Inflammation-induced myeloid-derived suppressor cells associated with squamous cell carcinoma of the head and neck.

BACKGROUND: The purpose of this study was to present our assessment of the significance of myeloid-derived suppressor cells (MDSCs) in head and neck squamous cell carcinoma (HNSCC). METHODS: We examined the percentage of MDSCs in the peripheral blood of patients with HNSCC. The relationship among MDSC recruitment, tumor progression, and cyclooxygenase (COX)-2 inhibition was also evaluated by animal models. RESULTS: Circulating MDSCs were significantly increased in patients with HNSCC compared with healthy people, and this was associated with the clinical tumor burden. In immunocompetent 4-nitroquinoline-1-oxide (4-NQO)-induced oral tumor and immunocompromised tumor implantation animal models, MDSC recruitment was associated with the duration of 4-NQO treatment and tumor progression. The responsible mechanisms included the suppressive ability of T-cell proliferation and augmenting angiogenesis by MDSC. Blockade of COX-2 attenuated the induction and function of MDSCs and subsequently inhibited tumor growth. CONCLUSION: The levels of MDSC are linked with tumor progression in HNSCC. Moreover, targeting COX-2 could be a promising strategy for the treatment of HNSCC. © 2016 Wiley Periodicals, Inc. Head Neck 39: 347-355, 2017.

Correction: IL-6 Expression Regulates Tumorigenicity and Correlates with Prognosis in Bladder Cancer.

[This corrects the article DOI: 10.1371/journal.pone.0061901.].

The role of PD-L1 in the radiation response and prognosis for esophageal squamous cell carcinoma related to IL-6 and T-cell immunosuppression.

The aim of this study was to assess the significance of programmed cell death 1 ligand 1 (PD-L1) in esophageal squamous cell carcinoma (ESCC) and its association with IL-6 and radiation response. Weretrospectively enrolled 162 patients with ESCC, and examined the correlation between PD-L1 levels and clinical outcomes in esophageal cancer patients. Furthermore, the human esophageal SCC cell line CE81T and TE2 were selected for cellular experiments to investigate the role of PD-L1 in T cell functions and radiation response. Here we demonstrated that PD-L1 expression was significantly higher in esophageal cancer specimens than in non-malignant epithelium. In clinical outcome analysis, this staining of PD-L1 was positively linked to the clinical T4 stage (p=0.004), development of LN metastasis (p=0.012) and higher loco-regional failure rate (p=0.0001). In addition, the frequency of PD-L1 immunoreactivity was significantly higher in IL-6-positive esophageal cancer specimens. When IL-6 signaling was inhibited in vitro, the level of PD-L1 is significantly down-regulated. PD-L1 is a significant predictor for poor treatment response and shorter survival.As demonstrated through in vitro experiments, Irradiation increased PD-L1 expression in human esophageal cancer cells. The inhibition of T cell functions including proliferation and cytotoxicity against tumor cells might be the mechanisms responsible to the role of PD-L1 in radiation response. In conclusion, PD-L1 is important in determining the radiation response and could predict the prognosis of patients with esophageal SCC. Therefore, we suggest inhibition of PD-L1 as a potential strategy for the treatment of esophageal SCC.

DNMT1-dependent suppression of microRNA424 regulates tumor progression in human bladder cancer.

The aim of this study was to examine the role of miRNAs regulation by DNMT1 and its underlying mechanisms in bladder cancer. The choice of target miRNAs was based on the analysis of a TaqMan MicroRNA Panel assay. The role of target miRNA in tumor behavior and the related signaling pathways were assessed using the human bladder cancer cell lines. We also evaluated the predictive power of the target miRNA and its link to DNMT1 from 124 clinical bladder cancer specimens. Our results revealed that the miR-424 level is significantly increased when blocking DNMT1 in bladder cancer cells. From the clinical specimen analysis, the staining of miR-424 was inversely correlated with DNMT1 immunoreactivity. The lack of miR-424 expression was significantly linked to aggressive tumor growth, advanced clinical stage and poor prognosis in bladder cancer. Increased miR-424 suppressed the tumor growth rate and invasion ability determined in vitro and in vivo. Furthermore, the EGFR pathway plays a role in the transmission of the miR-424 signal that regulates cell growth and the epithelial-to-mesenchymal transition. These results highlight a potential role for miR-424 as a molecular predictor and therapeutic target in bladder cancer.

