Human Kallikrein 8 Expression in Salivary Gland Tumors

Human papillomavirus (HPV) infection is the world's most common sexually transmitted infection and is responsible for most cases of cervical cancer. Previous studies of global gene expression changes induced by HPV infection have focused on the cancerous stages of infection, and therefore, not much is known about global gene expression changes at early preneoplastic stages of infection. We show for the first time the global gene expression changes during early-stage HPV16 infection in cervical tissue using 3-dimensional organotypic raft cultures, which produce high levels of progeny virions. cDNA microarray analysis showed that a total of 594 genes were upregulated and 651 genes were downregulated at least 1.5-fold with HPV16 infection. Gene ontology analysis showed that biological processes including cell cycle progression and DNA metabolism were upregulated, while skin development, immune response, and cell death were downregulated with HPV16 infection in cervical keratinocytes. Individual genes were selected for validation at the transcriptional and translational levels, including , which was central to the protein association network of immune response genes, and top downregulated genes, ,, and In particular, and were shown to be upregulated in cancer, which contrasts with the gene regulation during the productive replication stage. Organotypic raft cultures, which allow full progression of the HPV life cycle, allowed us to identify novel gene modulations and potential therapeutic targets of early-stage HPV infection in cervical tissue. Additionally, our results suggest that early-stage productive infection and cancerous stages of infection are distinct disease states expressing different host transcriptomes. Persistent HPV infection is responsible for most cases of cervical cancer. The transition from precancerous to cancerous stages of HPV infection is marked by a significant reduction in virus production. Most global gene expression studies of HPV infection have focused on the cancerous stages. Therefore, little is known about global gene expression changes at precancerous stages. For the first time, we measured global gene expression changes at the precancerous stages of HPV16 infection in human cervical tissue producing high levels of virus. We identified a group of genes that are typically overexpressed in cancerous stages to be significantly downregulated at the precancerous stage. Moreover, we identified significantly modulated genes that have not yet been studied in the context of HPV infection. Studying the role of these genes in HPV infection will help us understand what drives the transition from precancerous to cancerous stages and may lead to the development of new therapeutic targets.

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“…Ϫ25.8 Bladder (100), ovarian (101), salivary gland (107), cervical (76), OSCC (75), colorectal (106) KLK10…”

Section: Cancers In Which Gene Expression Increases And/or Promotes Dmentioning

confidence: 99%

Effect of Productive Human Papillomavirus 16 Infection on Global Gene Expression in Cervical Epithelium

Kang

Chatterjee

Alam

et al. 2018

J Virol

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“…For example, FUCA1 is a carbohydrate degrading enzyme and FUCA1 gene-mutations are linked to fucosidosis that causes severe skin abnormalities due to disturbed carbohydrate metabolism 55 . The human kallikrein 8 protein (KLK8) is expressed in many normal tissues including the salivary gland 56 . KLK8 serum levels are increased in psoriatic arthritis patients 57 and in the stratum spinosum during murine skin inflammation 58 .…”

Section: Discussionmentioning

confidence: 99%

Saliva proteomic patterns in patients with molar incisor hypomineralization

Bekes

Mitulović

Meißner³

et al. 2020

Sci Rep

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Molar incisor hypomineralization (MiH) is an endemic pediatric disease with an unclear pathogenesis. considering that saliva controls enamel remineralization and that MiH is associated with higher saliva flow rate, we hypothesized that the protein composition of saliva is linked to disease. To test this, we enrolled 5 children aged 6-14 years with MIH showing at least one hypersensitive molar and 5 cariesfree children without hypomineralization. Saliva samples were subjected to proteomic analysis followed by protein classification in to biological pathways. Among 618 salivary proteins identified with high confidence, 88 proteins were identified exclusively in MIH patients and 16 proteins in healthy controls only. Biological pathway analysis classified these 88 patient-only proteins to neutrophil-mediated adaptive immunity, the activation of the classical pathway of complement activation, extracellular matrix degradation, heme scavenging as well as glutathione-and drug metabolism. The 16 controlsonly proteins were associated with adaptive immunity related to platelet degranulation and the lysosome. This report suggests that the proteaneous composition of saliva is affected in MIH patients, reflecting a catabolic environment which is linked to inflammation. The term molar incisor hypomineralization (MIH) was coined in 2001 and defines a qualitative enamel defect affecting one or more first permanent molars with or without the involvement of permanent incisors 1. The global prevalence of MIH exceeds one-tenth of children, ranging from 0.5% to 40.2% and differing between countries 2. Demarcated hypomineralized enamel lesions are caused by the process of amelogenesis being altered or interrupted 3. Compared to normal teeth, affected enamel is characterized by a reduction in mineral quantity and quality, increased porosity and reduced hardness 4. The clinical management of MIH is challenging because of rapid wear, progressing enamel loss, increased susceptibility to caries, loss of fillings, and severe hypersensitivity 5. Although MIH is a pandemic pediatric disease, the etiology remains unknown 6. Several hypotheses are proposed, including childhood illness, genetic influences 7,8 , and a putative individual threshold of susceptibility 3. Thus, there is an increasing demand to better understand the cause and consequence(s) of MIH at the cellular and molecular level. Chronic subclinical pulpal inflammation is a consequence of increased enamel porosity and reduced hardness in MIH 9. Pulpitis is characterized by enhanced neutrophil emigration into the pulp tissue 10,11 and biomarkers can be identified in gingival crevicular fluid 12. Moreover, in periodontitis patients, neutrophils constantly migrate through the oral epithelia into the saliva 13 , with increasing numbers exhibiting apoptosis and augmented levels of degranulation markers 14. Further, saliva of MIH patients reportedly displays altered physicochemical properties such as altered flow rates, viscosity, pH and acid buffering capacity 15. Thus, it is conceivabl...

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“…The KLK8 immunoreactivity was determined in normal salivary gland tissue and in malignant salivary gland tumors. In general, all the tumors showed a relatively high overall staining for both ductal and non-ductal cells, particularly mucoepidermoid carcinomas and adenocarcinoma NOS (Darling et al, 2008).…”

Section: Diseasementioning

confidence: 94%

“…Diffuse cytoplasmic staining was observed for KLK8 in the secretory segment in eccrine sweat glands and in the intradermal sensory nerve (Komatsu et al, 2005). KLK8 is present in relatively high levels in ductal cells, as well as in non-ductal cells, of normal salivary gland tissues and benign and malignant salivary gland tumors (Darling et al, 2008). In brain, KLK8 is expressed in the cell body of oligodendrocytes (He et al, 2001).…”

Section: Localisationmentioning

confidence: 99%

“…KLK8 has also been involved in skin desquamation and wound healing and in keratinocyte proliferation (Inoue et al, 1998;Kirihara et al, 2003;Kishibe et al, 2007;Yoshida, 2010;Eissa et al, 2011;Kishibe et al, 2012). It has been shown that KLK8 is differentially expressed in a number of malignancies, including ovarian, cervical, head and neck, breast and salivary gland cancers Cane et al, 2004;Borgono et al, 2006;Darling et al, 2008;Liu et al, 2008;Kountourakis et al, 2009), but the mechanisms of its involvement in these cancer have yet to be determined. In lung cancer, KLK8 suppress tumor cell invasiveness in vitro and in vivo (Sher et al, 2006).…”

Section: Functionmentioning

confidence: 99%

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