Identification of cytokeratin24 as a tumor suppressor for the management of head and neck cancer

Abstract

To improve management of head and neck squamous cell carcinoma patients, we need to increase our understanding of carcinogenesis, to identify biomarkers, and drug targets. This study aimed to identify novel biomarkers by providing transcriptomics profiles of matched primary tumors, lymph node metastasis, and non-malignant tissue of 20 HNSCC patients as well as by bioinformatic analyses of a TCGA HNSCC cohort, comprising 554 patients. We provide cancer cell signaling networks differentially expressed in tumors versus metastases, such as mesenchymal–epithelial transition, and structural integrity networks. As a proof of principle study, we exploited the data sets and performed functional analyses of a novel cytokeratin, cytokeratin24 (cKRT24), which had not been described as biomarker for tumors before. Survival analysis revealed that low cKRT24 expression correlated with poor overall survival in HNSCC. Experimentally, downregulation of cKRT24 in primary tumors, metastases, and HNSCC cell lines was verified on mRNA and protein level. Cloning and ectopic overexpression of cKRT24 not only affected viability and growth of HNSSC cell lines, but also inhibited tumor growth in murine xenograft studies. We conclude that cKRT24 functions as a tumor suppressor in HNSCC, and may serve as an additional prognostic biomarker and novel target to support current HNSCC treatments.

Proteome Profiling of Brain Vessels in a Mouse Model of Cerebrovascular Pathology

“…In line with this, upregulation in ADGRG2 transcripts has been reported during the transformation of quiescent human coronary artery smooth muscle cells to a proliferative and migratory phenotype observed in atherosclerosis [80]. Cytokeratin Krt24, a known anti-proliferative factor in the epidermis [81,82], was decreased in the TGF cerebrovasculature. Given that differential expression of cytokeratins has been observed in vascular smooth muscle cells, often in the setting of a proliferative state [83], a decreased Ktr24 level likely contributes to cell proliferation and remodeling.…”

Proteome profiling of brain vessels in a mouse model of cerebrovascular pathology

“…In line with this, upregulation in ADGRG2 transcripts has been reported during the transformation of quiescent human coronary artery smooth muscle cells to a proliferative and migratory phenotype observed in atherosclerosis [80]. Cytokeratin Krt24, a known anti-proliferative factor in the epidermis [81,82], was decreased in the TGF cerebrovasculature. Given that differential expression of cytokeratins has been observed in vascular smooth muscle cells, often in the setting of a proliferative state [83], decreased Ktr24 level likely contributes to cell proliferation and remodeling.…”

Profiling Cisplatin Resistance in Head and Neck Cancer: A Critical Role of the VRAC Ion Channel for Chemoresistance

“…Previous studies aimed to identify gene signatures for HNSCC, allowing predicting patients' therapy responses, pathobiology, and survival. However, the suggested signatures still failed to be used in the clinical routine to guide (targeted therapy) treatments for all patients [11,12]. Alongside methodological complications, the fact that HNSCC is characterized by highly heterogeneous tumors and anatomical localizations makes the selection of relevant patient subpopulations difficult and prevents rapid progress.…”