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Immunomodulatory role of Keratin 76 in oral and gastric cancer.

ABSTRACT: Keratin 76 (Krt76) is expressed in the differentiated epithelial layers of skin, oral cavity and squamous stomach. Krt76 downregulation in human oral squamous cell carcinomas (OSCC) correlates with poor prognosis. We show that genetic ablation of Krt76 in mice leads to spleen and lymph node enlargement, an increase in regulatory T cells (Tregs) and high levels of pro-inflammatory cytokines. Krt76-/- Tregs have increased suppressive ability correlated with increased CD39 and CD73 expression, while their effector T cells are less proliferative than controls. Loss of Krt76 increases carcinogen-induced tumours in tongue and squamous stomach. Carcinogenesis is further increased when Treg levels are elevated experimentally. The carcinogenesis response includes upregulation of pro-inflammatory cytokines and enhanced accumulation of Tregs in the tumour microenvironment. Tregs also accumulate in human OSCC exhibiting Krt76 loss. Our study highlights the role of epithelial cells in modulating carcinogenesis via communication with cells of the immune system.

SUBMITTER: Sequeira I

PROVIDER: S-EPMC6109110 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Immunomodulatory role of Keratin 76 in oral and gastric cancer.

Sequeira Inês I Neves Joana F JF Carrero Dido D Peng Qi Q Palasz Natalia N Liakath-Ali Kifayathullah K Lord Graham M GM Morgan Peter R PR Lombardi Giovanna G Watt Fiona M FM

Nature communications 20180824 1

Keratin 76 (Krt76) is expressed in the differentiated epithelial layers of skin, oral cavity and squamous stomach. Krt76 downregulation in human oral squamous cell carcinomas (OSCC) correlates with poor prognosis. We show that genetic ablation of Krt76 in mice leads to spleen and lymph node enlargement, an increase in regulatory T cells (Tregs) and high levels of pro-inflammatory cytokines. Krt76<sup>-/-</sup> Tregs have increased suppressive ability correlated with increased CD39 and CD73 expre ...[more]

PMID: 30143634

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Project description:Nanotechnology-based drug delivery systems have been widely used for oral and systemic dosage forms delivery depending on the mucoadhesive interaction, and keratin has been applied for biomedical applications and drug delivery. However, few reports have focused on the keratin-based mucoadhesive drug delivery system and their mechanisms of mucoadhesion. Thus, the mucoadhesion controlled kerateine (reduced keratin, KTN)/keratose (oxidized keratin, KOS) composite nanoparticles were prepared via adjusting the proportion of KTN and KOS to achieve controlled gastric mucoadhesion and drug release based on their different mucoadhesive abilities and pH-sensitive properties. Furthermore, the mechanisms of mucoadhesion for KTN and KOS were also investigated in the present study.The composite keratin nanoparticles (KNPs) with different mass ratio of KTN to KOS, including 100/0 (KNP-1), 75/25 (KNP-2), 50/50 (KNP-3), and 25/75 (KNP-4), displayed different drug release rates and gastric mucoadhesion capacities, and then altered the drug pharmacokinetic performances. The stronger mucoadhesive ability of nanoparticle could supply longer gastric retention time, indicating that KTN displayed a stronger mucoadhesion than that of KOS. Furthermore, the mechanisms of mucoadhesion for KTN and KOS at different pH conditions were also investigated. The binding between KTN and porcine gastric mucin (PGM) is dominated by electrostatic attractions and hydrogen bondings at pH 4.5, and disulfide bonds also plays a key role in the interaction at pH 7.4. While, the main mechanisms of KOS and PGM interactions are hydrogen bondings and hydrophobic interactions in pH 7.4 condition and were hydrogen bondings at pH 4.5.The resulting knowledge offer an efficient strategy to control the gastric mucoadhesion and drug release of nano drug delivery systems, and the elaboration of mucoadhesive mechanism of keratins will enable the rational design of nanocarriers for specific mucoadhesive drug delivery.

Dataset Information

Immunomodulatory role of Keratin 76 in oral and gastric cancer.

Publications

Immunomodulatory role of Keratin 76 in oral and gastric cancer.

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