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A 38-year-old woman underwent a hysterectomy for a uterine tumor. A giant circumscribed nodule with a diameter of 20 cm at its widest point was found within the myometrium of the uterine corpus without hemorrhage or necrosis. More than 10 specimens were pathologically examined. Eleven years after hysterectomy, she developed fi ve tumors (the largest diameter = 2 cm) in the right lung and retroperitoneal tumor (the largest diameter = 9.5 cm). Microscopic examination indicated uterine, retroperitoneal and pulmonary foci, which were characterized by a benign appearance, including nodular smoothmuscle proliferation. The smooth muscle cells had an oval shape with relatively clear cytoplasm and a few irregular nuclei. In each specimen, spindle-shaped cells showed an interlacing bundle pattern with intermediated cellularity. The mitotic index was very low and no nuclear atypia was observed (Fig.1). Even though the serial pathological examination did not indicate any malignant potential, we diagnosed this case as benign metastasizing leiomyoma (BML). In the present case, pulmonary (BML-P) and retroperitoneal (BML-R) metastases and primary foci (BML-U) of uterine leiomyoma were examined with one case of non-metastasizing leimyoma of the uterus (NML) and one case of leiomyosarcoma (LS) as control. All tissues were fi xed in 4% neutralized formaldehyde, embedded in paraffi n and cut into 4 μm sections. These sections were stained by HE 1:100), p53 (DAKO, USA; 1:100), bcl-2 (DAKO, USA;1:80), ER (NovoCastra, UK;1:80), and PR (Novo Castra, UK;1:100) antibodies. P53, ER and PR stained the nucleus, whereas desmin, bcl-2 stained the cytoplasm. Immunostaining showed that smooth muscle cells of the BML strongly expressed the desmin protein, in accordance with the NML (Fig.1). As shown in the Fig.1, primary or metastatic foci of the BML exhibited an intermediate expression pattern of p53, bcl-2, ER and PR between NML and LS. There was strong expression of p53 and bcl-2 in the retroperitoneal or pulmonary foci of the BML respectively, compared with the primary foci. The converse was true for the PR.

Bcl-2-associated athanogene 3 (Bag-3) belongs to a member of the Hsc70 binding co-chaperone Bag-family proteins and has critical roles in protein homeostasis, cell survival, actin organization, cell adhesion, cell motility and tumor metastasis. To clarify the role of Bag-3 in colorectal carcinogenesis and subsequent development, its expression was examined by immunohistochemistry (IHC) and in situ hybridization (ISH) on tissue microarrays containing colorectal carcinomas, adenomas, non-neoplastic mucosa (NNM) and metastatic carcinomas in lymph node and liver. Colorectal carcinoma tissue and cell lines were studied for Bag-3 expression by RT-PCR, Western blot and immunofluorescence. The results demonstrated that Bag3 was distinctly expressed in Colo201, Colo205, DLD-1, HCT-15, HCT-116, HT-29, KM-12, SW480, SW620, and WiDr at both mRNA and protein levels. Carcinoma showed stronger Bag-3 expression than adjacent NNM by IHC and Western blot (P0.05). Our study indicated that aberrant Bag-3 expression might be involved in colorectal adenoma-adenocarcinoma sequence and subsequent progression.

REIC is down-regulated in immortalized cell lines compared with the parental normal counterparts, and could inhibit colony formation, tumor growth and induce apoptosis. Here, its expression was examined by immunohistochemistry on tissue microarray containing colorectal non-neoplastic mucosa (NNM), adenoma and adenocarcinoma. Colorectal carcinoma tissue and cell lines were studied for REIC expression or its secretory level by Western blot, RT-PCR or enzyme-linked immunosorbent assay (ELISA). The results demonstrated that REIC was differentially expressed in Colo201, Colo205, DLD-1, HCT-15, HCT-116, HT-29, KM-12, SW480, SW620, and WiDr with its secretion concentration less than 300 pg/mL. Carcinomas showed statistically lower REIC expression than matched NNM with no difference for protein content. Immunohistochemically, REIC expression was significantly decreased from NNM, adenoma to adenocarcinoma (p0.05). Kaplan-Meier analysis indicated that REIC expression was not associated with the prognosis of colorectal carcinomas (p>0.05). Cox’s analysis demonstrated that lymphatic and venous invasion, lymph node metastasis, and UICC staging were independent prognostic factors for carcinoma (p

