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Cysteine/histidine-rich 1 (CYHR1) was first discovered in a yeast two-hybrid screen with murine galectin-3, and no previous reports have described a relationship between the CYHR1 gene and human cancer. The current study evaluated the role and significance of CYHR1 in esophageal cancer. The human esophageal squamous cell carcinoma (ESCC) cell line TE-8 and the CYHR1 knock-down cell line TE-8/small interfering (si)-CYHR1 were used for in vitro and in vivo assays. For clinical study, ESCC tissues (n = 104) were used. Compared with parental cells, TE-8/si-CYHR1 cells had suppressed proliferation and invasion activities. In the in vivo assay, the tumors from TE-8 cells treated with si-CYHR1 had abrogated tumorigenicity. In the clinical study, the expression of CYHR1 mRNA was associated with lymph node metastasis and stage and shown to be an independent prognostic factor. As the findings show, CYHR1 may represent not only a valuable prognostic marker but also a therapeutic target for ESCC patients.

While chemoradiation therapy (CRT) is one of the most useful treatments for esophageal squamous cell carcinoma (ESCC), it is important to predict response prior to treatment by using markers because some patients respond well and others do not. Fifty-nine patients with ESCC were treated with neoadjuvant CRT at the Kagoshima University Hospital. The expression of seven types of biomarker candidate proteins in biopsy specimens of untreated primary tumors was evaluated to determine whether it correlated with response and prognosis. The positive expression rates were 47% for p53, 83% for CDC25B, 68% for 14-3-3sigma, 76% for p53R2, 75% for ERCC1, 32% for Gli-1, and 54% for Nrf2. In terms of histological response, tumor grade of the 59 patients was 48.8% for grade 1 as the non-responder, 29.2% for grade 2, and 22.0% for grade 3 as the responder. CRT was significantly effective in p53(−), p53R2(−), ERCC1(−), and Nrf2(−) tumors, while p53(−), p53R2(−), and ERCC1(−) were factors independently correlated with effective histological response. Their combined expression of two or three negative expressions had 100% effective response and was a significant prognostic factor. Our results suggest that two or three negative expressions of p53, p53R2, and ERCC1 in biopsy specimens of primary tumors were associated with a favorable response to CRT for ESCC. Assessment of tumor suppressor and DNA repair protein expressions in biopsy specimens may be useful for the potential utility of CRT therapy for patients with ESCC prior to treatment.

The prognosis of patients with esophageal squamous-cell cancer (ESCC) and multiple lymph-node metastases is quite poor. We examined whether neoadjuvant chemoradiation therapy (CRT) has a beneficial effect in such patients. A total of 50 consecutive patients with T3–4 tumors and without organ metastases were prospectively enrolled. Of those patients, 20, who had four or more nodal metastases, underwent neoadjuvant CRT (CRT group), and the remaining 30 patients, who had three or fewer nodal metastases, underwent surgery alone (surgery group). CRT consisted of 5-fluorouracil plus cisplatin and 40 Gy of radiation. The groups’ clinical outcomes were compared. Surgery was performed in 48 patients: all enrolled patients except for 2 who had organ metastasis after CRT. In the CRT group, the number of patients with pathological complete response was observed in 8 patients (44 %), mean nodal metastases number was changed from 8.2 to 2.6 and 9 patients had pN0. The 3-year survival rate was 76 % in the CRT group (4 patients relapsed) and 68 % in the surgery group (8 patients relapsed), which is not a statistically significant difference (P = 0.61). Neoadjuvant CRT is beneficial for locally advanced ESCC with four or more lymph-node metastases.

Background Bone morphogenetic proteins (BMPs) are secreted signaling molecules belonging to the transforming growth factor-β (TGF-β) superfamily of growth factors. Recent studies have shown that the influence of the expression of BMP7 was altered in several tumors. The purpose of the current study was to examine the expression of BMP7 in esophageal squamous cell carcinoma and to clarify the clinical impact of BMP7 expression in esophageal squamous cell carcinoma (ESCC). Methods A total of 180 patients with ESCC who underwent surgical resection from 1991 to 2004 were eligible for this study. The expression of BMP7 in esophageal tumor tissues was examined immunohistochemically. Results BMP7 expression was found in the cytoplasm of cancer cells. BMP7 positivity was observed in 61.7% of tumors. The BMP7-positive group had deeper progression, more advanced stages, and greater venous invasion than those without BMP7 expression (p

