Dissimilarity in gene expression profiles of lung adenocarcinoma in Japanese men and women.

BACKGROUND: Although clinical differences in lung cancer between men and women have been noted, few studies have examined the sex dissimilarity using gene expression analysis. OBJECTIVE: The purpose of this study was to determine the different molecular carcinogenic mechanisms involved in lung cancers in Japanese men and women. METHODS: Patients who received surgery for stage I lung adenocarcinoma were included. RNA was extracted from cancerous and normal tissue, and gene expression was then examined with oligonucleotide microarray analysis. A quantitative polymerase chain reaction assay was performed. RESULTS: In a microarray analysis of tissue from 13 men and 6 women, 12 genes were under-expressed and 24 genes were overexpressed in lung adenocarcinoma in women compared with men. Genes related to cell cycle were present in underexpressed genes, and genes related to apoptosis, ubiquitination, and metabolism were observed in overexpressed genes. Of interest among the selected genes were WAP four-disulfide core domain 2 (WFDC2) and major histocompatibility complex, class II, DM alpha (HLA-DMA); these genes were classified into 2 groups by hierarchical clustering analysis. Expression of WFDC2 in nonsmokers was significantly higher than that in smokers (P=0.023). However, there was no significant difference in HLA-DMA expression between smokers and nonsmokers. CONCLUSION: Thirty-six genes that characterize lung adenocarcinoma by sex were selected. This information may contribute to the development of novel diagnostic techniques and treatment modalities that consider sex differences in lung adenocarcinoma.

Down-regulation of transcription elogation factor A (SII) like 4 (TCEAL4) in anaplastic thyroid cancer.

BACKGROUND: Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies and appears to arise mainly from transformation of pre-existing differentiated thyroid cancer (DTC). However, the carcinogenic mechanism of anaplastic transformation remains unclear. Previously, we investigated specific genes related to ATC based on gene expression profiling using cDNA microarray analysis. One of these genes, transcription elongation factor A (SII)-like 4 (TCEAL4), encodes a member of the transcription elongation factor A (SII)-like gene family. The detailed function of TCEAL4 has not been described nor has any association between this gene and human cancers been reported previously. METHODS: To investigate the role of TCEAL4 in ATC carcinogenesis, we examined expression levels of TCEAL4 in ACLs as well as in other types of thyroid cancers and normal human tissue. RESULTS: Expression of TCEAL4 was down-regulated in all 11 ACLs as compared to either normal thyroid tissues or papillary and follicular thyroid cancerous tissues. TCEAL4 was expressed ubiquitously in all normal human tissues tested. CONCLUSION: To our knowledge, this is the first report of altered TCEAL4 expression in human cancers. We suggest that loss of TCEAL4 expression might be associated with development of ATC from DTC. Further functional studies are required.

Growth-suppressive function of phosphatidylethanolamine-binding protein in anaplastic thyroid cancer.

BACKGROUND: A cDNA microarray analysis of anaplastic thyroid cancer cell lines (ACL) was recently performed and the down-regulation of phosphatidylethanolamine-binding protein (PBP) [RAF kinase inhibitor protein (RKIP)] in ACL compared to normal thyroid tissues was identified. MATERIALS AND METHODS: The expression levels of PBP in primary anaplastic and papillary thyroid cancer, thyroid cancer cell lines (anaplastic, papillary and follicular) and several normal human organs were examined. To examine the function of PBP, cell-growth assays were performed. RESULTS: PBP expression was reduced in anaplastic thyroid cancers, compared to either normal thyroid tissues or differentiated thyroid cancers. PBP was expressed ubiquitously in normal human tissues. Exogenous PBP expression suppressed ACL growth, and suggested a tumor suppressive function of PBP in ACL. CONCLUSION: This is the first report demonstrating that PBP may be a tumor suppressor whose loss is associated with development of anaplastic thyroid cancer from differentiated thyroid cancer.

