Loss of Robustness and Addiction to IGF1 during Early Keratinocyte Transformation by Human Papilloma Virus 16

Geiger, Tamar; Levitzki, Alexander

doi:10.1371/journal.pone.0000605

Cited by 6 publications

(8 citation statements)

References 45 publications

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“…Nonetheless, we have recently noted (40) similarities in the stress response of our L cells and of an independently derived HPV16-transformed cell line, HPKII (41). Strikingly, we have shown a marked convergence between our data regarding gene expression in L and BP cells and the data of Santin et al (6) (Fig.…”

Section: Discussionsupporting

confidence: 75%

Shift from Apoptotic to Necrotic Cell Death during Human Papillomavirus-induced Transformation of Keratinocytes

Kravchenko‐Balasha¹,

Mizrachy-Schwartz²,

Klein

et al. 2009

Journal of Biological Chemistry

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Oncogenic transformation is a complex, multistep process, which goes through several stages before complete malignant transformation occurs. To identify early processes in carcinogenesis, we used an in vitro model, based on the initiating event in cervical cancer, papillomavirus transformation of keratinocytes. We compared gene expression in primary keratinocytes (K) and papillomavirus-transformed keratinocytes from early (E) and late (L) passages and from benzo[a]pyrene-treated L cells (BP). The transformed cells exhibit similar transcriptional changes to clinical cervical carcinoma. The number of transcripts expressed progressively decreased during the evolution from K to BP cells. Bioinformatic analysis, validated by detailed biochemical analysis, revealed substantial contraction of both pro-and antiapoptotic networks during transformation. Nonetheless, L and BP cells were not resistant to apoptotic stimuli. At doses of cisplatin that led to 30 -60% apoptosis of K and E cells, transformed L and BP cells underwent 80% necrotic cell death, which became the default response to genotoxic stress. Moreover, appreciable necrotic fractions were observed in the cervical carcinoma cell line, HeLa, in response to comparable doses of cisplatin. The shrinkage of biochemical networks, including the apoptotic network, may allow a cancer cell to economize on energy usage to facilitate enhanced proliferation but leaves it vulnerable to stress. This study supports the hypothesis that the process of cancer transformation may be accompanied by a shift from apoptosis to necrosis.Cancer is an evolving, complex process, which goes through several stages before full malignancy. In vivo, cell immortalization is followed by the development of benign lesions, which later progress into malignant tumors, finally metastasizing to other tissues. As it evolves, a cancer cell relinquishes pathways that interfere with proliferation and escapes from some of the restrictions of multicellular organisms. This process enables the cancer cell to proliferate in a broad range of naturally occurring microenvironments but may leave it vulnerable to rare or unexpected perturbations (1) (e.g. genotoxic stress). The reactions of cancer cells, which acquire numerous molecular changes, may differ significantly from the reactions of normal cells to genotoxic stress.Apoptosis is tightly controlled by the ability of the cell to integrate many pro-and antiapoptotic signals. Thus, the decision to live or to die in response to death signals is a choice the cell makes in the face of its cellular context. Molecular changes acquired by cancer cells may influence the connectivity of the signaling pathways and disturb the apoptotic network. As a result, the cancer cell may die by alternative death modes in response to genotoxic drugs.In order to follow the changes that occur during the evolution of cancer, we use a model in which one can follow the progression from the normal phenotype all the way to the transformed phenotype, based on the natural evolution of cervica...

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Section: Discussionsupporting

confidence: 75%

Shift from Apoptotic to Necrotic Cell Death during Human Papillomavirus-induced Transformation of Keratinocytes

Kravchenko‐Balasha¹,

Mizrachy-Schwartz²,

Klein

et al. 2009

Journal of Biological Chemistry

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“…We have recently described an in-vitro model for cervical cancer development, using the continuous passaging of HPV 16-immortalized human keratinocytes [15] , [16] . Here we have combined molecular biology, immuno-fluorescence microscopy, time-lapse video microscopy and electron microscopy to study the cellular features of pre-cancerous stages of HPV16-induced transformation.…”