We sought to identify genes associated with the progression and metastasis of esophageal squamous-cell cancer by comparing the expression profiles of normal, primary cancer, and metastatic cancer cells isolated with laser microdissection. Oligo microarray analysis identified several lymph node-specific, metastasis-related genes. STC2 (stanniocalcin 2), which was overexpressed in esophageal cancer cases, was chosen for further characterization. Quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry were used to explore the clinicopathologic significance of STC2 expression status in 70 cases. Additionally, the functional role of STC2 in esophageal cancer was studied by the attenuation of STC2 in an esophageal cancer cell line. Laser microdissection and oligo microarray analysis identified 63 candidate genes. Among them, STC2 showed higher expression in cancer tissue than in corresponding normal tissue (P < 0.001). STC2 expression was significantly correlated with lymph node metastasis, lymphatic invasion, and distant metastasis (P = 0.005, 0.007, and 0.038, respectively). Patients whose tumors had high STC2 expression had a worse 5-year survival rate than patients whose tumors had a low STC2 expression level (P = 0.016). STC2 transfected cells had a significantly higher proliferation rate than control cells (P < 0.001). Additionally, STC2 transfected cells were more invasive in vitro (P < 0.001) than control cells. These findings were validated by means of RNA interference assays. We identified lymph node-specific, metastasis-related genes in esophageal cancer cells. One of these, STC2, may be associated with lymph node metastasis, making it a potential prognostic marker for esophageal cancer patients.

The transcription factor NF-E2-related factor 2 (Nrf2) was originally identified to be a critical regulator of intracellular antioxidants and phase II detoxification enzymes. Recent studies have shown that high Nrf2 expression gives cancer cells an advantage for survival from anticancer chemotherapy and radiation therapy. The aims of this retrospective study were to examine the expression of Nrf2 in biopsy specimens of esophageal squamous cell carcinoma (ESCC) and to evaluate whether such expression is useful for predicting the response to chemoradiation therapy (CRT). A total of 46 patients with ESCC who received curative surgery after CRT from 1997 to 2011 were enrolled in the current study. Nrf2 expression in the biopsy specimens before CRT was examined immunohistochemically using anti-Nrf2 antibody. The correlations between Nrf2 expression and clinical factors and histological and clinical response to CRT were analyzed. The rate of Nrf2-positive expression was 39 %. Both clinically and histologically, significant correlations were found between positive Nrf2 expression and unfavorable response to CRT. Furthermore, Nrf2 was significantly correlated with clinical lymph node metastases and patients’ postoperative outcomes. Multivariate analysis showed that Nrf2 expression status was an independent prognostic factor. Nrf2 expression was found to be closely related to the effect of CRT and could predict the CRT outcome in patients with ESCC.

To assess the clinical usefulness and significance of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in superficial esophageal squamous cell carcinoma (ESCC).We examined FDG-PET for 80 consecutive patients with superficial ESCC without neoadjuvant treatment. Fifty-seven patients underwent radical esophagectomy, and 23 patients received endoscopic resection. The FDG uptake index was evaluated with clinicopathological findings, and glucose transporter 1 (Glut-1) expression in primary tumors was examined immunohistochemically.The FDG uptake in primary tumors correlated with histology, depth of tumor invasion, lymph node metastasis, lymphatic invasion, vascular invasion, and Glut-1 expression. All patients with more than 4.4 maximum standardized uptake value (SUVmax) had deeper invasion of submucosa. Among 16 patients with lymph node metastasis, only two were found to have lymph node metastasis. FDG uptake, depth of tumor invasion, lymph node metastasis, and histology were found to be prognostic factors, and histology was an independent prognostic factor. In FDG uptake-positive patients, depth of tumor invasion and histology were prognostic factors.FDG-PET is useful for diagnosing tumors with deeper invasion of submucosa and is helpful in making decisions regarding endoscopic treatment for superficial ESCC. Patients with FDG uptake-positive disease, deeper invasion of submucosa, poorly differentiated tumor, and poor prognosis should receive multimodal treatment.

