ABSTRACT
Cellular senescence is an antiproliferative response with essential functions in tumor suppression and tissue homeostasis. Here we show that SIX1, a member of the SIX family of homeobox transcriptional factors, is a novel repressor of senescence. Our data show that SIX1 is specifically downregulated in fibroblasts upon oncogenic stress and other pro-senescence stimuli, as well as in senescent skin premalignant lesions. Silencing of SIX1 in human fibroblasts suffices to trigger senescence, which is mediated by p16INK4A and lacks a canonical senescence-associated secretory phenotype. Interestingly, SIX1-associated senescence is further characterized by the expression of a set of development and differentiation-related genes that significantly overlap with genes associated with SIX1 in organogenesis or human tumors, and show coincident regulation in oncogene-induced senescence. Mechanistically, we show that gene regulation by SIX1 during senescence is mediated, at least in part, by cooperation with Polycomb repressive complexes. In summary, our results identify SIX1, a key development regulator altered in human tumors, as a critical repressor of cellular senescence, providing a novel connection between senescence, differentiation and tumorigenesis.
Subject(s)
Cell Differentiation/genetics , Cellular Senescence/genetics , Cyclin-Dependent Kinase Inhibitor p16/genetics , Fibroblasts/metabolism , Homeodomain Proteins/genetics , Animals , Blotting, Western , Cell Line , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Fibroblasts/cytology , Gene Expression Profiling/methods , Homeodomain Proteins/metabolism , Humans , Immunohistochemistry , Mice, 129 Strain , Papilloma/genetics , Papilloma/metabolism , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , Skin Neoplasms/genetics , Skin Neoplasms/metabolismABSTRACT
Introducción. La infiltración eosinofílica del músculo esquelético es rara, no existe en muchos casos un factor etiológico identificable, se trata de miositis eosinofílicas aisladas. Puede asociarse a infecciones parasitarias o a fármacos, y puede ser manifestación de raras condiciones sistémicas de hipereosinofilia como el síndrome mialgia-eosinofilia y el síndrome idiopático hipereosinofílico. Las miopatías eosinofílicas deben distinguirse de las miopatías inflamatorias más comunes como polimiositis y dermatomiositis. Caso clínico. Niño de 9 años con discreta torpeza motora, desarrollo psicomotor y exploración neurológica normales. En la analítica destacaba elevación de transaminasas (GOT 271, GPT 157 UI/L), CPK 7.517 UI/L y eosinofilia (707/ mL). La mioglobinuria fue negativa; serologías de cisticercosis, triquinosis, hidatidosis y toxocariasis, negativas; parásitos en heces, negativos; gammaglobulinas, normales; anticuerpos antimúsculo liso, antinucleares y anti-KLM, negativos. Estudio cardiológico normal. El padre, madre y los dos hermanos mostraban una analítica normal. La biopsia muscular reveló miopatía inflamatoria con abundantes eosinófilos, sin evidencia de parásitos ni de alteración de las proteínas de membrana: distrofina, sarcoglicanos y merosina. Dos años después permanece asintomático y mantiene elevadas las enzimas musculares en todos los controles, con cifras de CPK entre 3.065 y 9.616 UI/L, y eosinofilia con oscilación entre 634 y 1.026/ mL. Se ensayó tratamiento corticoideo sin obtenerse respuesta. Conclusión. Pensamos que se trata de una polimiositis eosinofílica, que plantea numerosos interrogantes en cuanto a etiopatogenia, manejo y evolución (AU)
Subject(s)
Child , Male , Humans , Steroids , Eosinophilia-Myalgia Syndrome , Muscle, Skeletal , Treatment Failure , Anti-Inflammatory Agents , BiopsyABSTRACT
INTRODUCTION: Eosinophil infiltration of skeletal muscle is rare, but often no etiological factor can be identified and these are isolated eosinophilic myositis. They may be associated with parasite infections or drugs, or be features of rare systemic disorders of hypereosinophilia, such as the myalgia eosinophilia syndrome and the idiopathic hypereosinophilic syndrome. The eosinophilic myopathies should be distinguished from the commoner inflammatory myopathies such as polymyositis and dermatomyositis. CLINICAL CASE: A nine year old boy with slight motor clumsiness but normal psychomotor development and neurological findings. Laboratory findings showed slightly raised serum transaminases (SGOT 271, SGPT 157 UI/L), CPK 7517 UI/L and eosinophilia (707/mL). Investigations for myoglobin cysticercosis, trichinosis, hydatidosis and toxicariasis were negative. No parasites were found in the faeces. The gammaglobulins were normal. Anti smooth muscle, antinuclear and anti KLM antibodies were negative. Cardiological studies were normal. His father, mother and two siblings had normal results of laboratory tests. Muscle biopsy showed inflammatory myopathy with abundant eosinophils, no evidence of parasites, no alteration of membrane proteins: dystrophin, sarcoglycan and merosine. Two years later he remains asymptomatic, maintains raised muscle enzyme levels in all tests with figures for CPK between 3,065 and 9,616UI/L, and eosinophilia ranging between 634 and 1,026/mL. Corticosteroid treatment was tried but no response obtained. CONCLUSION: We consider this to be a case of eosinophilic polymyositis which gives rise to many questions regarding etiopathogenesis, management and prognosis.