1α,25-Dihydroxyvitamin D3 Inhibits Esophageal Squamous Cell Carcinoma Progression by Reducing IL6 Signaling.

The aim of this study was to highlight the role of 1α,25-dihydroxyvitamin D3 (calcitriol) in esophageal squamous cell carcinoma (SCC). The human esophageal SCC cell lines CE81T and TE2 were selected for cellular and animal experiments to investigate the changes in tumor behavior after calcitriol supplementation and the underlying mechanisms. Moreover, we evaluated the relationship between calcitriol supplementation, myeloid-derived suppressor cell (MDSC) recruitment, IL6 levels, and tumor progression by a 4-nitroquinoline 1-oxide (4-NQO)-induced esophageal tumor animal model. In this study, we demonstrated that calcitriol supplementation inhibited aggressive tumor behavior both in vitro and in vivo. The underlying changes included increased cell death, a lower degree of epithelial-mesenchymal transition, and inhibited IL6 signaling. In the 4-NQO-induced esophageal tumor animal model, increased IL6 and MDSC recruitment were linked with invasive esophageal tumors. Supplementation with calcitriol attenuated the level of IL6, the induction of MDSCs, and the incidence of 4-NQO-induced invasive tumors. Moreover, the IL6-induced changes in C57 mice, including augmented MDSC recruitment, increased levels of ROS and p-Stat3 in MDSCs, and higher suppressive function of MDSCs in T-cell proliferation, which were abrogated by calcitriol supplementation. On the basis of our results, we concluded that calcitriol abrogated the IL6-induced aggressive tumor behavior and MDSC recruitment to inhibit esophageal tumor promotion. Therefore, we suggest that supplementation with vitamin D3 may be a promising strategy for the prevention and treatment of esophageal SCC.

IL-6-stimulated CD11b+ CD14+ HLA-DR- myeloid-derived suppressor cells, are associated with progression and poor prognosis in squamous cell carcinoma of the esophagus.

The aim of this study was to assess the significance of myeloid-derived suppressor cells (MDSCs) and their association with IL-6 in esophageal squamous cell carcinoma (SCC). We examined the percentage of CD11b+CD14+HLA-DR- myeloid cells and the levels of IL-6 in the peripheral blood of 50 patients with esophageal SCC and 12 healthy controls. Moreover, we evaluated the relationship between MDSC recruitment, IL-6 levels, and tumor progression by adding 4-nitroquinoline 1-oxide (4-NQO) to the drinking water of mice to induce esophageal tumors. Here we demonstrated that circulating CD11b+CD14+HLA-DR- cells were significantly increased in esophageal SCC patients compared with healthy people, and this was associated with the clinical stage, treatment response and circulating IL-6 levels. In a 4-NQO-induced esophageal tumor animal model, MDSC recruitment was associated with invasive esophageal tumors and with increased IL-6 levels. IL-6 stimulated reactive oxygen species, arginase 1 and p-STAT3 in MDSCs. Blockade of IL-6 prevented induction of MDSCs and the incidence of 4-NQO- induced invasive tumors. In conclusion, the levels of MDSCs and IL-6 predicted the prognosis of patients with esophageal SCC. Moreover, we suggest inhibition of IL-6 as a potential strategy for the treatment of esophageal SCC.

Thrombomodulin expression regulates tumorigenesis in bladder cancer.

