Frequent Alteration of Annexin A9 and A10 in HPV-Negative Head and Neck Squamous Cell Carcinomas: Correlation with the Histopathological Differentiation Grade.

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.

Dysregulation of Mir-196b in Head and Neck Cancers Leads to Pleiotropic Effects in the Tumor Cells and Surrounding Stromal Fibroblasts.

The miR-196 family members have been found dysregulated in different cancers. Therefore, they have been proposed as promising biomarkers and therapeutic targets. This study is the first to investigate the role of miR-196b in the development and progression of head and neck squamous cell carcinomas (HNSCC), and also the impact on the surrounding tumor microenvironment. Increased miR-196b levels were detected in 95% of primary tumors and precancerous lesions, although no significant differences were observed between non-progressing versus progressing dysplasias. Furthermore, increased levels of both miR-196a and miR-196b were successfully detected in saliva samples from HNSCC patients. The functional consequences of altered miR-196 expression were investigated in both HNSCC cell lines and cancer-associated fibroblasts (CAFs) by transfection with specific pre-miR precursors. Results showed that both miR-196a and miR-196b elicit cell-specific responses in target genes and downstream regulatory pathways, and have a distinctive impact on cell proliferation, migration and invasion. These data reveal the early occurrence and prevalence of miR-196b dysregulation in HNSCC tumorigenesis, suggesting its utility for early diagnosis and/or disease surveillance and also as a non-invasive biomarker in saliva. The pleiotropic effects of miR-196a/b in HNSCC cell subpopulations and surrounding CAFs may complicate a possible therapeutic application.

Annexin A1 down-regulation in head and neck squamous cell carcinoma is mediated via transcriptional control with direct involvement of miR-196a/b.

Annexin A1 (ANXA1) down-regulation is an early and frequent event in the development of head and neck squamous cell carcinomas (HNSCC). In an attempt to identify the underlying mechanisms of reduced ANXA1 protein expression, this study investigated ANXA1 mRNA expression in HNSCC specimens by both in situ hybridization and RT-qPCR. Results showed a perfect concordance between the pattern of ANXA1 mRNA and protein detected by immunofluorescence in tumors, precancerous lesions and normal epithelia, reflecting that ANXA1 down-regulation occurs at transcriptional level. We also found that both miR-196a and miR-196b levels inversely correlated with ANXA1 mRNA levels in paired HNSCC tissue samples and patient-matched normal mucosa. In addition, endogenous levels of ANXA1 mRNA and protein were consistently and significantly down-regulated upon miR-196a and miR-196b over-expression in various HNSCC-derived cell lines. The direct interaction of both mature miR-196a and miR-196b was further confirmed by transfection with Anxa1 3'UTR constructs. Combined bioinformatics and functional analysis of ANXA1 promoter activity contributed to identify key regions and potential mediators of ANXA1 transcriptional control. This study unveils that, in addition to miR-196a, miR-196b also directly targets ANXA1 in HNSCC.

Adenocarcinoma mucinoso pulmonar con patrón de células en anillo de sello: una entidad infrecuente / Mucinous adenocarcinoma of the lung with signet-ring cell pattern: an infrequent entity

El adenocarcinoma mucinoso de pulmón con patrón de células en anillo de sello es una entidad infrecuente de diagnóstico fácil. Presentamos el caso de un paciente de 55 años con antecedente de cardiopatía isquémica y diagnóstico actual de adenocarcinoma primario pulmonar con patrón de células en anillo de sello. Es necesario descartar un origen primario extrapulmonar, principalmente de localización digestiva. Las técnicas inmunohistoquímicas son de gran utilidad a la hora de establecer diagnósticos diferenciales.

Mucinous adenocarcinoma of the lung with signet-ring cell pattern is an infrequent entity of easy diagnosis. We report the case of a 55 year-old patient with preexisting ischemic heart disease and recent diagnosis of pulmonary adenocarcinoma with signet-ring cell pattern. It is necessary discard a primary extrapulmonar location (digestive tract). Immunohistochemistry is a useful tool in the differential diagnosis.

Annexin A2 localizes to the basal epithelial layer and is down-regulated in dysplasia and head and neck squamous cell carcinoma.

Annexin A2 is a highly expressed gene with important roles in cell membrane physiology and is frequently dysregulated in cancer. The objective of this study was to determine the pattern of expression and prognostic significance of annexin A2 protein in head and neck squamous cell carcinoma. We assessed both quantitative changes and qualitative distribution of annexin A2 mRNA and protein expression in normal and diseased tissues by immunohistochemistry, immunofluorescence and in situ hybridization. Annexin A2 expression was confined to the basal and suprabasal cells of normal epithelium and the protein cellular location was consistently observed at the cell membrane. Expression levels correlated with histopathological grade, showing significant suppression in moderately and poorly differentiated tumours. We conclude that annexin A2 exhibits a characteristic pattern of expression, distinct from other annexins and suggestive of a cell-specific functional role. The marked reduction of annexin A2 in poorly differentiated tumours and dysplastic tissue is expected to result in a loss of function aimed at the coordination of membrane signalling enzyme complexes, actin polymerization and extracellular matrix proteolysis. The phenotypic consequences may become manifest in an alteration of epithelial tissue growth and remodelling with secondary influence on tumour development, progression and metastasis.

Annexin A1 expression in nasopharyngeal carcinoma correlates with squamous differentiation.

