neck cancers (1-11). As these HR HPV infections are linked to malignancies, much focus has been placed on studying the cellular changes these viruses trigger that lead to cancer and on studying the functions of two oncogenes expressed by HR HPV, E6 and E7.HR E6 induces oncogenic changes primarily through its interactions with host cell proteins, and those interactions block apoptotic signaling and drive cellular immortalization (for a review, see reference 12). E6-associated protein (E6AP) is an E3 ubiquitin ligase that is the most well-studied protein partner of HR E6 (13-19). However, HR E6 interacts with other cellular proteins, such as NFX1 splice variants, and these are important in oncogenesis as well (20,21).In human epithelial cells, NFX1 is a gene expressed as two splice variants, . NFX1-91 has been shown to transcriptionally repress telomerase expression in epithelial cells, and HR HPV 16E6 with E6AP targets NFX1-91 for degradation (22,23). Our work has focused on NFX1-123, the longer splice variant of NFX1, and on its role with 16E6 in oncogenesis. Previously we had shown that 16E6 bound NFX1-123 in its central domain, but unlike NFX1-91 it was not degraded; together, 16E6 and NFX1-123 increased hTERT expression and telomerase activity in human foreskin keratinocytes (HFKs) through a posttranscriptional mechanism (20). 16E6 and NFX1-123 increased hTERT by utilizing both the PAM2 motif and R3H domain of the NFX1-123 protein. The N-terminal PAM2 motif is required to interact with cytopl...

show abstract

supporting

confidence: 74%

NFX1-123 and Human Papillomavirus 16E6 Increase Notch Expression in Keratinocytes

Vliet-Gregg¹,

Hamilton²,

Katzenellenbogen

2013

J Virol

View full text Add to dashboard Cite

show abstract

“…Such sub-sets often upregulate the expression of pluripotency factors, Oct4, Nanog, Sox2 and cell survival pathways such as Notch Signaling (4,7–10). We have recently identified a subset of cells in cervical cancers with enhanced tumorigenic and metastatic functions (10). These cells are sustained by Notch signaling and are distinct in their expression of CD66.…”

Section: Introductionmentioning

confidence: 99%

“…The transmembrane protein CD66, a member of the carcinoembryonic antigen family, has been implicated in invasive functions in different solid tumours, including ovarian cancer and estrogen deprived breast cancer cells (11–14). CD66+ cells in cervical cancers have higher expression of the pluripotency factors Oct4 and Nanog, as well as drug transporters (10). Other groups have reported CD49f, a marker of basal undifferentiated keratinocytes, Sox2, one of the induced pluripotency genes and CD44+ Cytokeratin 17+ subsets to be linked to tumourigenic traits and sub-sets in cervical cancer (15,16).…”

Section: Introductionmentioning

confidence: 99%

CD66+ Cells in Cervical Precancers Are Partially Differentiated Progenitors with Neoplastic Traits

et al. 2014

Self Cite

View full text Add to dashboard Cite

Cervical cancers, a malignancy associated with oncogenic papillomaviruses, remain a major disease burden in the absence of effective implementation of preventive strategies. CD66+ cells have previously been identified as a tumor propagating subset in cervical cancers. We investigated the existence, differentiation state and neoplastic potential of CD66+ cells in a pre-cancer cell line harboring HPV31b episomes. The gene expression profile of CD66High cells overlaps with differentiated keratinocytes, neoplastic mesenchymal transition, cells of the squamo-columnar junction and cervical cancer cell line derived spheroids. There is elevated expression of DNMT1, Notch1 and the viral gene product E1^E4, in CD66High cells. Thus CD66High cells, in the absence of differentiating signals, express higher levels of key regulators of keratinocytes stemness, differentiation and the viral life cycle respectively. We also find a striking association of neoplastic traits including migration, invasion and colony formation in soft agar with CD66High cells. These properties and a distinct G2M enriched cell cycle profile are conserved in cells from cervical cancers. Principally, using a precancerous cell line, we propose that CD66High cells have an intermediate differentiation state with a cellular milieu connected with both viral replication and neoplastic potential and validate some key features in pre-cancer lesions. Such pathophysiologically relevant systems for defining cellular changes in the early phases of the disease process provide both mechanistic insight and potential therapeutic strategies. Collectively, our data provides a rationale for exploring novel therapeutic targets in CD66+ sub-sets during cancer progression.

show abstract

“…29 Of the protein encoding transcripts upregulated in all three cultures, the cell adhesion molecules CEACAM5 and EPCAM have both been linked to migration, invasion and/or metastasis in numerous cancer types 35,36 and have further been associated with Notch signaling in human cervical cancers and pancreatic tumors, where Notch inhibition resulted in downregulation of CEACAM5 and EPCAM respectively. 37,38 A correlation between CEACAM5/EPCAM and Notch in GBM has yet to be reported. However, our results suggest that the correlation is in opposite as compared with cervical and pancreatic cancer as we found these cell adhesion molecules to be upregulated upon Notch inhibition.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Notch signaling alters the phenotype of orthotopic tumors formed from glioblastoma multiforme neurosphere cells but does not hamper intracranial tumor growth regardless of endogene Notch pathway signature

Kristoffersen

Nedergaard

Villingshøj

et al. 2014

Cancer Biology & Therapy

View full text Add to dashboard Cite

Notch Signaling in CD66+ Cells Drives the Progression of Human Cervical Cancers

Cited by 32 publications

References 47 publications

NFX1-123 and Human Papillomavirus 16E6 Increase Notch Expression in Keratinocytes

NFX1-123 and Human Papillomavirus 16E6 Increase Notch Expression in Keratinocytes

CD66+ Cells in Cervical Precancers Are Partially Differentiated Progenitors with Neoplastic Traits

Inhibition of Notch signaling alters the phenotype of orthotopic tumors formed from glioblastoma multiforme neurosphere cells but does not hamper intracranial tumor growth regardless of endogene Notch pathway signature

Contact Info

Product

Resources

About