BACKGROUND: The identification of potential tumor markers will help improve therapeutic planning and patient management. Thrombomodulin (TM) is a sensitive urothelial marker. TM was reported to be one of the endogenous anti-metastatic factors and has diagnostic and prognostic values for the progression of carcinoma. In the present study, we examine the role of TM in bladder cancer. METHODS: We studied the role of TM in tumor behavior and related signaling pathways in vitro using the human bladder cancer cell lines HT1376, HT1197, J82 and T24, and in vivo using animal models. We also selected clinical specimens from 100 patients with bladder cancer for immunohistochemical staining to evaluate the predictive capacity of TM in tumor invasiveness. RESULTS: The data revealed that positive immunoreactivity for TM was inversely correlated with clinical stage and DNA methyltransferase 1 immunoreactivity. Decreased TM expression could predict the aggressive tumor growth and advanced clinical stage in bladder cancer. When TM was inhibited, tumor growth rate and invasion ability were augmented in vitro and in vivo. The underlying changes included increased cell proliferation, enhanced epithelial-mesenchymal transition (EMT) and angiogenesis. Moreover, inhibition of NF-κB activation significantly increased TM expression and attenuated tumor aggressiveness in bladder cancer. CONCLUSIONS: TM plays an important role in bladder cancer tumor aggressiveness in vitro and in vivo and is a clinically significant predictor that may represent a suitable therapeutic target for bladder cancer.

Significance of DNMT3b in oral cancer.

The aim of this study was to explore specific molecular markers that could lead to new insights into the identification of innovative treatments. The role of DNMT3b and its predictive power in the prognosis of oral cancer were identified. Human oral cancer cell lines including SCC4 and SCC25 were selected for cellular experiments. Changes in tumor growth, aggressiveness and the responsible signaling pathway were investigated in vitro and in vivo. Furthermore, 125 oral cancer tissue specimens were analyzed using immunohistochemical staining on tissue microarray slides, and correlations calculated between the level of DNMT3b and the clinical outcome of patients. Our data revealed that inhibition of DNMT3b resulted in slower tumor growth, attenuated tumor invasion ability and epithelial mesenchymal transition, as determined by in vitro and in vivo experiments. Activated IL-6 signaling might be responsible to the induction of DNMT3b overexpression on oral cancer. Regarding clinical data, the incidence of DNMT3b immunoreactivity in oral cancer specimens was significantly higher than in non-malignant epithelium, and positively linked to expression of IL-6. Furthermore, expression of DNMT3b was significantly linked with the risk of lymph node involvement, disease recurrence and shorter survival in patients with pathological stage III-IV oral cancer. In conclusion, IL-6 -DNMT3b axis could be used to predict the prognosis of oral cancer in clinics, and targeting DNMT3b could represent a promising treatment strategy.

IL-6 expression regulates tumorigenicity and correlates with prognosis in bladder cancer.

Identification of potential tumor markers will help stratify and identify a tumor's malignant potential and its response to specific therapies. IL-6 has been reported to be a predictor in various cancers. Therefore, the present study was performed to highlight the role of IL-6 in improving treatment and determining prognosis of bladder cancer. The human bladder cancer cell lines HT1376 and HT1197 were selected for cell and animal experiments, in which biological changes after experimental manipulation of IL-6 were explored, including tumor behavior and related signaling in bladder cancer. In addition, clinical specimens from 85 patients with muscle-invasive, and 50 with non-muscle invasive bladder cancers were selected for immunohistochemical staining to evaluate the predictive capacity of IL-6 in relation to clinical outcome. The data revealed that IL-6 was overexpressed in the bladder cancer specimens compared with non-malignant tissues at both mRNA and protein levels. Positive staining of IL-6 was significantly correlated with higher clinical stage, higher recurrence rate after curative treatment, and reduced survival rate. Tumor growth and invasive capability were attenuated when IL-6 was blocked. The underlying changes included decreased cell proliferation, less epithelial-mesenchymal transition (EMT), decreased DNA methyltransferase 1 expression and attenuated angiogenesis. In conclusion, our findings showed that IL-6 could be a significant predictor for clinical stage and prognosis of bladder cancer. Moreover, targeting IL-6 may be a promising strategy for treating bladder cancer.

IL-6 expression predicts treatment response and outcome in squamous cell carcinoma of the esophagus.

