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Okudela K.,Yokohama City University | Mitsui H.,Yokohama City University | Woo T.,Yokohama City University | Arai H.,Kanagawa Prefectural Cardiovascular and Respiratory Center Hospital | And 7 more authors.
Pathology International | Year: 2016

We herein investigated the potential role of cathepsin L in lung carcinogenesis. Lung cancer cell lines and surgically resected tumors were examined for the expression of the cathepsin L protein and copy number alterations in its gene locus. Cathepsin L was stably expressed in bronchiolar epithelial cells. Neoplastic cells expressed cathepsin L at various levels, whereas its expression was completely lost in most of the lung cancer cell lines (63.6%, 7/11) examined. Furthermore, expression levels were lower in a large fraction of lung tumors (69.5%, 139/200) than in bronchiolar epithelia. The expression of cathepsin L was lost in some tumors (16.0%, 32/200). In adenocarcinomas, expression levels were significantly lower in high-grade tumors than in low-grade tumors (one-way ANOVA, P < 0.0500). Copy number alterations were found in 18.0% (36 [32 gain + 4 loss] /200) of lung tumors. No relationship existed between cathepsin L protein expression levels and the copy number of its gene locus (Spearman's rank-order correlation, P = 0.3096). Collectively, these results suggest that the down-regulated expression of cathepsin L, which is caused by an undefined mechanism other than copy number alterations, is involved in the progression of lung adenocarcinomas. © 2016 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd Source


Okudela K.,Yokohama City University | Katayama A.,Tokyo Medical University | Woo T.,Yokohama City University | Mitsui H.,Yokohama City University | And 8 more authors.
PLoS ONE | Year: 2014

This study investigated the proteome modulated by oncogenic KRAS in immortalized airway epithelial cells. Chloride intracellular channel protein 4 (CLIC4), S100 proteins (S100A2 and S100A11), tropomyosin 2, cathepsin L1, integrinsa3, eukaryotic elongation factor 1, vimentin, and others were discriminated. We here focused on CLIC4 to investigate its potential involvement in carcinogenesis in the lung because previous studies suggested that some chloride channels and chloride channel regulators could function as tumor suppressors. CILC4 protein levels were reduced in some lung cancer cell lines. The restoration of CLIC4 in lung cancer cell lines in which CLIC4 expression was reduced attenuated their growth activity. The immunohistochemical expression of the CLIC4 protein was weaker in primary lung cancer cells than in non-tumorous airway epithelial cells and was occasionally undetectable in some tumors. CLIC4 protein levels were significantly lower in a subtype of mucinous ADC than in others, and were also significantly lower in KRAS-mutated ADC than in EGFR-mutated ADC. These results suggest that the alteration in CLIC4 could be involved in restrictedly the development of a specific fraction of lung adenocarcinomas. The potential benefit of the proteome modulated by oncogenic KRAS to lung cancer research has been demonstrated. © 2014 Okudela et al. Source


Okudela K.,Yokohama City University | Mitsui H.,Yokohama City University | Suzuki T.,Yokohama City University | Woo T.,Yokohama City University | And 6 more authors.
International Journal of Clinical and Experimental Pathology | Year: 2014

Our previous studies identified important molecules involved in lung carcinogenesis through a comprehensive search for the downstream targets of oncogenic KRAS, and these findings suggested that an investigation into the downstream targets of oncogenic KRAS might represent a useful strategy for elucidating the common molecular bases of lung cancer. Among the downstream targets of oncogenic KRAS, a focus was placed on HDAC9, a member of the histone deacetylase family, in the present study because epigenetic modification of DNA or the histone proteins is known to play an important role in carcinogenesis. The immunohistochemical expression of HDAC9 was examined in surgically resected primary lung cancers (130 adenocarcinoma, 49 squamous cell carcinomas, one large cell carcinoma, and 6 small cell carcinomas) and potential associations between its expression level and pathologic factors were analyzed. The results showed that HDAC9 expression levels were lower in lung cancer cells than in non-tumor epithelial cells, and were also significantly lower in adenocarcinomas among the histological types. Moreover, HDAC9 expression levels were significantly lower in adenocarcinomas with lymphatic canal involvement. The restoration of HDAC9 in lung cancer cells losing its expression severely attenuated their growth activity in vitro. These results suggest that HDAC9 may be a suppressor and its downregulation might promote the progression process, especially in lung adenocarcinomas. Source


Okudela K.,Yokohama City University | Okudela K.,Kanagawa Prefectural Cardiovascular and Respiratory Center Hospital | Umeda S.,Yokohama City University | Umeda S.,Kanagawa Prefectural Cardiovascular and Respiratory Center Hospital | And 6 more authors.
Pathology International | Year: 2014

We herein describe a case of a benign pulmonary tumor with distinctive histopathological features. A 55-year-old Japanese male presented with a well-demarcated tumor in the left upper lobe of his lung, which gradually increased in size from 18 to 21mm over 24 months. The resected tumor consisted of an epithelial component of compact irregular glands and mesenchymal component of fascicles between the glands. The differentiation of pneumocytes and smooth muscle cells was immunohistochemically detected in the epithelial component and the mesenchymal component, respectively. No mitosis, necrosis, bleeding, or invasion was observed. A histopathologic diagnosis of fibroleiomyomatous hamartoma was made. We also review previously reported tumors with similar histopathological features and discuss their differential diagnosis and histogenesis. © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd. Source


Okudela K.,Yokohama City University | Yazawa T.,Yokohama City University | Tajiri M.,Kanagawa Prefectural Cardiovascular and Respiratory Center Hospital | Omori T.,Kanagawa Prefectural Cardiovascular and Respiratory Center Hospital | And 5 more authors.
Pathology Research and Practice | Year: 2010

We present a case of a polypoid tumor located in the right middle lobe bronchus. The tumor was composed of bi-layered glandular or ductular structures consisting of inner cuboidal cells and outer multipolar cells. Immunohistochemical examinations confirmed epithelial and myoepithelial differentiation in the inner and outer components, respectively. Consequently, the tumor was diagnosed as an epithelial-myoepithelial carcinoma. Epithelial-myoepithelial carcinomas of the bronchus are very rare neoplasms with low-grade malignant potential. To date, including our case, only 27 cases have been reported in the English literature. Here, we review the reported cases and compare them with other salivary gland-type carcinomas regarding clinical, biological, and genetic features. © 2009 Elsevier GmbH. All rights reserved. Source

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