Overexpressed in anaplastic thyroid carcinoma-1 (OEATC-1) as a novel gene responsible for anaplastic thyroid carcinoma.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is one of the most fulminant human malignancies. However, the molecular carcinogenic mechanisms of ATC are understood poorly. Recently, the authors performed a cyclic DNA (cDNA) microarray analysis with 11 anaplastic thyroid carcinoma cell lines (ACLs) and discovered several novel responsible genes for ACLs and ATC. From the extended list, they focused on hypothetical and anonymous genes and investigated a novel gene, named the overexpressed in anaplastic thyroid carcinoma-1 (OEATC-1) gene. METHODS: To investigate the role of the OEATC-1 gene in ATC carcinogenesis, first, the expression levels of OEATC-1 in ACLs, in various types of carcinoma cell lines, and in normal human tissues were examined with reverse transcriptase-polymerase chain reaction analysis. To explore the effect of OEATC-1 in ATC development, a cell-growth assay was performed with KTA2 cells under OEATC-1 gene silencing using small-interfering RNA (siRNA). RESULTS: OEATC-1 was overexpressed significantly in ACLs and in other types of carcinoma cell lines with various expression levels. Conversely, in normal human tissues, OEATC-1 was expressed weakly in placenta, kidney, spleen, thymus, small intestine, and thyroid gland. To evaluate the effects of OEATC-1 on tumor cell growth, gene silencing was caused by transfecting the plasmid-generating siRNA effect to KTA2 cells. Consequently, the silencing of OEATC-1 significantly suppressed the cell growth compared with controls. CONCLUSIONS: The current results indicated that OEATC-1 may have some oncogenic or cell growth-promoting function in ACL. OEATC-1 is considered a novel responsible gene in ATC.

Upregulation and overexpression of DVL1, the human counterpart of the Drosophila dishevelled gene, in prostate cancer.

AIMS AND BACKGROUND: The Wnt/beta-catenin signaling pathway is one of the main carcinogenic mechanisms in human malignancies including prostate cancer. Recently, the DVL1 gene was identified as a middle molecule of the Wnt/beta-catenin signaling pathway. In addition, alterations of the DVL1 gene have been reported in breast and cervical cancer. The abnormality of beta-catenin in prostate cancer has been well studied, so the examination of the DVL1 gene in prostate cancer is appealing. METHODS: We investigated DVL1 messenger RNA alterations by semiquantitative PCR (SQ-PCR) in 20 primary prostate cancers and assessed the protein expression by immunohistochemical analysis in the same samples. In addition, DVL1 and beta-catenin protein expression was evaluated with a new validated set of 20 prostate cancers. RESULTS: SQ-PCR revealed significant overexpression of DVL1 in prostate cancer (65%). Upregulation of the DVL1 gene product in prostate cancer was confirmed by immunostaining. With SQ-PCR and immunostaining, none of the cases showed underexpression or downregulation of DVL1. In addition, the data showed correlations between DVL1 mRNA and protein expression. Interestingly, the expression level of DVL1 increased with worsening histological grade. In addition, a correlation between DVL1 expression and beta-catenin expression was confirmed. CONCLUSIONS: DVL1 was overexpressed in prostate cancer and its overexpression might be related to prostate cancer progression through the Wnt/beta-catenin pathway.

Up-regulation of transcriptional factor E2F1 in papillary and anaplastic thyroid cancers.

Expression of genes in the Rb-E2F signaling pathway is controlled by E2F transcriptional factors originally defined as molecules that bind to the promoter of E2 adenovirus. The E2F gene family consists of six members and is designated E2F1-6. The Rb-E2F signaling pathway is among the main regulators of the cell cycle, hence its importance in differentiation and oncogenesis. We document here up-regulation of E2F1, but not other members of the E2F gene family, in 15 of 18 primary papillary thyroid cancers examined (83%) in comparison to corresponding noncancerous thyroid tissues and in all of 11 anaplastic thyroid cancer (ATC) cell lines (100%). The E2F4 gene, however, was down-regulated in 12 of the papillary thyroid cancers (67%). Immunohistochemical analysis with antibody to E2F1 revealed prominent intracellular E2F1 protein in most of the primary papillary cancers (16 of 18; 89%) but was not detectable in normal thyroid tissues. These data indicated that increased expression of the E2F1 gene might play a significant role in human thyroid carcinogenesis through derangement of the Rb-E2F signaling pathway.