BACKGROUND: The identification of potential tumor markers can improve therapeutic planning and patient management. The aim of this study was to highlight the significance of IL-6 in esophageal squamous cell carcinoma (SCC). METHODS: We retrospectively analyzed the clinical outcomes of 173 patients with esophageal SCC, and examined the correlation between IL-6 levels and clinical outcomes in esophageal cancer patients. Furthermore, the human esophageal SCC cell line CE81T was selected for cellular and animal experiments to investigate changes in tumor behavior and treatment response after manipulation of IL-6 expression. RESULTS: In clinical outcome analysis, positive IL-6 staining and poor treatment response was significantly associated with shorter survival. Furthermore, the frequency of IL-6 immunoreactivity was significantly higher in esophageal cancer specimens than in non-malignant epithelium, and this staining was positively linked to the development of distant metastasis (p = 0.0003) and lower treatment response rates (p = 0.0001).By ELISA analysis, IL-6 serum levels were significantly elevated in patients developing disease failure.When IL-6 expression was inhibited, aggressive tumor behavior and radiation resistance could be overcome in vitro and in vivo. The underlying changes included increased cell death, less epithelial-mesenchymal transition and attenuated STAT3 activation. IL-6 inhibition was also associated with attenuated angiogenesis in tumor-bearing mice. CONCLUSIONS: IL-6 was significantly associated with poor prognosis in patients with esophageal cancer. Targeting this cytokine could be a promising strategy for treatment of esophageal cancer, as evidenced by inhibition of aggressive tumor behavior and treatment resistance.

The role of DNA methyltransferase 3b in esophageal squamous cell carcinoma.

BACKGROUND: The identification of potential tumor markers can improve therapeutic planning and patient management. The objective of this study was to highlight the role of DNA methyltransferase 3b (DNMT3b) in esophageal squamous cell carcinoma (SCC). METHODS: One hundred seventy-three esophageal SCC samples were analyzed using immunohistochemical staining to correlate the expression of DNMT3b with clinical outcome. Furthermore, a human esophageal SCC cell line, CE81T, was selected for cellular and animal experiments to investigate changes in tumor behavior and treatment response after the manipulation of DNMT3b expression. RESULTS: The incidence of nuclear DNMT3b immunoreactivity in esophageal cancer specimens was significantly higher than in nonmalignant epithelium, and this incidence was linked positively to developing distant metastasis (56% in localized disease vs 80% in distant metastasis; P = .002). Furthermore, increased expression of DNMT3b was linked significantly to lower treatment response rates (P = .002) and reduced survival rates (P = .000). Inhibition of DNMT3b expression resulted in slower cellular proliferation, increased cell death, a less invasive capacity, and less epithelial-mesenchymal-transition changes. Moreover, DNMT3b silencing vectors sensitized esophageal cancer cells to irradiation and cisplatin treatment. The current results also indicated that constitutional activation of signal transducer and activator of transcription 3 (STAT3) signaling associated with inhibited expression of suppressor of cytokine signaling 3 (SOCS3) may be the mechanism underlying more aggressive tumor growth in DNMT3b-positive esophageal cancer. CONCLUSIONS: DNMT3b was linked significantly to a poor prognosis for patients with esophageal cancer. Moreover, the current results indicated that targeting this enzyme may be a promising strategy for treating esophageal cancer, as evidenced by inhibited aggressive tumor behavior and treatment resistance.

Role of interleukin 1 beta in esophageal squamous cell carcinoma.

Interleukin (IL)-1 beta has been reported to be a marker of shorter survival in gastric and colorectal adenocarcinoma. In the present study, we examined the potential role and prognostic value of IL-1 beta in esophageal squamous cell carcinoma (SCC). Human esophageal SCC cell line, CE81T, was selected for cellular and animal experiments, in which biological changes after experimental manipulation of IL-1 beta signaling were explored, including tumor growth, invasion capacity, and the sensitivity to treatment. Moreover, 147 esophageal SCC samples were analyzed using immunohistochemical staining to correlate the expression of IL-1 beta with clinical outcome. Our data revealed that IL-1 beta was significantly overexpressed both at mRNA and protein levels in cancer specimens compared to nonmalignant tissues. When IL-1 beta signaling was blocked, tumor growth, invasion ability, and treatment resistance were attenuated. Activation of NF-kappa B, increase of E2-EPF ubiquitin carrier protein and subsequent epithelial-mesenchymal transition might be the underlying mechanisms of the more aggressive tumor growth in IL-1 beta-positive esophageal cancer. The immunochemistry findings indicate that positivity staining of IL-1 beta correlated significantly with higher clinical stage, lower response rate to concurrent chemoradiotherapy (CCRT), and higher recurrence rate after curative treatment. Moreover, IL-1 beta was a significant predictor of survival in patients undergoing surgical intervention or definite CCRT. In conclusion, IL-1 beta is significantly linked to poor prognosis for patients with esophageal cancer and may be a promising molecular target for therapeutic intervention for esophageal SCC.

