Prognostic significance of S100A4 expression in gallbladder cancer

Ajiki, Tetsuo; Murao, Shinichi; Kamigaki, Takashi; Maeda, Sakan; Ku, Yonson; Kuroda, Yoshikazu

doi:10.3892/ijo.20.5.937

Cited by 31 publications

(32 citation statements)

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“…In humans, an increase in S100A4 expression has been correlated with aggressiveness and worse prognosis for patients with different types of carcinoma, including colorectal, gallbladder, pancreas, bladder, gastric, breast, non-small cell lung, and prostate cancers. [11][12][13][14][15][16][17][18] The exact mechanism for the metastasis-promoting activity by S100A4 is poorly understood. S100A4 may influence growth regulation, remodeling of the extracellular matrix, angiogenesis, cell detachment, and cell motility.…”

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Hypomethylation-induced expression of S100A4 in endometrial carcinoma

et al. 2007

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Expression of various S100 genes has been associated with clinically aggressive subtypes in a variety of different cancers. We hypothesized that S100A4 would be overexpressed in endometrial carcinoma compared to benign endometrium. Quantitative real-time RT-PCR (qRT-PCR) was used to quantify the mRNA level of S100A4 in benign endometrium (n ¼ 19), endometrioid adenocarcinoma (n ¼ 87), and non-endometrioid tumors (n ¼ 21). Immunohistochemistry was used to verify the results of qRT-PCR and to assess protein localization. Possible mechanisms of S100A4 gene regulation were also examined. S100A4 was overexpressed in the grade 3 endometrioid tumors, uterine papillary serous carcinoma, and uterine malignant mixed mü llerian tumor. Expression in grade 1 and grade 2 endometrioid tumors was comparable to that of normal endometrium, which was quite low. Expression was significantly higher in stage III and IV tumors compared with stage I. By immunohistochemistry, S100A4 was expressed in the tumor cell cytoplasm of poorly differentiated tumors, but was not detected in normal endometrial glandular epithelium. In benign endometrium, S100A4 expression was confined to stromal cells. S100A4 was not regulated by estrogen or progesterone, and its expression in tumors was not significantly correlated to estrogen receptor or progesterone receptor content. However, methylation of the S100A4 gene was detected in benign endometrium and grade 1 tumors with low S100A4 expression. In contrast, grade 3 endometrioid tumors with high S100A4 mRNA and protein expression showed no methylation of the gene. These methylation results were verified in endometrial cancer cell lines with differential baseline levels of S100A4 protein. These results suggest that hypomethylation is an important mechanism of regulating the expression of the S100A4 gene. These results support the emerging concept that hypomethylation may play a role in the upregulation of genes during later stages of tumorigenesis. Keywords: endometrial cancer; S100A gene family; S100A4; methylation Endometrial carcinoma is the most common malignant neoplasm of the female genital tract and the fourth most frequently diagnosed cancer in women, following cancers of the breast, lung, and colon. 1 On the basis of histological and clinical features, endometrial carcinoma has been classified into two types. 2-4 Type I tumors (approximately 80% of all endometrial carcinomas) are typically low-grade (grade 1 or grade 2) endometrioid adenocarcinoma, most of which are confined to the uterus and have a favorable prognosis. Type II tumors (approximately 20%) are comprised of uterine papillary serous carcinoma, malignant mixed mü llerian tumors, and clear cell carcinoma. The nature of high-grade (grade 3) endometrioid adenocarcinoma is more controversial, as a subset may behave more like the Type II tumors. Type II cancers are associated with extrauterine spread and carry a high mortality rate. Previous studies have documented interesting molecular differences between endometrioid and nonendometrioid ...

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Hypomethylation-induced expression of S100A4 in endometrial carcinoma

et al. 2007

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“…The presence of the EF-hand-containing calcium-binding protein S100A4 in carcinoma cells has been associated with a poor prognosis in patients with carcinomas of the bladder, colorectum, gall bladder, oesophagus and lung (Kimura et al, 2000;Ninomiya et al, 2001;Davies et al, 2002;Gongoll et al, 2002;Nakamura et al, 2002). In an archival set of 349 breast cancer patients, less than 20% of patients with S100A4 in their carcinoma cells were alive after 20 years, whereas greater than 90% of patients with less than 1% S100A4 positive carcinoma cells survived over the same period .…”

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Mutually antagonistic actions of S100A4 and S100A1 on normal and metastatic phenotypes

et al. 2004

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Increased levels of the homodimeric calcium-binding protein, S100A4, have been shown to cause a metastatic phenotype in at least three independent model systems of breast cancer and its presence in carcinoma cells has been shown to be associated with a reduction in the survival of patients suffering from a range of different cancers. S100A4 has been shown to interact in vitro with another member of the S100 family of proteins, S100A1. The purpose of the present study was to find out whether S100A1 could affect S100A4 function. Fluorescence resonance energy transfer was used to show the interaction of S100A4 and S100A1 in living cells and the binding affinities between S100A4 and S100A1 were determined using a biosensor. S100A1 reduced the S100A4 inhibition of nonmuscle myosin A self-association and phosphorylation in vitro. S100A1 reduced S100A4 induced motility and growth in soft agar and metastasis in vivo. The results show for the first time that interactions between different S100 proteins can affect cancer-related activity, and that the presence of S100A1 protein in carcinoma cells might modulate the effect of S100A4 on their metastatic abilities.

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“…Several studies have associated the S100A4 protein with increased metastatic capacity of cancer cells (Davies et al, 1993;Maelandsmo et al, 1996;Levett et al, 2002), and more recently a correlation between the level of S100A4 protein and prognostic outcome has been reported in various types of cancer (lung gall bladder, oesophageal, gastric, breast and colon) Rudland et al, 2000;Yonemura et al, 2000;Ninomiya et al, 2001;Gongoll et al, 2002;Nakamura et al, 2002). Several laboratories have studied the involvement of S100A4 in invasion and metastasis, but little is still understood of the mechanism by which it exerts the metastasis-promoting effects.…”

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Interferon-γ suppresses S100A4 transcription independently of apoptosis or cell cycle arrest

et al. 2003

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The S100A4 protein has been associated with increased metastatic capacity of cancer cells, and recent studies have suggested a correlation between the expression level of S100A4 and the prognostic outcome for patients with various types of cancer. The knowledge about the mechanisms underlying the metastasis-promoting effects is still limited, and the aim of the present study was to elucidate signal transduction pathways involved in the regulation of S100A4. After treatment of human carcinoma cells with interferon-gamma (IFN-g), we observed downregulation of S100A4 both at mRNA and protein levels. The effect was not dependent on IFN-g-induced apoptosis or IFN-g-mediated cell cycle arrest. Moreover, IFN-g-mediated decrease in mRNA stability could not account for the observed decrease in S100A4 transcript level. Finally, microarray analysis suggests ISGF3G, ETV5, ZNF133 and CEBPG as possible candidate genes involved in IFN-g-mediated repression of S100A4.

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Prognostic significance of S100A4 expression in gallbladder cancer

Cited by 31 publications

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Hypomethylation-induced expression of S100A4 in endometrial carcinoma

Hypomethylation-induced expression of S100A4 in endometrial carcinoma

Mutually antagonistic actions of S100A4 and S100A1 on normal and metastatic phenotypes

Interferon-γ suppresses S100A4 transcription independently of apoptosis or cell cycle arrest

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