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1.
Cancers (Basel) ; 11(3)2019 Mar 01.
Article in English | MEDLINE | ID: mdl-30823625

ABSTRACT

The SOX2 gene located at 3q26 is frequently amplified and overexpressed in multiple cancers, including head and neck squamous cell carcinomas (HNSCC). The tumor-promoting activity and involvement of SOX2 in tumor progression has been extensively demonstrated, thereby emerging as a promising therapeutic target. However, the role of SOX2 in early stages of tumorigenesis and its possible contribution to malignant transformation remain unexplored. This study investigates for the first time SOX2 protein expression by immunohistochemistry and gene amplification by real-time PCR using a large series of 94 laryngeal precancerous lesions. Correlations with the histopathological classification and the risk of progression to invasive carcinoma were established. Nuclear SOX2 expression was frequently detected in 38 (40%) laryngeal dysplasias, whereas stromal cells and normal adjacent epithelia showed negative expression. SOX2 gene amplification was detected in 18 (33%) of 55 laryngeal dysplasias. Univariate Cox analysis showed that SOX2 gene amplification (p = 0.046) and protein expression (p < 0.001) but not histological grading (p = 0.432) were significantly associated with laryngeal cancer risk. In multivariate stepwise analysis including age, tobacco, histology, SOX2 gene amplification and SOX2 expression, SOX2 expression (HR = 3.531, 95% CI 1.144 to 10.904; p = 0.028) was the only significant independent predictor of laryngeal cancer development. These findings underscore the relevant role of SOX2 in early tumorigenesis and a novel clinical application of SOX2 expression as independent predictor of laryngeal cancer risk in patients with precancerous lesions beyond current WHO histological grading. Therefore, targeting SOX2 could lead to effective strategies for both cancer prevention and treatment.

2.
J Clin Med ; 8(2)2019 Feb 10.
Article in English | MEDLINE | ID: mdl-30744186

ABSTRACT

The annexin protein superfamily has been implicated in multiple physiological and pathological processes, including carcinogenesis. Altered expression of various annexins has frequently been observed and linked to the development and progression of various human malignancies. However, information is lacking on the expression and clinical significance of annexin A9 (ANXA9) and A10 (ANXA10) in head and neck squamous cell carcinomas (HNSCC). ANXA9 and ANXA10 expression was evaluated in a large cohort of 372 surgically treated HPV-negative HNSCC patients and correlated with the clinicopathologic parameters and disease outcomes. Down-regulation of ANXA9 expression was found in 42% of HNSCC tissue samples, compared to normal epithelia. ANXA9 expression in tumors was significantly associated with oropharyngeal location and histological differentiation grade (P < 0.001). In marked contrast, ANXA10 expression was absent in normal epithelium, but variably detected in the cytoplasm of cancer cells. Positive ANXA10 expression was found in 64% of tumors, and was significantly associated with differentiation grade (P < 0.001), being also more frequent in oropharyngeal tumors (P = 0.019). These results reveal that the expression of both ANXA9 and ANXA10 is frequently altered in HNSCC and associated to the tumor differentiation grade, suggesting that they could be implicated in the pathogenesis of these cancers.

4.
J Immunol ; 197(1): 296-302, 2016 07 01.
Article in English | MEDLINE | ID: mdl-27259858

ABSTRACT

Matrix metalloproteases (MMPs) regulate innate immunity acting over proinflammatory cytokines, chemokines, and other immune-related proteins. MMP-25 (membrane-type 6-MMP) is a membrane-bound enzyme predominantly expressed in leukocytes whose biological function has remained largely unknown. We have generated Mmp25-deficient mice to elucidate the in vivo function of this protease. These mutant mice are viable and fertile and do not show any spontaneous phenotype. However, Mmp25-null mice exhibit a defective innate immune response characterized by low sensitivity to bacterial LPS, hypergammaglobulinemia, and reduced secretion of proinflammatory molecules. Moreover, these immune defects can be tracked to a defective NF-κB activation observed in Mmp25-deficient leukocytes. Globally, our findings provide new mechanistic insights into innate immunity through the activity of MMP-25, suggesting that this proteinase could be a potential therapeutic target for immune-related diseases.