Significance of the TGF-ß1/IL-6 axis in oral cancer.

The aim of the present study was to explore specific molecular markers that could lead to new insights into the identification of innovative treatments in oral cancer. The role of TGF-ß1 (transforming growth factor-ß1) and its predictive power in the prognosis of oral cancer has been identified. Human oral cancer cell lines, including SCC4 and SCC25, were selected for cellular experiments. Changes in tumour aggressiveness, responses to treatment and the signalling pathway responsible were investigated in vitro. Furthermore, 125 oral cancer tissue specimens were constructed into tissue microarray blocks for immunohistochemical analysis to correlate the expression of TGF-ß1 with clinical outcome. Using in vitro experiments, our results revealed that activated TGF-ß1 signalling resulted in more aggressive tumour growth, augmented the epithelial-mesenchymal transition and more resistance to treatment. Activated IL-6 (interleukin-6) signalling could be the mechanism underlying the effects of TGF-ß1 on oral cancer. Regarding clinical data, the incidence of TGF-ß1 immunoreactivity in oral cancer specimens was significantly higher than in non-malignant epithelium and positively linked to IL-6 staining. Furthermore, expression of TGF-ß1 was significantly correlated with the risk of lymph node involvement, disease recurrence and shorter survival in patients with pathological stage III-IV oral cancer. In conclusion, the TGF-ß1/IL-6 axis had predictive power in the prognosis of oral cancer, and targeting TGF-ß1 could represent a promising treatment strategy.

Expression and function role of DNA methyltransferase 1 in human bladder cancer.

BACKGROUND: The identification of potential tumor markers will help improve therapeutic planning and patient management. Therefore, the aim of this study was to highlight the role of DNA methyltransferase 1 (DNMT1) in bladder cancer. METHODS: A total of 50 samples of nonmalignant urothelium, 65 of muscle-invasive bladder cancers, 15 of distant metastasis, and 50 of nonmuscle-invasive bladder cancers were selected for immunohistochemical staining analysis. Furthermore, human bladder cancer cell lines HT1376 and HT1197 were selected for cell and animal experiments investigating changes in tumor behavior, treatment response, and related signaling in bladder cancer. RESULTS: The incidence of nuclear DNMT1 immunoreactivity in the bladder cancer specimens (45%) was significantly higher than in nonmalignant urothelium (15%, P = .0005), and the incidence in cancer was positively linked to clinical stage (24% in ≤T1 vs 55% in T2-T4, P = .0007). The staining of DNMT1 was also significantly linked to lower complete response rates (P = .0014) and reduced survival rates (P = .000). By in vitro and in vivo experiments, DNMT1 silencing vector reduced tumor growth and attenuated treatment resistance in bladder cancer cells. Less epithelial-mesenchymal transition, less invasion, and slower tumor growth were noted in cancer cells with inhibited DNMT1. Furthermore, the epidermal growth factor receptor-mediated phosphatidylinositol 3'-kinase-protein kinase B pathway might be the mechanism underlying the effects of DNMT1 on bladder cancer. CONCLUSIONS: DNMT1 could be a significant clinical predictor for stage and treatment response of bladder cancer. Moreover, targeting this enzyme could be a promising strategy for treating bladder cancer, as evidenced by inhibited tumor growth and enhanced radiosensitivity.

Role of DNA methyltransferase 1 in pharyngeal cancer related to treatment resistance.