Summary. To clarify the role of p33ING1b in tumorigenesis and progression of head and neck squamous cell carcinoma (HNSCC), we examined the expression and subcellular localization of p33ING1b in 214 HNSCC cases in parallel with 60 dysplasia samples and 48 normal epithelium samples by immunohistochemistry, and analyzed correlations of expression of p33ING1b in HNSCC cases with clinicopathological variables, apototic index and expression of 14-3-3η, p300, p21 and PCNA. Although 12% of HNSCC cases lost expression of p33ING1b, most cases of HNSCC retained expression of p33ING1b with levels similar to those in non-cancerous epithelia. Nuclear expression of p33ING1b was significantly decreased in HNSCC compared to normal epithelia. In contrast, cytoplasmic expression of p33ING1b was found to be significantly higher in HNSCC. An abundance of p33ING1b in cytoplasm positively correlated with poor differentiation and tumor progression. Corresponding to those clinicopathogical features, high expression of p33ING1b in the cytoplasm correlated with PCNA labelling index but in contrast, that in the nuclei correlated with apoptosis. In nuclei, p33ING1b is coexpressed with p300 and p21, implying its roles in tumor suppression. Elevated expression of 14-3-3η was associated with cytoplasmic expression of p33ING1b and immunofluorescence study suggested association of p33ING1b and 14-3-3η. Among three cell lines derived from oral SCC, poorly-differentiated SAS cells showed a relatively high expression of p33ING1b in cytoplasm with

The incidence of lung adenocarcinoma has been remarkably increasing in recent years due to the introduction of filter cigarettes and secondary-hand smoking because the people are more exposed to higher amounts of nitrogen oxides, especially 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK), which is widely applied in animal model of lung tumors. In NNK-induced lung tumors, genetic mutation, chromosome instability, gene methylation, and activation of oncogenes have been found so as to disrupt the expression profiles of some proteins or enzymes in various cellular signal pathways. Transgenic animal with specific alteration of lung cancer-related molecules have also been introduced to clarify the molecular mechanisms of NNK in the pathogenesis and development of lung tumors. Based on these animal models, many antioxidant ingredients and antitumor chemotherapeutic agents have been proved to suppress the NNK-induced lung carcinogenesis. In the future, it is necessary to delineate the most potent biomarkers of NNK-induced lung tumorigenesis, and to develop efficient methods to fight against NNK-associated lung cancer using animal models.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world. The evolution and progression of HNSCC are considered to result from multiple stepwise alterations of cellular and molecular pathways in squamous epithelium. Recently, inhibitor of growth gene (ING) family consisting of five genes, ING1 to ING5, was identified as a new tumor suppressor gene family that was implicated in the downregulation of cell cycle and chromatin remodeling. In contrast, it has been shown that ING1 and ING2 play an oncogenic role in some cancers, this situation being similar to TGF-β. In HNSCC, the ING family has been reported to be downregulated, and ING translocation from the nucleus to the cytoplasm may be a critical event for carcinogenesis. In this paper, we describe our recent results and briefly summarize current knowledge regarding the biologic functions of ING in HNSCC.

Parafibromin is a protein encoded by the hyperparathyroidism 2 oncosuppressor gene and its down-regulated expression is involved in the pathogenesis of parathyroid, gastric and colorectal carcinomas. To clarify the roles of parafibromin expression in lung carcinomas, it was examined by immunohistochemistry and in situ hybridization on tissue microarray containing lung carcinomas (n=144) and normal lung tissue (n=20), with a comparison to clinicopathological parameters of carcinomas. Lung carcinoma cell lines and tissues were studied for parafibromin expression by Western blot and RT-PCR. Down-regulated expression of parafibromin mRNA was found in lung carcinoma in comparison with matched normal tissue (p0.05). The Kaplan-Meier method indicated that nuclear parafibromin expression was positively correlated with adenocarcinoma patients (p

