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In a wide range of human cancers, increased levels of heat shock protein 27 (Hsp27) are closely associated with tumorigenesis, metastasis, resistance to anticancer therapeutics, and thus poor prognosis. In this study, we evaluate the radiosensitizing effects of Hsp27 gene silencing using OGX-427, a second-generation antisense oligonucleotide (ASO), on the radioresistant head and neck squamous cell carcinoma (HNSCC) SQ20B cells. In vitro, the downregulation of Hsp27 significantly enhanced radiation-induced apoptotic and clonogenic death, and promoted Akt inactivation. In vivo, combining OGX-427 with local tumor irradiation (5 x 2 Gy) led to a significant regression of SQ20B tumors related to a high rate of apoptosis and decreased levels of glutathione antioxidant defenses. Increasing the total radiation dose (15 x 2 Gy) significantly amplified the radiosensitizing effect of OGX-427. Treatment of tumors with OGX-427 plus radiation resulted in a decrease in angiogenesis associated with a reduced activation of the Akt pathway. Furthermore, the combined treatment enhanced the survival of SQ20B-bearing mice and showed no signs of acute and delayed toxicity. Our findings demonstrate for the first time that Hsp27 knockdown enhances the cytotoxic effects of radiotherapy in vivo and provide preclinical proof of principle for clinical trials using Hsp27 antisense technology in the treatment of patients with HNSCC radioresistant cancers.

Lung cancer is most prevalent human cancer worldwide. However, no molecular markers are currently available for predicting lung cancer prognosis. Therefore, identifying novel biomarkers may be useful for improving clinical diagnosis and patient stratification. Krüppel-like factor 4 (KLF4) is a transcription factor with opposing roles in different human cancers. Its overexpression in several cancers is correlated with a poor prognosis. However, the expression and role of KLF4 in lung cancer remains to be elucidated. The aim of this study was to determine the profile of KLF4 expression in different types of lung cancer. The KLF4 protein expression level was tested and evaluated by immunohistochemical analysis in 47 lung tumors and normal tissues, and then correlated with clinical characteristics. A differential expression of KLF4 was observed between normal tissue and each of the lung cancer types. A significant decrease in KLF4 expression was observed in non-small-cell lung cancer (NSCLC) compared with that in normal tissue, while significant overexpression was detected in small-cell lung cancer. Furthermore, a higher rate of expression was observed in stage II, III and IV disease compared with stage I disease in NSCLC tissues. KLF4 expression was not found to be associated with age or gender. Our results suggested that the KLF4 protein level may be a potential biomarker in patients with advanced lung cancer.

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Ceramide-induced endothelial cell apoptosis boosts intestinal stem cell radiosensitivity.However, the molecular connection between these two cellular compartments has not been clearly elucidated. Here we report that Ceramide and its related enzyme acid sphingomyelinase (ASM) are secreted by irradiated endothelial cells and act as bystander factors to enhance the radiotoxicity of intestinal epithelium. Ceramide and the 2 isoforms of ASM were acutely secreted in the blood serum of wild-type mice after 15Gy radiation dose, inducing a gastrointestinal syndrome. Interestingly, serum Ceramide was not enhanced in irradiated ASMKO mice, which are unable to develop intestinal failure injury. Since ASM/Ceramide were secreted by primary endothelial cells, their contribution was studied in intestinal epithelium dysfunction using co-culture of primary endothelial cells and intestinal T84 cells. Adding exogenous ASM or Ceramide enhanced epithelial cell growth arrest and death. Conversely, blocking their secretion by endothelial cells using genetic, pharmacological, or immunological approaches abolished intestinal T84 cell radiosensitivity. Use of enteroid models revealed ASM and Ceramide-mediated deleterious mode-of-action: when Ceramide reduced the number of intestinal crypt-forming enteroids without affecting their structure, ASM induced a significant decrease of enteroid growth without affecting their number. Identification of specific and different roles for Ceramide and ASM secreted by irradiated endothelial cells opens new perspectives in the understanding of intestinal epithelial dysfunction after radiation and defines a new class of potential therapeutic radiomitigators. Significance: This study identifies secreted ASM and Ceramide as paracrine factors enhancing intestinal epithelial dysfunction, revealing a previously unknown class of mediators of radiosensitivity.

Abstract. Late detection and lack of standard treatment strategies in larynx cancer patients result in high levels of mortality and poor prognosis. Prognostic stratification of larynx cancer patients based on molecular prognostic tumor biomarkers may lead to more efficient clinical management. Krüppel-like factor 4 (KLF4) and Heat Shock Protein 27 (HSP27) have an important role in tumorigenesis and are considered promising candidate biomarkers for various types of cancer. However, their role in larynx carcinoma remains to be elucidated. The present study aimed to determine KLF4 and HSP27 expression profiles in laryngeal tumors. The protein and mRNA expression levels of KLF4 and HSP27 were evaluated by immunohistochemical and reverse transcription-polymerase chain reaction analyses in 44 larynx carcinoma samples and 21 normal tissue samples, and then correlated with clinical characteristics. A differential expression of KLF4 and HSP27 was observed between normal and tumor tissues. The protein and mRNA expression levels of KLF4 were significantly decreased in larynx squamous cell carcinoma (LSCC) compared with normal tissue, whereas HSP27 was significantly overexpressed in tumor tissues compared with normal tissues, at the protein and mRNA levels. KLF4 expression decreased gradually with tumor progression whereas HSP27 expression increased. A significant difference was observed between stages I and IV. KLF4 and HSP27 exhibit opposite functions and roles in the carcinogenic process of LSCC. Their role in laryngeal cancer initiation and progression emphasizes their use as potential future targets for prognosis and treatment. KLF4 and HSP27 expression levels may act as potential biomarkers in patients with cancer of the larynx.