Previous studies suggest that some S100 proteins are involved in the progression of certain types of cancer. However, no comprehensive data is currently available on the expression of S100 family genes in lung adenocarcinomas. Oligonucleotide array, quantitative reverse transcription-polymerase chain reaction and western blot analyses of lung adenocarcinoma cell lines and bronchiolar epithelial cells (SAEC and NHBE) revealed that S100A2 and S100A4 were the most strikingly downregulated and upregulated members of the S100 family, respectively. Immunohistochemical analyses of 94 primary lung adenocarcinomas showed that positive S100A2 expression (33/94, 35.1%) was significantly associated with lymphatic invasion (P = 0.0233) and positive S100A4 expression (19/94, 20.2%) with vascular invasion (P = 0.0454). Interestingly, a strong inverse relationship was found between S100A4 and p53 expression (P = 0.0008). Survival analyses showed that S100A4 positivity was associated with poor patient prognosis (P = 0.042). S100A2 positivity was not associated with patient survival when the whole patient group was analyzed; however, S100A2 positivity was a favorable prognostic indicator in patients with p53-negative tumors (P = 0.0448). Finally, we used oligonucleotide array analyses and identified potential S100A2 and S100A4 target genes involved in cancer progression: S100A2 induced RUNX3 and REPRIMO; S100A4 induced EZRIN, RUNX1 and WISP1; S100A2 repressed EGFR, NFKB2 and RELA2; and S100A4 repressed ANXA10 and IL1RN. Thus, the present study demonstrates involvement of S100A2 and S100A4 in the progression of lung adenocarcinomas and an inverse association between S100A4 and p53 expression, and provides a list of targets regulated by S100A2 and S100A4.

No abstract

The KT tumor is a transplantable strain of a human Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC), established in severe combined immunodeficiency (SCID) mice, with which the cytokine expression of EBVaGC can be investigated without interference from the infiltrating lymphocytes. As a part of a highdensity oligonucleotide array (GeneChip) analysis of EBVaGC, the interleukin-1␤ (IL-1␤) gene was the only cytokine gene that showed markedly higher expression in the KT tumor cells than in two tumor strains of EBV-negative GC. The results were confirmed by Northern blotting, Western blotting, and enzyme-linked immunosorbent assay. Furthermore, we demonstrated a positive signal for IL-1␤ mRNA in the carcinoma cells of a surgically resected EBVaGC, but not in EBV-negative GC, by in situ hybridization. In vitro, IL-1␤ increased the cell growth of a GC cell line, TMK1. Thus, IL-1␤ may act as an autocrine growth factor in EBVaGC.

Tumor hypoxia is associated with a malignant phenotype of cancer cells and poor patient prognosis. To investigate the role of hypoxia in tumor progression, we studied the effects of hypoxia in the A549 lung adenocarcinoma cell line. First, we showed that hypoxic treatment decreased cell-cell adhesion and induced a scattering of cancer cells. Concomitant with these morphological changes, the motility of cancer cells was increased, as demonstrated by the Boyden chamber assay. Then, we used oligonucleotide array analyses to identify the genes causally related to the hypoxia-induced motile phenotype. The results showed that the expression of approximately 100 genes was induced more than 5-fold by hypoxia. These included (among others) epidermal growth factor receptor (EGFR), as well as other well-known hypoxia-induced genes, such as vascular endothelial growth factor. Immunohistochemical analyses of primary lung adenocarcinomas confirmed the induction of EGFR in tumor cells in the vicinity of necrotic areas, a histological indicator of tumor hypoxia. Remarkably, the EGFR inhibitor AG1478 (10 µM) completely blocked the increased cell motility induced by hypoxia. Thus, the present study demonstrates the importance of the EGFR pathway in the increased motility of cancer cells that occurs in a hypoxic tumor environment. (Cancer Sci 2007; 98: 506-511) L ung cancer is the leading cause of cancer mortality in the USA, Japan and other developed countries.(1) Among the four major histological subtypes, the increased incidence of lung adenocarcinoma is widely recognized.(2) The prognosis for lung carcinoma patients is generally poor: even if diagnosed and treated successfully, patients with stage I lung carcinoma have a 5-year survival rate of only 70% after surgical resection. Currently, the molecular mechanisms underlying the progression of lung adenocarcinomas are not well understood.(4,5) Clearly, the understanding of these mechanisms is essential in establishing more rational therapeutic approaches for the treatment of lung adenocarcinoma patients.Epidermal growth factor receptor (EGFR) is a receptor-type tyrosine kinase that is frequently overexpressed in lung cancer. (6) Besides this overexpression, gene mutation and amplification of EGFR also occurs in lung cancer, especially in lung adenocarcinomas.(7-11) Although it is generally assumed that EGFR is involved in tumor cell proliferation, migration and antiapoptotic signaling, (6) our knowledge concerning the roles of EGFR signaling in the development and progression of lung cancer is still incomplete.There is now increased recognition that hypoxia plays important roles in tumor biology. (12)(13)(14)(15) It has been shown experimentally that hypoxia induces genetic instability, promotes the selection of hypoxia-resistant clones, and facilitates the metastasis of cancer cells.(12-15) Also, low oxygen tension in tumors is associated with a poor prognosis for patients.(13) With regard to cell motility, studies indicate that hypoxia increases the motility of cancer cells ...