Increased Expression of Cytokeratins 14, 18 and 19 Correlates with Tumor Progression in the Uterine Cervix

Nair, S. Asha; Nair, M. Balaraman; Jayaprakash, P. G.; Rajalekshmy, T. N.; Nair, Manjusha; Pillai, M. Radhakrishna

doi:10.1159/000164110

Cited by 8 publications

(9 citation statements)

References 19 publications

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“…Up to now analyses of the specific epithelial keratin profile in HPV infected oral mucosa and in HPV related oral and oropharyngeal cancers are scanty and questionable. Although it is well known that CK19 and/or its fragment CYFRA 21–1 correlate with tumor progression both in the uterine cervix and in the upper aerodigestive tract [ 31 – 33 ] and are statistically significantly connected to patients outcome [ 34 – 36 ], the exact role of CK19 in the genesis of HPV related oral and oropharyngeal cancer requires further assessment [ 37 ].…”

Section: Introductionmentioning

confidence: 99%

Relationship between CK19 expression, deregulation of normal keratinocyte differentiation pattern and high risk-human papilloma virus infection in oral and oropharyngeal squamous cell carcinoma

Santoro¹,

Pannone

Ninivaggi

et al. 2015

Infect Agents Cancer

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BackgroundSimple epithelial keratins appear early during embryonic development and are expressed in non-stratified, ductal and pseudo-stratified epithelial tissues. CK19, the lowest molecular weight keratin, is also expressed in basal layer of squamous epithelia of mucosal surfaces. Previous studies have shown that High Risk-Human Papilloma Virus (HR-HPV) epithelial infection induces cell immortalization via E6 and E7 viral proteins and this, in turn, impairs cytokeratin expression in cancerous cells lines derived from uterine cervix. Here, we demonstrate the possible relationship between HR-HPV+ oral/oropharyngeal cancer and the high levels of CK19 expression.MethodsWe analyzed 38 cases of Oral Squamous Cell Carcinomas/ Oro-Pharyngeal Squamous Cell Carcinomas (OSCCs/OPSCCs) by Immunohistochemistry (IHC) using specific antibody (Ab) detecting CK19, by In Situ Hybridization (ISH) and Polymerase Chain Reaction (PCR) based methods in order to define the HPV infectious status. We also evaluated the variation of CK19 expression in UPCI-SCC-131 (HPV−) and UPCI-SCC-154 (HPV+) cell lines by immunocytochemistry (ICC) and flow cytometry.ResultsCK19 OSCC/OPSCC score has been identified multiplying percentage of cancer expressing cells to staining intensity. CK19 expression score in OSCCs/OPSCCs was very different between HPV+ (mean: 288.0 ± 24.3) and HPV− cancers (mean: 66.2 ± 96.9). This difference was statistically significant (p < 0.001) with a strong evidence of correlation (p < 0.001; Spearman’s R: +0.72). ROC curve analysis was performed on CK19 expression index related to HPV positivity. Heterogeneous areas of immunoreactivity varying in percentage value, intensity and/or localization were observed in normal epithelium, both perilesional and distant from the tumor with important differences between HR-HPV+ and HR-HPV− carcinomas. By ICC and flow cytometry, the two analyzed cell lines were both CK19 positive but showed a different level of expression, in particular it should be noted that the UPCI-SCC-154 (HPV+) cell line had a higher expression than UPCI-SCC-131 (HPV−).ConclusionsIn this study we demonstrated, for the first time, strong association between CK19 up-regulation and HR-HPV+ OSCCs/OPSCCs. This test has a good accuracy. We identified ROC curve with a cut-off > 195 for HR-HPV positive results (Sensitivity: 92.3 %; Specificity: 89.3 %). Furthermore, in OSCC/OPSCC, the CK19 test may be useful in identifying HR-HPV infection, the latter being related to HPV E7 potential to disrupt normal cytokeratin expression pattern.

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Section: Introductionmentioning

confidence: 99%

Relationship between CK19 expression, deregulation of normal keratinocyte differentiation pattern and high risk-human papilloma virus infection in oral and oropharyngeal squamous cell carcinoma

Santoro¹,

Pannone

Ninivaggi

et al. 2015

Infect Agents Cancer

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“…If we assume proper sample collection in every case, it is confounding why samples with advanced lesions (C1, C4, C6-C9) or even cancer (C2, C3) would show such low levels of keratins 5, 8, and 18. One would be inclined to expect the opposite, as dyplastic cells harboring these basal keratins should increase with disease progression [24,29,30,32]. Nevertheless, we do see cases where proper samples have not necessarily been obtained.…”

Section: Discussionmentioning

confidence: 73%

“…Although their biology is complex and over 50 functional keratin genes exist, studies have shown general expression patterns in normal cervical epithelium [27]. "Maturation" keratins normally present in differentiated intermediate and superficial squamous cells include keratins 4, 10, and 13, while stably expressed keratins localized to undifferentiated basal/parabasal/ reserve, squamous metaplastic, and endocervical columnar cells include keratins 5, 8, and 18 [28][29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

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Development of a novel enzyme-linked immunosorbent assay for the detection of cytokeratins 5, 8, and 18, and its implications in cervical cancer screening standardization