Glucose-related proteins (GRPs) are ubiquitously expressed in the endoplasmic reticulum and assist in protein folding and assembly, consequently considered to be molecular chaperones. GRP78 and GRP94 expression was induced by glucose starvation and up-regulated in samples taken from several different malignant tissues. To clarify the roles of both molecules in tumorigenesis and progression of colorectal carcinomas, immunohistochemistry (IHC) was performed on tissue microarrays containing colorectal carcinomas, adenomas and the non-neoplastic mucosa (NNM) using antibodies against GRP78 and GRP94. Their expression was correlated with the clinicopathological parameters of carcinomas. Both proteins were also studied in colorectal carcinoma cell lines (DLD-1, HCT-15, SW480 and WiDr) by IHC and Western blot. There was a gradually increased GRP78 expression from colorectal NNMs, carcinomas, to low-grade and high-grade adenomas (P0.05). Multivariate analysis showed that venous invasion, lymph node metastasis and UICC staging (P0.05), were independent prognostic factors for carcinomas. It is suggested that up-regulated expression of GRP78 and GRP94 could possibly be involved in the pathogenesis of colorectal carcinomas.

To clarify the role of REG IV, a new member of the regenerating gene (REG) family, in tumorigenesis and progression of colorectal carcinoma (CRC), 320 CRC specimens, 123 corresponding adjacent noncancerous mucosa (ANCMs), 46 corresponding nonadjacent non-cancerous mucosa (NANCMs) and 86 adenomas were investigated immunohistochemically to compare REG IV expression with clinicopathological features. In addition, double immunofluorescence labeling was performed to analyze the localization of REG IV and the intestinal mucin, MUC2. The expression of REG IV in CRCs was significantly lower than in NANCMs, ANCMs or adenomas, and inversely correlated with poor differentiation and venous invasion. In cases of ANCM, REG IV expression was positively correlated with the depth of invasion, lymph node metastasis and Duke’s staging of corresponding cases. The expression of REG IV in CRC was significantly linked to that of MUC2 and the EGFR phosphorylated on Tyr1068, but not to that of MUC5AC, EGFR, Akt, or Akt phosphorylated on Ser473 or Thr308. The double immunofluorescence revealed coexpression, but independent localization, of REG IV and MUC2 in NANCMs, ANCMs, adenomas and CRCs, except for mucinous carcinomas. Univariate analysis using the Kaplan-Meier method indicated no correlation between REG IV expression and the cumulative survival rate of CRC patients. In conclusion, REG IV expression was upregulated in ANCMs and adenomas, then decreased in CRCs. This indicated that REG IV overexpression may be an early event in CRC carcinogenesis. Its expression in CRCs was positively linked to MUC2 and phosphorylation of the EGFR on Tyr1068, suggesting that REG IV may be a useful marker for intestinal type mucinous carcinoma and a good candidate as a molecular therapeutic target for CRCs.

Japan is a high-risk region for gastric carcinoma with a comparatively early stage and favorable prognosis. To clarify the pathobiological behaviors and prognosis of Japanese gastric adenocarcinoma, we analyzed the clinicopathological characteristics of different WHO subtypes of carcinomas. The expression of ki-67, CPP32, p53, FHIT, maspin, parafibromin, GRP78, GRP94, EMMPRIN, VEGF, P-GSK3ß-ser9, fascin, cortactin, Arp2, Arp3 MUC-2, MUC-5AC and MUC-6 was examined using immunohistochemistry and tissue microarrays. The majority of cases were well-, poorly-, or moderatelydifferentiated subtype, whereas the minority were papillary or signet ring cell carcinoma (SRC). Patients with poorly-differentiated or SRC carcinoma were predominantly young and female. Poorly-differentiated and mucinous carcinomas were larger, with deeper invasion, more venous or lymphatic invasion, frequent lymph node involvement and peritoneal dissemination, or higher staging. The SRC group exhibited weaker expression of ki-67, CPP32, p53, parafibromin, GRP78, GRP94, P-GSK3ß-ser9, VEGF or cortactin. The moderately-differentiated subtype exhibited lower expression of FHIT and Arp3 positivity. The poorlydifferentiated group showed weaker expression of CPP32, EMMPRIN, MUC-2, MUC-5AC, and MUC-6. Survival analysis indicated that the patients with poorlydifferentiated or mucinous subtypes had a lower cumulative survival rate than those with papillary, well-, moderately-differentiated, or SRC carcinomas (P