Among the ~22,000 human genes, very few remain that have unknown functions. One such example is suprabasin (SBSN). Originally described as a component of the cornified envelope, the function of stratified epithelia-expressed SBSN is unknown. Both the lack of knowledge about the gene role under physiological conditions and the emerging link of SBSN to various human diseases, including cancer, attract research interest. The association of SBSN expression with poor prognosis of patients suffering from oesophageal carcinoma, glioblastoma multiforme, and myelodysplastic syndromes suggests that SBSN may play a role in human tumourigenesis. Three SBSN isoforms code for the secreted proteins with putative function as signalling molecules, yet with poorly described effects. In this first review about SBSN, we summarised the current knowledge accumulated since its original description, and we discuss the potential mechanisms and roles of SBSN in both physiology and pathology.

• Klíčová slova
• MAPK signalling, cancer resistance, cancer stem-like cells, immunity, interferon, suprabasin,
• MeSH
• diferenciační antigeny * genetika   metabolismus   MeSH
• karcinogeneze * genetika   metabolismus   MeSH
• lidé MeSH
• nádorové proteiny * genetika   metabolismus   MeSH
• nádory * genetika   metabolismus   MeSH
• regulace genové exprese u nádorů * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• diferenciační antigeny * MeSH
• nádorové proteiny * MeSH
• SBSN protein, human MeSH Prohlížeč

Myelodysplastic syndromes (MDS) are preleukemic disorders characterized by clonal growth of mutant hematopoietic stem and progenitor cells. MDS are associated with proinflammatory signaling, dysregulated immune response, and cell death in the bone marrow (BM). Aging, autoinflammation and autoimmunity are crucial features of disease progression, concordant with promoting growth of malignant clones and accumulation of mutations. Suprabasin (SBSN), a recently proposed proto-oncogene of unknown function, physiologically expressed in stratified epithelia, is associated with poor prognosis of several human malignancies. Here, we showed that SBSN is expressed in the BM by myeloid cell subpopulations, including myeloid-derived suppressor cells, and is secreted into BM plasma and peripheral blood of MDS patients. The highest expression of SBSN was present in a patient group with poor prognosis. SBSN levels in the BM correlated positively with blast percentage and negatively with CCL2 chemokine levels and lymphocyte count. In vitro treatment of leukemic cells with interferon-gamma and demethylating agent 5-azacytidine (5-AC) induced SBSN expression. This indicated that aberrant cytokine levels in the BM and epigenetic landscape modifications in MDS patients may underlie ectopic expression of SBSN. Our findings suggest SBSN as a candidate biomarker of high-risk MDS with a possible role in disease progression and therapy resistance.

• Klíčová slova
• 5-azacytidine, MDS, MDSCs, biomarker, suprabasin,
• MeSH
• azacytidin farmakologie   MeSH
• biologické markery krev   metabolismus   MeSH
• chemokin CCL2 metabolismus   MeSH
• diferenciační antigeny krev   genetika   metabolismus   MeSH
• HEK293 buňky MeSH
• interferon gama farmakologie   MeSH
• kompartmentace buňky účinky léků   MeSH
• kostní dřeň metabolismus   MeSH
• leukocyty mononukleární metabolismus   MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• myelodysplastické syndromy krev   metabolismus   MeSH
• myeloidní buňky účinky léků   metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádorové proteiny krev   genetika   metabolismus   MeSH
• počet lymfocytů MeSH
• prognóza MeSH
• protoonkogen Mas MeSH
• regulace genové exprese u nádorů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• azacytidin MeSH
• biologické markery MeSH
• chemokin CCL2 MeSH
• diferenciační antigeny MeSH
• interferon gama MeSH
• MAS1 protein, human MeSH Prohlížeč
• messenger RNA MeSH
• nádorové proteiny MeSH
• protoonkogen Mas MeSH
• SBSN protein, human MeSH Prohlížeč