McNamara¹,

Kaufmann²,

Vasiljeva³

et al. 2018

J Clin Mol Med

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There is a dire need for improved cervical cancer screening methods. New tests are in the pipeline, but their diagnostic capabilities may be limited without a way to assess specimen validity. Here we describe an enzyme-linked immunosorbent assay (ELISA) that captures specific intermediate filament proteins (cytokeratins) from potentially transformable target cells located within or originating from the cervical transformation zone as a means of cervical specimens. Seventy-five uterine cervical samples negative for human papillomavirus (HPV) were grouped based on microscopic analysis for the presence or absence of cervical transformation zone cells, and all samples were tested in both a newly developed recom Well Keratin 5/8/18 ELISA and a pan keratin control ELISA. Additionally, 15 samples from HPVpositive patients manifesting histopathologic lesions or squamous cell carcinoma were tested. Our results demonstrate the presence and detectability by ELISA of keratins 5, 8, and 18 in parabasal, squamous metaplastic, and endocervical cells, while simultaneously suggesting their absence in differentiated squamous cells. We also validate with ELISA the expression of these keratins in HPV-induced disease-state individuals. Our findings indicate recom Well Keratin 5/8/18 ELISA may be useful as a standardizing tool in cervical cancer screening, or alternatively as a quality indicator to denote specimen adequacy.

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“…In molecular terms, it seems that CK19 might free the viral E7 mRNA from the translational block exerted by the CK7,7 thus leading to increased E7 protein level and, eventually, to the possibly related carcinogenic events. Indeed, CK19 and/or its fragment CYFRA 21‐1 correlate with tumor progression in the uterine cervix and the upper aerodigestive tract13, 14, 15 and are significantly connected to both disease‐free interval and survival of patients 16, 17, 18. In addition, wild‐type p53 inhibits CK19 expression with concomitant reconstruction of an epidermis more similar to that obtained with normal keratinocytes and characterized by the inversion of the proliferative compartment and the abnormal expression of CK19 19.…”

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confidence: 99%

Possible association between HPV16 E7 protein level and cytokeratin 19

Favia

Kanduc

Muzio

et al. 2004

Intl Journal of Cancer

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The mechanisms employed by human papillomaviruses (HPVs) to control the replication of the viral genome and the expression of the viral genes are extremely complex and further complicated by the fact that the viral life cycle is intricately tied to the differentiation program of its host epithelial tissue. Indeed, HPV-induced immortalization of keratinocytes and disruption of the normal cytokeratin (CK) expression pattern progress pari passu during the stepwise process that preludes to squamous cell carcinoma. A subset of HPVs, including type 16, are associated with squamous cervical and oropharyngeal carcinomas. 1-4 Two papillomaviral oncoproteins, E6 and E7, are likely to play a role in HPVassociated cancers. In particular, a number of data underline E7 oncogene implication. The E7 oncogene appears to redirect terminally differentiating epithelial cells to support viral DNA amplification, an important process in the generation of progeny virus. 5 In a recent study aimed to define the regulation of HPV16 E7 expression at the translational level, one of our labs described a molecular interaction occurring between HPV16 E7 mRNA and a 6-mer peptide having the amino acid sequence SEQIKA. It was demonstrated that the SEQIKA fragment binds to, prevents decay of and blocks translation of HPV16 E7 mRNA in in vitro experiments. The fragment was present in rabbit alpha 1-globin polypeptide, thus explaining the inefficient in vitro translation of E7 mRNA using rabbit reticulocyte cell free system. 6,7 Moreover, through similarity analysis it was demonstrated that the SEQIKA peptide is present in the human CK7 at the amino acid 91-96 position. The datum appeared of interest because of the specific CK7 localization in a large number of epithelial cell types including ductal and glandular epithelia, such as the squamo-columnar junction of the cervix, 8 -10 that is in areas where invasive squamous cell carcinomas arise. Finally, HPV16 E7 mRNA/CK7 interaction could also be demonstrated in the SiHa cancer cell line. 7 Here we extend these studies by comparatively analyzing the 2 HPV16-positive CaSki and SiHa cell lines.Indeed, a comparative analysis of CaSki and SiHa cells appeared suitable to further our understanding of the biologic function of HPV16 E7 mRNA/CK7 interaction and its role in HPV16 E7 oncoprotein expression for the following reasons. CaSki cells contain a high number of HPV16 DNA per cell, whereas the SiHa cell line contains 1 to 2 copies of HPV16 DNA per cell. Notwithstanding the striking difference in the number of HPV16 genome copies, it has been found that SiHa cells express more viral oncoprotein E7 per HPV16 genome harbored in the cell than CaSki cells. 11 Moreover, it has been established that although CaSki cells contain numerous copies of HPV16 genomes, the transcriptional activity of these genomes is relatively low and similar to that in SiHa cells. 12 Therefore, possibly different mechanisms are active at the translational level in the HPV16 E7 protein synthesis in SiHa and CaSki cells.As a first ste...

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Increased Expression of Cytokeratins 14, 18 and 19 Correlates with Tumor Progression in the Uterine Cervix

Cited by 8 publications

References 19 publications

Relationship between CK19 expression, deregulation of normal keratinocyte differentiation pattern and high risk-human papilloma virus infection in oral and oropharyngeal squamous cell carcinoma

Relationship between CK19 expression, deregulation of normal keratinocyte differentiation pattern and high risk-human papilloma virus infection in oral and oropharyngeal squamous cell carcinoma

Development of a novel enzyme-linked immunosorbent assay for the detection of cytokeratins 5, 8, and 18, and its implications in cervical cancer screening standardization

Possible association between HPV16 E7 protein level and cytokeratin 19

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