HPV16 Down-Regulates the Insulin-Like Growth Factor Binding Protein 2 to Promote Epithelial Invasion in Organotypic Cultures

Pickard, Adam; McDade, Simon S.; McFarland, Marie; McCluggage, W. Glenn; Wheeler, Cosette M.; McCance, Dennis J.

doi:10.1371/journal.ppat.1004988

Cited by 23 publications

(23 citation statements)

References 62 publications

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“…At least two nonexclusive hypotheses could explain this paracrine effect. First, the HPV oncogenes might alter the epithelial secretion repertoire in vivo as they do in keratinocytes cultured in organotypic rafts (44), leading to stromal changes. Second, changes in the number and/or content of extracellular vesicles secreted by HPV + epithelial cells and delivered to stromal cells might alter stromal gene expression.…”

Section: Discussionmentioning

confidence: 99%

Human papillomavirus oncogenes reprogram the cervical cancer microenvironment independently of and synergistically with estrogen

Spurgeon

Boon

Horswill

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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High-risk human papillomaviruses (HPVs) infect epithelial cells and are causally associated with cervical cancer, but HPV infection is not sufficient for carcinogenesis. Previously, we reported that estrogen signaling in the stromal tumor microenvironment is associated with cervical cancer maintenance and progression. We have now determined how HPV oncogenes and estrogen treatment affect genome-wide host gene expression in laser-captured regions of the cervical epithelium and stroma of untreated or estrogen-treated nontransgenic and HPV-transgenic mice. HPV oncogene expression in the cervical epithelium elicited significant gene-expression changes in the proximal stromal compartment, and estrogen treatment uniquely affected gene expression in the cervical microenvironment of HPV-transgenic mice compared with nontransgenic mice. Several potential estrogen-induced paracrine-acting factors were identified in the expression profile of the cervical tumor microenvironment. The microenvironment of estrogen-treated HPV-transgenic mice was significantly enriched for chemokine/cytokine activity and inflammatory and immune functions associated with carcinogenesis. This inflammatory signature included several proangiogenic CXCR2 receptor ligands. A subset of the same CXCR2 ligands was likewise increased in cocultures of early-passage cells from human cervical samples, with levels highest in cocultures of cervical fibroblasts and cancer-derived epithelial cells. Our studies demonstrate that high-risk HPV oncogenes profoundly reprogram the tumor microenvironment independently of and synergistically with estrogen. These observations illuminate important means by which HPVs can cause cancer through alterations in the tumor microenvironment.

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Section: Discussionmentioning

confidence: 99%

Human papillomavirus oncogenes reprogram the cervical cancer microenvironment independently of and synergistically with estrogen

Spurgeon

Boon

Horswill

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Cells were cultured in complete media (Dulbecco's modified Eagle's medium: Nutrient Mixture F-12 containing 4500 mg/L glucose, L-glutamine, and sodium bicarbonate, supplemented with 10% foetal calf serum) at 37 o C, in 5% CO2. Immortalized lines were generated by retroviral expression of mTERT 38 (iTTF), similarly to generate BiP overexpressing cells were we utilised pCMMP-BiP-IRES-mRFP a gift from Bill Sugden (Addgene plasmid #36975) 39 , using methods previously described 40 . BiP overexpressing cells were flow sorted based on mRFP expression.…”

Section: Cell Isolation and Culturementioning

confidence: 99%

Preservation of circadian rhythms by the protein folding chaperone, BiP

Pickard

Chang

Alachkar

et al. 2018

Preprint

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ER stress and dysregulation of collagen synthesis are associated with progression of disease in cancer and fibrosis. Collagen synthesis is co-ordinated with the circadian clock, which curiously in cancer cells, is deregulated by ER stress. We hypothesised that interplay exists between circadian rhythm, collagen synthesis and ER stress in normal cells. Here we show that fibroblasts with ER stress do not demonstrate circadian rhythms in gene expression upon clock-synchronizing time cues. Conversely, overexpression of BiP or treatment with chemical chaperones strengthens the oscillation amplitude of circadian rhythms. The significance of these findings was explored in tendon, where we showed that BiP expression is ramped preemptively prior to a surge in collagen synthesis at night, thereby preventing protein misfolding and ER stress. In turn, we propose, this forestalls activation of the unfolded protein response in order for circadian rhythms to be maintained. Thus, targeting ER stress could be used to modulate circadian rhythm and restore collagen homeostasis in disease.

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“…In addition, E7 interacts directly with IGFBP3 and inhibits apoptosis mediated by this protein [38]. It has also shown that in 85% of women with HSIL, IGFBP 2 loss expression occurs, which could has clinical utility for monitoring patients with a higher risk of CxCa progression [39]. Some epigenetic mechanisms have been described in CxCa, related to the effects of HPV on viral and host genome [40,41].…”

Section: Contribution Of Insulin Resistance To Cxca Riskmentioning

confidence: 99%

“…Some of them involve the components of the IGF system, such as IGF2 loss of imprinting, which can lead to some genes overexpression and overall chromatin instability [42] and E7 interaction with a group of lncRNA that modulate PI3K/Akt/mTOR and Wnt- catenin pathways in cervical carcinogenesis process [43]. It is expected that epigenetic factors that are induced by HPV or triggered in response to viral infection/viral protein expression could be important drug targets for viral associated cancers [39]. The reversibility of epigenetic modi ications makes such factors ideal therapeutic targets.…”

Section: Contribution Of Insulin Resistance To Cxca Riskmentioning

confidence: 99%

Could metabolic risk factors contribute to the development of cervical cancer?

Frontela-Noda¹,

Cabrera-Rode²,

Hernández-Menéndez³

et al. 2019

Ann Clin Endocrinol Metabol

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The role of human papillomavirus infection as etiological factor for cervical squamous intraepithelial lesions and cervical cancer is well established. However, the presence of this virus is not suffi cient condition for developing of cervical cancer. Currently, the contribution of other viral, environmental and host cofactors in triggering of this neoplasm is being investigated. Some metabolic risk factors have been associated with the development of several gynecological cancers such as endometrium, ovary and cervix. However, the mechanisms through which these factors contribute to carcinogenesis are complex and not fully elucidated. Few interventions regarding host metabolic factors have been performed on women at risk of developing cervical cancer. Some specifi c treatments and or changes in lifestyles could be carried out to avoid or delay progression to this kind of cancer. This paper aims to enlarge and update this topic based on the article ¨Association between components of the metabolic syndrome and degree of cervical squamous intraepithelial lesions in Cuban women¨, with emphasis on possible mechanisms that explain the link between central adiposity, insulin resistance and dyslipidemia with risk of premalignant lesions and cervical cancer.Could metabolic risk factors contribute to the development of cervical cancer? https://www.heighpubs.org/hcem 002 https://doi.

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HPV16 Down-Regulates the Insulin-Like Growth Factor Binding Protein 2 to Promote Epithelial Invasion in Organotypic Cultures

Cited by 23 publications

References 62 publications

Human papillomavirus oncogenes reprogram the cervical cancer microenvironment independently of and synergistically with estrogen

Human papillomavirus oncogenes reprogram the cervical cancer microenvironment independently of and synergistically with estrogen

Preservation of circadian rhythms by the protein folding chaperone, BiP

Could metabolic risk factors contribute to the development of cervical cancer?

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