Radiation and chemotherapy represent standard-of-care cancer treatments. However, most patients eventually experience tumour recurrence, treatment failure and metastatic dissemination with fatal consequences. To elucidate the molecular mechanisms of resistance to radio- and chemotherapy, we exposed human cancer cell lines (HeLa, MCF-7 and DU145) to clinically relevant doses of 5-azacytidine or ionizing radiation and compared the transcript profiles of all surviving cell subpopulations, including low-adherent stem-like cells. Stress-mobilized low-adherent cell fractions differed from other survivors in terms of deregulation of hundreds of genes, including those involved in interferon response. Exposure of cancer cells to interferon-gamma but not interferon-beta resulted in the development of a heterogeneous, low-adherent fraction comprising not only apoptotic/necrotic cells but also live cells exhibiting active Notch signalling and expressing stem-cell markers. Chemical inhibition of mitogen-activated protein kinase/ERK kinase (MEK) or siRNA-mediated knockdown of extracellular signal-regulated kinase 1/2 (Erk1/2) and interferon responsible factor 1 (IRF1) prevented mobilization of the surviving low-adherent population, indicating that interferon-gamma-mediated loss of adhesion and anoikis resistance required an active Erk pathway interlinked with interferon signalling by transcription factor IRF1. Notably, a skin-specific protein suprabasin (SBSN), a recently identified oncoprotein, was among the top scoring genes upregulated in surviving low-adherent cancer cells induced by 5-azacytidine or irradiation. SBSN expression required the activity of the MEK/Erk pathway, and siRNA-mediated knockdown of SBSN suppressed the low-adherent fraction in irradiated, interferon-gamma- and 5-azacytidine-treated cells, respectively, implicating SBSN in genotoxic stress-induced phenotypic plasticity and stress resistance. Importantly, SBSN expression was observed in human clinical specimens of colon and ovarian carcinomas, as well as in circulating tumour cells and metastases of the 4T1 mouse model. The association of SBSN expression with progressive stages of cancer development indicates its role in cancer evolution and therapy resistance.

• Klíčová slova
• 5-azacytidine, cancer stem-like cells, interferon response, suprabasin, therapy-resistance,
• MeSH
• anoikis účinky léků   účinky záření   MeSH
• azacytidin farmakologie   MeSH
• chemorezistence MeSH
• diferenciační antigeny genetika   MeSH
• interferony farmakologie   MeSH
• lidé MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky účinky léků   metabolismus   účinky záření   MeSH
• nádorové proteiny genetika   MeSH
• nádory farmakoterapie   genetika   radioterapie   MeSH
• protinádorové látky farmakologie   MeSH
• regulace genové exprese u nádorů účinky léků   účinky záření   MeSH
• upregulace účinky léků   účinky záření   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• azacytidin MeSH
• diferenciační antigeny MeSH
• interferony MeSH
• nádorové proteiny MeSH
• protinádorové látky MeSH
• SBSN protein, human MeSH Prohlížeč
• suprabasin protein, mouse MeSH Prohlížeč

Over a half million new cases of Head and Neck Squamous Cell Carcinoma (HNSCC) are diagnosed annually worldwide, however, 5 year overall survival is only 50% for HNSCC patients. Recently, high throughput technologies have accelerated the genome-wide characterization of HNSCC. However, comprehensive pipelines with statistical algorithms that account for HNSCC biology and perform independent confirmatory and functional validation of candidates are needed to identify the most biologically relevant genes. We applied outlier statistics to high throughput gene expression data, and identified 76 top-scoring candidates with significant differential expression in tumors compared to normal tissues. We identified 15 epigenetically regulated candidates by focusing on a subset of the genes with a negative correlation between gene expression and promoter methylation. Differential expression and methylation of 3 selected candidates (BANK1, BIN2, and DTX1) were confirmed in an independent HNSCC cohorts from Johns Hopkins and TCGA (The Cancer Genome Atlas). We further performed functional evaluation of NOTCH regulator, DTX1, which was downregulated by promoter hypermethylation in tumors, and demonstrated that decreased expression of DTX1 in HNSCC tumors maybe associated with NOTCH pathway activation and increased migration potential.

• Klíčová slova
• DTX1, HNSCC, expression, integration, methylation,
• MeSH
• dospělí MeSH
• epigenomika * MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• metylace DNA MeSH
• nádorové buněčné linie MeSH
• nádory hlavy a krku genetika   patologie   MeSH
• pohyb buněk genetika   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• receptory Notch genetika   MeSH
• regulace genové exprese u nádorů * MeSH
• RNA interference MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• shluková analýza MeSH
• signální transdukce genetika   MeSH
• spinocelulární karcinom genetika   patologie   MeSH
• stanovení celkové genové exprese metody   MeSH
• tumor supresorové geny * MeSH
• ubikvitinligasy genetika   MeSH
• výpočetní biologie metody   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DTX1 protein, human MeSH Prohlížeč
• receptory Notch MeSH
• ubikvitinligasy MeSH