Subject(s)
Hypergammaglobulinemia/immunology , Leukocytes/immunology , Matrix Metalloproteinases, Membrane-Associated/metabolism , Animals , Cells, Cultured , Cytokines/metabolism , GPI-Linked Proteins/genetics , GPI-Linked Proteins/metabolism , Immunity, Innate/genetics , Inflammation Mediators/metabolism , Lipopolysaccharides/immunology , Matrix Metalloproteinases, Membrane-Associated/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , NF-kappa B/metabolism , Protein Binding , Signal Transduction
5.
J Blood Med ; 5: 157-67, 2014.
Article in English | MEDLINE | ID: mdl-25170286

ABSTRACT

Dyskeratosis congenita (DC) is an inherited bone marrow failure (BMF) syndrome characterized by the classic triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia. However, patients usually develop BMF and are predisposed to cancer, with increased risk for squamous cell carcinoma and hematolymphoid neoplasms. DC is a disease of defective telomere maintenance and is heterogeneous at the genetic level. It can be inherited in X-linked, autosomal dominant, or autosomal recessive patterns. Mutations in at least ten telomere- and telomerase-associated genes have been described in DC. There are no targeted therapies for DC and patients usually die of BMF due to a deficient renewing capability of hematopoietic stem cells. Allogeneic hematopoietic stem cell transplantation is the only curative treatment for BMF.

6.
Cell Rep ; 8(2): 542-56, 2014 Jul 24.
Article in English | MEDLINE | ID: mdl-25017063

ABSTRACT

We generated mice deficient in Lon protease (LONP1), a major enzyme of the mitochondrial quality control machinery. Homozygous deletion of Lonp1 causes early embryonic lethality, whereas its haploinsufficiency protects against colorectal and skin tumors. Furthermore, LONP1 knockdown inhibits cellular proliferation and tumor and metastasis formation, whereas its overexpression increases tumorigenesis. Clinical studies indicate that high levels of LONP1 are a poor prognosis marker in human colorectal cancer and melanoma. Additionally, functional analyses show that LONP1 plays a key role in metabolic reprogramming by remodeling OXPHOS complexes and protecting against senescence. Our findings demonstrate the relevance of LONP1 for cellular and organismal viability and identify this protease as a central regulator of mitochondrial activity in oncogenesis.


Subject(s)
ATP-Dependent Proteases/metabolism , Colorectal Neoplasms/metabolism , Melanoma/metabolism , Mitochondria/metabolism , Oxidative Phosphorylation , Skin Neoplasms/metabolism , ATP-Dependent Proteases/genetics , Animals , Cell Proliferation , Cellular Senescence/genetics , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Gene Deletion , HCT116 Cells , HEK293 Cells , Haploinsufficiency , Homozygote , Humans , Melanoma/genetics , Melanoma/pathology , Mice , Skin Neoplasms/genetics , Skin Neoplasms/pathology
7.
Nat Commun ; 4: 2268, 2013.
Article in English | MEDLINE | ID: mdl-23917225

ABSTRACT

Defining the relationship between ageing and cancer is a crucial but challenging task. Mice deficient in Zmpste24, a metalloproteinase mutated in human progeria and involved in nuclear prelamin A maturation, recapitulate multiple features of ageing. However, their short lifespan and serious cell-intrinsic and cell-extrinsic alterations restrict the application and interpretation of carcinogenesis protocols. Here we present Zmpste24 mosaic mice that lack these limitations. Zmpste24 mosaic mice develop normally and keep similar proportions of Zmpste24-deficient (prelamin A-accumulating) and Zmpste24-proficient (mature lamin A-containing) cells throughout life, revealing that cell-extrinsic mechanisms are preeminent for progeria development. Moreover, prelamin A accumulation does not impair tumour initiation and growth, but it decreases the incidence of infiltrating oral carcinomas. Accordingly, silencing of ZMPSTE24 reduces human cancer cell invasiveness. Our results support the potential of cell-based and systemic therapies for progeria and highlight ZMPSTE24 as a new anticancer target.


