Urokinase gene expression indicates early invasive growth in squamous cell lesions of the uterine cervix

Riethdorf, Lutz; Petersen, Sonja; Bauer, Michael; Herbst, Hermann; Jänicke, F.; Löning, Thomas

doi:10.1002/(sici)1096-9896(199910)189:2<245::aid-path427>3.0.co;2-z

Cited by 27 publications

(12 citation statements)

References 27 publications

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“…HPV-16 E6 controls miR-23b probably through its target protein p53 as: (i) HPV-16 E6 suppresses, whereas knockdown HPV-16 E6 induced cell migration and invasiveness through miR-23b/uPA uPA is known to be involved in cell migration, metastasis and invasiveness (Duffy et al, 1999). It is considered as a prognostic indicator of cervical cancer as its expression is only detected in HPV-16-infected cervical squamous cell carcinoma, but not in other low-grade or high-grade squamous intraepithelial lesions and normal mucosa (Riethdorf et al, 1999). mR-23b was found to target uPA in hepatocellular carcinoma cells (Salvi et al, 2009).…”

Section: Hpv-16 E6 Repression Of Mir-23b In Human Cervical Cancer Cellsmentioning

confidence: 99%

“…High level of uPA in cancers is correlated with poor patient prognosis (Andreasen et al, 1997). uPA is reported to be overexpressed in cervical cancer (Riethdorf et al, 1999) and upregulated in HPV-16-transformed keratinocytes (Turner and Palefsky, 1995). Thus, uPA may be downstream of the HPV oncoproteins and may participate in the development of cervical cancer.…”

Section: Introductionmentioning

confidence: 99%

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Human papillomavirus type 16 E6 induces cervical cancer cell migration through the p53/microRNA-23b/urokinase-type plasminogen activator pathway

et al. 2011

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Deregulation of microRNA (miRNA or miR) expression in human cervical cancer is associated frequently with human papillomavirus (HPV) integration. miR-23b is often downregulated in HPV-associated cervical cancer. Interestingly, urokinase-type plasminogen activator (uPA), the miR-23b target, is detected in cervical cancer, but not in normal cervical tissues. Thus, the importance of miR-23b and uPA in HPV-associated cervical cancer development is investigated. In this study, the high-risk subtype HPV-16 E6 oncoprotein was found to decrease the expression of miR-23b, increase the expression of uPA, and thus induce the migration of human cervical carcinoma SiHa and CaSki cells. uPA is the target gene for miR-23b as the miR repressed uPA expression and interacted with the 3 0 -untranslated region of uPA mRNA. The tumor suppressor p53 is known to be inactivated by HPV-16 E6. A consensus p53 binding site is detected in the promoter region of miR-23b, whereas p53 transactivated and also interacted with the miR's promoter. Therefore, p53 is believed to mediate the HPV-16 E6 downregulation of miR-23b. From the above, miR-23b/ uPA are confirmed to be involved in HPV-16 E6-associated cervical cancer development.

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Section: Hpv-16 E6 Repression Of Mir-23b In Human Cervical Cancer Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human papillomavirus type 16 E6 induces cervical cancer cell migration through the p53/microRNA-23b/urokinase-type plasminogen activator pathway

et al. 2011

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“…Moreover, uPAR expression has been found to correlate with a poor prognosis and mortality in patients with various types of solid tumors [64][65][66][67]. Antibodies that bind uPAR and prevent its interactions with uPA have been shown to inhibit in vitro invasiveness [68,69], and to decrease the formation of metastatic foci and the incidence of metastasis in experimental tumors [18,[63][64][65][66]. Rofstad and colleagues reported that, in contrast to control tumors showing diffuse invasion and lacking a distinct boundary, tumors collected from mice treated with an anti-uPAR antibody were surrounded by a thin capsule of stroma and showed a well-defined borderline against adjacent tissue [70].…”

Section: Hypoxia and Tumor Cell Invasion Of The Basement Membrane Andmentioning

confidence: 99%

Hypoxia-driven selection of the metastatic phenotype

Sullivan

Graham

2007

Cancer Metastasis Rev

382

292

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Intratumoral hypoxia is an independent indicator of poor patient outcome and increasing evidence supports a role for hypoxia in the development of metastatic disease. Studies suggest that the acquisition of the metastatic phenotype is not simply the result of dysregulated signal transduction pathways, but instead is achieved through a stepwise selection process driven by hypoxia. Hypoxia facilitates disruption of tissue integrity through repression of E-cadherin expression, with concomitant gain of N-cadherin expression which allows cells to escape anoikis. Through upregulation of urokinase-type plasminogen activator receptor (uPAR) expression, hypoxia enhances proteolytic activity at the invasive front and alters the interactions between integrins and components of the extracellular matrix, thereby enabling cellular invasion through the basement membrane and the underlying stroma. Cell motility is increased through hypoxia-induced hepatocyte growth factor (HGF)-MET receptor signaling, resulting in cell migration towards the blood or lymphatic microcirculation. Hypoxia-induced vascular endothelial growth factor (VEGF) activity also plays a critical role in the dynamic tumor-stromal interactions required for the subsequent stages of metastasis. VEGF promotes angiogenesis and lymphangiogenesis in the primary tumor, providing the necessary routes for dissemination. VEGF-induced changes in vascular integrity and permeability promote both intravasation and extravasation, while VEGF-induced angiogenesis in the secondary tissue is essential for cell proliferation and establishment of metastatic lesions. Through regulation of these critical molecular targets, hypoxia promotes each step of the metastatic cascade and selects tumor cell populations that are able to escape the unfavorable microenvironment of the primary tumor.

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“…Moreover, the reduce expression of miR23b was related to invasion and metastasis, being considered a prognostic factor of cervical carcinoma [64].…”

Section: High-risk Hpv Infection Modulates Mirna Expression In Cervicmentioning

confidence: 99%

The Role of miRNAs in Diagnosis, Prognosis and Treatment Prediction in Cervical Cancer

Bălăcescu¹,

Bălăcescu²,

Baldasici³

et al. 2017

Colposcopy and Cervical Pathology

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Cervical cancer represents one of the major problems of health women worldwide, especially in the developing countries. If discovered in its earliest stages, cervical cancer is successfully treatable; however, due to lack of proper implementation of screening programs, the majority of cervical cancer patients are diagnosed in advanced stages, which dramatically influence their outcome. Almost a half of these patients will suffer recurrence or metastasis in the following 2 years after therapy. If there are no immediate prospects in terms of developing new or more effective therapies, identifying new tools for early diagnosis, prognosis and treatment prediction remains a big challenge for cervical cancer. miRNAs have been validated to be key players in cell physiology, alterations in miRNA expression being associated with cancer progression and response to therapy. Cervical cancer studies have showed that alterations of miRNA expression can be identified in tumor tissues, exfoliated cervical cells and patients serum and that their transcription pattern is regulated by the present HPV genotype. Furthermore, miRNAs have been associated with patients response to therapy, therefore suggesting their potential to be used as biomarkers for cervical cancer diagnosis, prognosis and treatment response.

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Urokinase gene expression indicates early invasive growth in squamous cell lesions of the uterine cervix

Cited by 27 publications

References 27 publications

Human papillomavirus type 16 E6 induces cervical cancer cell migration through the p53/microRNA-23b/urokinase-type plasminogen activator pathway

Human papillomavirus type 16 E6 induces cervical cancer cell migration through the p53/microRNA-23b/urokinase-type plasminogen activator pathway

Hypoxia-driven selection of the metastatic phenotype

The Role of miRNAs in Diagnosis, Prognosis and Treatment Prediction in Cervical Cancer

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