If the sentinel node (SN) concept is established for esophageal cancer, it will be possible to reduce safely the extent of lymphadenectomy. Our objective was to perform SN mapping in esophageal cancer to assess distribution of lymph node metastases with the goal to reduce the need for extensive lymphadenectomy.A total of 134 patients who underwent esophagectomy with lymph node dissection were enrolled. The number of patients with clinical T1, T2, and T3 tumors was 60, 31, and 32, respectively. Eleven patients also received neoadjuvant chemoradiation therapy (CRT). (99m)Tc-Tin colloid was injected endoscopically into the esophageal wall around the tumor 1 day before surgery. SNs were identified by using radioisotope (RI) uptake. RI uptake of all dissected lymph nodes was measured during and after surgery. Lymph node metastases, including micrometastases, were confirmed by hematoxylin eosin and immunohistochemical staining.Detection rates of SNs were 93.3% in cT1, 100% in cT2, 87.5% in cT3, and 45.5% in CRT patients. In the 120 cases where SNs were identified, lymph node metastases were found in 12 patients with cT1, 18 with cT2, 24 with cT3 tumors, and 3 with CRT. Accuracy rate of SN mapping was 98.2% in cT1, 80.6% in cT2, 60.7% in cT3, and 40% in CRT patients. Although one false-negative case had cT1 tumor, the lymph node metastasis was detected preoperatively.SN mapping can be applied to patients with cT1 and cN0 esophageal cancer. SN concept might enable to perform less invasive surgery with reduction of lymphadenectomy.

Stanniocalcins are glycoprotein hormones that were originally found in the endocrine gland of bony fish. Microarray expression data from 32 paired samples of gastric cancer and normal mucosa in a public microarray database showed that the expression level of Stanniocalcin 2 was higher in gastric cancer than in normal gastric mucosa. The clinical significance of Stanniocalcin 2 expression has been observed for several cancers. However, the relationship between Stanniocalcin 2 and clinicopathological factors in gastric cancer has not yet been investigated.We examined the clinical significance of Stanniocalcin 2 in gastric cancer in 108 gastric cancer samples using real-time reverse transcription-polymerase chain reaction (RT-PCR). Immunohistochemical studies were conducted with paraffin sections. The suppression analysis of Stanniocalcin 2 using siRNA was done to determine Stanniocalcin 2's biological roles.The level of Stanniocalcin 2 in cancer tissues was higher than in normal tissues (P = .0002). The high Stanniocalcin 2 expression group (n = 54) had more progressive lymph node metastasis (P = .07) and venous invasion (P = .028) than the low-expression group (n = 54). High Stanniocalcin 2 expression was an independent prognostic factor in gastric cancer patients (P = .02). Moreover, siRNA suppression of Stanniocalcin 2 in a gastric cancer cell line inhibited cellular proliferation (P .05).The high expression level of Stanniocalcin 2 in gastric cancer tissues could be a very powerful marker of poor prognosis. Therefore, Stanniocalcin 2 is a promising candidate for a molecular target for the treatment of gastric cancer.

Human prominin-1 (PROM1, CD133) was used as a marker to detect stem cells (progenitor cells) and cancer stem cells (tumor-initiating cells) in various tissues. The purpose of this study was to investigate the biological and genetic characteristics of tumor-initiating cells in colon cancer with both in vitro and in vivo analyses. The CD133 expression of 12 colon cancer cell lines was evaluated. CD133+ cells were isolated by flow cytometry and examined for in vivo tumor formation, in vitro proliferation, colony formation, and invasion ability. Additionally, we used microarray analysis to compare gene expression profiles between CD133+ and CD133– isolated cells. CD133+ cells were found in 5 of 12 colon cancer cell lines. Isolated CD133+ cells from the HT29 colon cancer cell line exhibited a higher tumorigenic potential than CD133– cells in the in vivo tumor formation assay. Furthermore, it was shown that CD133+ cells are more proliferative and have higher colony-forming and invasive abilities than CD133– cells in vitro. Microarray analysis found differential gene expression correlating with CD133 expression. It was confirmed that CD133+ cells in colon cancer are useful markers for the detection of tumor-initiating cells. Intimate biological and genetic features of CD133+ cells in colon cancer cell lines were also revealed. The biological characteristics of CD133+ cells and differentially expressed genes in these cells will help elucidate more details of tumor-initiating cells in colon cancer.