Section: Introductionmentioning

confidence: 99%

“…Early HF1 cells are ∼60 doublings post transfection and late HF1 cells are ∼1000 doublings post transfection of HPV16. Late HF1 cells have a high proliferation rate, form small colonies in soft agar [16] , and show many overlapping features in gene expression with cervical cancers (Kravchenko-Balasha et al, submitted), however they do not form tumors in nude mice, and are therefore considered to be in an advanced stage of the pre-cancerous phase. In order to examine the generality of our observations we studied also the cervical cancer cell line SiHa.…”

Section: Introductionmentioning

confidence: 99%

Anomalous Features of EMT during Keratinocyte Transformation

et al. 2008

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During the evolution of epithelial cancers, cells often lose their characteristic features and acquire a mesenchymal phenotype, in a process known as epithelial-mesenchymal transition (EMT). In the present study we followed early stages of keratinocyte transformation by HPV16, and observed diverse cellular changes, associated with EMT. We compared primary keratinocytes with early and late passages of HF1 cells, a cell line of HPV16-transformed keratinocytes. We have previously shown that during the progression from the normal cells to early HF1 cells, immortalization is acquired, while in the progression to late HF1, cells become anchorage independent. We show here that during the transition from the normal state to late HF1 cells, there is a progressive reduction in cytokeratin expression, desmosome formation, adherens junctions and focal adhesions, ultimately leading to poorly adhesive phenotype, which is associated with anchorage-independence. Surprisingly, unlike “conventional EMT”, these changes are associated with reduced Rac1-dependent cell migration. We monitored reduced Rac1-dependent migration also in the cervical cancer cell line SiHa. Therefore we can conclude that up to the stage of tumor formation migratory activity is eliminated.

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“…For instance, IGF1 (insulin‐like growth factor 1) is a growth factor that regulates proliferation of both normal and cancer cells in an autocrine, paracrine (Baxter, ), and potentially endocrine manner (D'Ercole and Calikoglu, ). HPV transformed keratinocytes were found to be addicted to IGF1 signaling for survival, underlining the importance of this pathway for cervical cancer development (Geiger and Levitzki, ). IGFBP3, central to this signaling pathway, is transcriptionally regulated by p53 and (among others) suppresses proliferation and induces apoptosis (the process of programmed cell death).…”

Section: Illustrationmentioning

confidence: 99%

Ridge estimation of the VAR(1) model and its time series chain graph from multivariate time‐course omics data

2016

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Omics experiments endowed with a time-course design may enable us to uncover the dynamic interplay among genes of cellular processes. Multivariate techniques (like VAR(1) models describing the temporal and contemporaneous relations among variates) that may facilitate this goal are hampered by the high-dimensionality of the resulting data. This is resolved by the presented ridge regularized maximum likelihood estimation procedure for the VAR(1) model. Information on the absence of temporal and contemporaneous relations may be incorporated in this procedure. Its computational efficient implemention is discussed. The estimation procedure is accompanied with an LOOCV scheme to determine the associated penalty parameters. Downstream exploitation of the estimated VAR(1) model is outlined: an empirical Bayes procedure to identify the interesting temporal and contemporaneous relationships, impulse response analysis, mutual information analysis, and covariance decomposition into the (graphical) relations among variates. In a simulation study the presented ridge estimation procedure outperformed a sparse competitor in terms of Frobenius loss of the estimates, while their selection properties are on par. The proposed machinery is illustrated in the reconstruction of the p53 signaling pathway during HPV-induced cellular transformation. The methodology is implemented in the ragt2ridges R-package available from CRAN.

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Loss of Robustness and Addiction to IGF1 during Early Keratinocyte Transformation by Human Papilloma Virus 16

Cited by 6 publications

References 45 publications

Shift from Apoptotic to Necrotic Cell Death during Human Papillomavirus-induced Transformation of Keratinocytes

Shift from Apoptotic to Necrotic Cell Death during Human Papillomavirus-induced Transformation of Keratinocytes

Anomalous Features of EMT during Keratinocyte Transformation

Ridge estimation of the VAR(1) model and its time series chain graph from multivariate time‐course omics data

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