Subject(s)
Neoplasms/pathology , Nuclear Proteins/metabolism , Progeria/metabolism , Progeria/pathology , Protein Precursors/metabolism , Aging/pathology , Animals , Biomarkers/metabolism , Carcinogenesis/pathology , Female , Humans , Lamin Type A , Male , Membrane Proteins/deficiency , Membrane Proteins/metabolism , Metalloendopeptidases/deficiency , Metalloendopeptidases/metabolism , Mice , Mosaicism , Neoplasm Invasiveness , Neoplasms/metabolism , Phenotype
8.
Autophagy ; 9(8): 1188-200, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23782979

ABSTRACT

The identification of inflammatory bowel disease (IBD) susceptibility genes by genome-wide association has linked this pathology to autophagy, a lysosomal degradation pathway that is crucial for cell and tissue homeostasis. Here, we describe autophagy-related 4B, cysteine peptidase/autophagin-1 (ATG4B) as an essential protein in the control of inflammatory response during experimental colitis. In this pathological condition, ATG4B protein levels increase in parallel with the induction of autophagy. Moreover, ATG4B expression is significantly reduced in affected areas of the colon from IBD patients. Consistently, atg4b (-/-) mice present Paneth cell abnormalities, as well as an increased susceptibility to DSS-induced colitis. atg4b-deficient mice exhibit significant alterations in proinflammatory cytokines and mediators of the immune response to bacterial infections, which are reminiscent of those found in patients with Crohn disease or ulcerative colitis. Additionally, antibiotic treatments and bone marrow transplantation from wild-type mice reduced colitis in atg4b (-/-) mice. Taken together, these results provided additional evidence for the importance of autophagy in intestinal pathologies and describe ATG4B as a novel protective protein in inflammatory colitis. Finally, we propose that atg4b-null mice are a suitable model for in vivo studies aimed at testing new therapeutic strategies for intestinal diseases associated with autophagy deficiency.


Subject(s)
Autophagy , Colitis/pathology , Colitis/prevention & control , Cysteine Endopeptidases/metabolism , Homeostasis , Intestinal Mucosa/metabolism , Intestines/pathology , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Autophagy/drug effects , Autophagy-Related Proteins , Colitis/drug therapy , Cysteine Endopeptidases/deficiency , Cytokines/metabolism , Dextran Sulfate , Disease Susceptibility , Hematopoiesis/drug effects , Homeostasis/drug effects , Ileum/drug effects , Ileum/pathology , Inflammation Mediators/metabolism , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/pathology , Intestines/drug effects , Mice , Mice, Inbred C57BL , Paneth Cells/drug effects , Paneth Cells/pathology , Paneth Cells/ultrastructure
9.
J Biol Chem ; 288(20): 14647-14656, 2013 May 17.
Article in English | MEDLINE | ID: mdl-23548910

ABSTRACT

Human MMP-1 is a matrix metalloproteinase repeatedly associated with many pathological conditions, including cancer. Thus, MMP1 overexpression is a poor prognosis marker in a variety of advanced cancers, including colorectal, breast, and lung carcinomas. Moreover, MMP-1 plays a key role in the metastatic behavior of melanoma, breast, and prostate cancer cells. However, functional and mechanistic studies on the relevance of MMP-1 in cancer have been hampered by the absence of an in vivo model. In this work, we have generated mice deficient in Mmp1a, the murine ortholog of human MMP1. Mmp1a(-/-) mice are viable and fertile and do not exhibit obvious abnormalities, which has facilitated studies of cancer susceptibility. These studies have shown a decreased susceptibility to develop lung carcinomas induced by chemical carcinogens in Mmp1a(-/-) mice. Histopathological analysis indicated that tumors generated in Mmp1a(-/-) mice are smaller than those of wild-type mice, consistently with the idea that the absence of Mmp-1a hampers tumor progression. Proteomic analysis revealed decreased levels of chitinase-3-like 3 and accumulation of the receptor for advanced glycation end-products and its ligand S100A8 in lung samples from Mmp1a(-/-) mice compared with those from wild-type. These findings suggest that Mmp-1a could play a role in tumor progression by modulating the polarization of a Th1/Th2 inflammatory response to chemical carcinogens. On the basis of these results, we propose that Mmp1a knock-out mice provide an excellent in vivo model for the functional analysis of human MMP-1 in both physiological and pathological conditions.


Subject(s)
Gene Expression Regulation, Enzymologic , Inflammation/metabolism , Lung Neoplasms/metabolism , Matrix Metalloproteinase 1/metabolism , Animals , Carcinoma/metabolism , Cell Proliferation , Disease Progression , Mice , Mice, Inbred C57BL , Mice, Knockout , Neoplasm Metastasis , Peptide Hydrolases/metabolism , Prognosis , Urethane
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