BACKGROUND: Alterations of annexin A1 (ANXA1) expression have been reported in various cancers. However, no data are available about the expression of this protein in nasopharyngeal carcinomas (NPCs). The objective of this study was to investigate the expression of ANXA1 in these tumors. METHODS: We examined noncancerous nasopharyngeal mucosa (4 cases) and NPC (20 cases) for ANXA1 expression using immunohistochemistry. RESULTS: All tumor tissues showed markedly reduced ANXA1 expression compared with a strong positive signal observed in the corresponding normal epithelia. We found that ANXA1 expression is associated with the histological type in NPC. Only squamous cell carcinomas presented a positive ANXA1 signal in differentiated areas whereas all poorly differentiated tumors exhibited negative staining. CONCLUSION: Our data show for the first time that ANXA1 expression is down-regulated in NPC and that its expression seems to be related with the squamous differentiation status of these tumors.

Annexin A1 down-regulation in head and neck cancer is associated with epithelial differentiation status.

Annexin A1 (ANXA1) protein expression was evaluated by Western blot in a series of 32 head and neck squamous cell carcinomas (HNSCCs) in a search for molecular alterations that could serve as useful diagnostic/prognostic markers. ANXA1 down-regulation was observed in 24 cases (75%) compared with patient-matched normal epithelium. In relation to clinicopathological variables, ANXA1 down-regulation was significantly associated with advanced T stages (P = 0.029), locoregional lymph node metastases (P = 0.038), advanced disease stage (P = 0.006), hypopharyngeal localization (P = 0.038), and poor histological differentiation (P = 0.005). ANXA1 expression was also analyzed by immunohistochemistry in paraffin-embedded sections from 22 of 32 HNSCCs and 8 premalignant lesions. All dysplastic tissues showed significantly reduced ANXA1 expression compared to a strong positive signal observed in adjacent normal epithelia (except basal and suprabasal cells). A close association was observed between ANXA1 expression and the histological grade in HNSCC. Well-differentiated tumors presented a positive ANXA1 signal in highly keratinized areas whereas moderately and poorly differentiated tumors exhibited very weak or negative staining. Our findings clearly identify ANXA1 as an effective differentiation marker for the histopathological grading of HNSCCs and for the detection of epithelial dysplasia.

Acidos grasos esengiales en eritrocitos de sangre umbilical de recién nacidos prematuros y de término, pequeños o adecuados a la edad gestacional / Essential fatty acids in cord blood erythrocytes for premature and term neonates, both small and adequate for gestational age

Objetivos: Comparar la composición porcentual de los ácidos grasas esenciales poliinsaturados de cadena larga en los fosfolípidos de los eritrocitos de lo sangre de cordón en nacidos de término y pretérmino. Método: La composición porcentual de los ácidos grasas escenciales se determinó por cromatograpia gas-líquido en once recién nacidos de término con peso adecuado para la edadgestacional, once de término pequeños para la edad gestacional y 22prematuros sanos de peso adecuado para la edad gestacional. Resultados: Con respecto los nacidos de término com peso adecuado, los contenidos de ácido araquidónico (20:4 6; ARA) v de ácido dcosahexaenoico (22:6 3; DHA) estaban significativamente diminuidos (p < 0,05) en los eritrocitos de los nacidos pretérmino de peso adecuado. En los de término pequeños sólo era menor la proporción de DHA (p < 0,05), mientras que el porcentaje de ácido linoleico (18:2 6) estaban aumentado, la relación ARA/DHA en los fosfolípidos diferenció significativamente (p < 0,05) a los tres grupos de recién nacidos, siendo menor (2,82) en los de término adecuados, intermedia en los pretérmino (3,46) y más alta (4,22) en los de término pequeños. Conlusión: Probablemente el apoyo nutricional perinatal con ácidos grasas poliinsaturados de cadena larga tendría que ser diferente para los recién nacidos de bajo peso de nacimiento prematuros y de término

Acidos grasos esenciales en eritrocitos de sangre umbilical de recién nacidos prematuros y de término, pequeños o adecuados a la edad gestacional / Essential fatty acids in red blood cells from umbilical cord of preterm and full term newborn infants with either adequate or low bithweight for gestational age

Objetivo: comparar la composición porcentual de los ácidos grasas esenciales poliinsaturados de cadena largo en los fosfolípidos de los eritrocitos de la sangre de cordón en racidos de término y pretérmino. Método: la composición porcenpual de los ácidos grasos escenciales se determinó por cromatografía gas-líquido en once recién nacidos de término con peso adecuado para la edad gestacional, 11 de término pequeños para la edad gestacional y 22 prematuros sanos de peso adecuado para la edad gestacional. Resultados: con respecto los nacidos de término con peso adecuado, los contenidos de ácidos arquidónico (20:4 w 6; ARA) y de ácido docosahexaenoico (22:6 w 3; DHA) estaban significativamente disminuidos (p <0,05) en los eritrocitos de los nacidos pretérmino de peso adecuado. En los de término pequeños sólo era menor la proporción de DHA (p< 0,05), mientras que el porcentaje de ácido linoleico (18:2 v 6) estaba aumentado. La relación ARA/DHA en los fosfolípidos diferenció significativamente (p< 0,05) a los tres grupos de recién nacidos, siendo menor (2,82) en los de término adecuados, intermedia en los pretérmino (3,46) y más alta (4,22) en los de término pequeños. Conclusión: probablemente el apoyo nutricional perinatal con ácidos grasos poliinsaturados de cadena larga tendría que ser diferente para los recién nacidos de bajo peso de nacimiento prematuros y de término