BACKGROUND: The purpose of the present study was to highlight the role of DNA methyltransferase 1 (DNMT1) and its potential for improving treatment and informing prognosis for pharyngeal cancer. METHODS: Human pharyngeal cancer cell lines FaDu and its derivative FaDu-C225-R were selected for cellular experiments. Furthermore, 95 pharyngeal cancer tissue specimens were analyzed by immunohistochemical staining. RESULTS: DNMT1 was over-expressed in pharyngeal cancer specimens and cells with activated interleukin (IL)-6 signaling. When DNMT1 activity was blocked, accelerated tumor growth and treatment resistance were overcome as demonstrated by cell culture and animal experiments. The reduction in DNMT1 was associated with increased apoptosis, cell cycle arrest, and augmented irradiation-induced free radical levels and DNA damage. Furthermore, positive staining for DNMT1 in clinical cancer specimens was significantly linked to lower rates of response to treatments and shorter survival of patients with pharyngeal cancer. CONCLUSION: DNMT1 may be a significant clinical predictor and a potential treatment strategy against head and neck cancer.

Role of peroxiredoxin I in rectal cancer and related to p53 status.

BACKGROUND: Neoadjuvant chemoradiotherapy is widely accepted for the treatment of localized rectal cancer. Although peroxiredoxin I (PrxI) and p53 have been implicated in carcinogenesis and cancer treatment, the role of PrxI and its interaction with p53 in the prognosis and treatment response of rectal cancer remain relatively unstudied. METHODS AND MATERIALS: In the present study, we examined the levels of PrxI and p53 in rectal cancer patients using membrane arrays and compared them with normal population samples. To demonstrate the biologic changes after manipulation of PrxI expression, we established stable transfectants of HCT-116 (wild-type p53) and HT-29 (mutant p53) cells with a PrxI silencing vector. The predictive capacities of PrxI and p53 were also assessed by relating the immunohistochemical staining of a retrospective series of rectal cancer cases to the clinical outcome. RESULTS: The membrane array and immunochemical staining data showed that PrxI, but not p53, was significantly associated with the tumor burden. Our immunochemistry findings further indicated that PrxI positivity was linked to a poor response to neoadjuvant therapy and worse survival. In cellular and animal experiments, the inhibition of PrxI significantly decreased tumor growth and sensitized the tumor to irradiation, as indicated by a lower capacity to scavenge reactive oxygen species and more extensive DNA damage. The p53 status might have contributed to the difference between HCT-116 and HT-29 after knockdown of PrxI. CONCLUSION: According to our data, the level of PrxI combined with the p53 status is relevant to the prognosis and the treatment response. We suggested that PrxI might be a new biomarker for rectal cancer.

Significance of interleukin-6 signaling in the resistance of pharyngeal cancer to irradiation and the epidermal growth factor receptor inhibitor.

PURPOSE: Tumor eradication by chemoradiotherapy for pharyngeal cancer has not been particularly successful. Targeting epithelial growth factor receptor (EGFR) could be a potential treatment strategy providing additional benefits, but only a subset of these tumors gives a clinically significant response to EGFR inhibitors. The aim has been to identify the role of interleukin-6 (IL-6) signaling and its predictive power in the treatment response of pharyngeal cancer. METHODS AND MATERIALS: Human pharyngeal cancer cell lines, including the hypopharyngeal cancer cell line FaDu and its derived cell line FaDu-C225-R, were selected. Changes in tumor growth, response to treatment, and responsible signaling pathway were investigated in vitro. Furthermore, 95 pharyngeal cancer tissue specimens were analyzed by immunohistochemical staining, and correlations were made between levels of IL-6, IL-6 receptor (IL-6R), p-AKT, and p-STAT3 expression and the clinical outcome of patients. RESULTS: In vitro, either extrinsic IL-6 stimulation of cancer cells or intrinsically activated IL-6 signaling detected in FADu-C225-R cells results in resistance to irradiation and EGFR inhibitor. Blocking IL-6 signaling attenuated aggressive tumor behavior and sensitized the cells to treatments. The responsible mechanisms included decreased p-STAT3, less nuclear translocation of EGFR, and subsequently attenuated epithelial-mesenchymal transition. Regarding clinical data, staining of p-STAT3 and IL-6 was significantly linked with lower response rates to treatments and shorter survival in pharyngeal cancer patients. CONCLUSIONS: IL-6 and p-STAT3 may be significant predictors of pharyngeal carcinoma, and regulating IL-6 signaling can be considered a promising therapeutic approach.

Androgen deprivation modulates the inflammatory response induced by irradiation.

BACKGROUND: The aim of this study was to determine whether radiation (RT)-induced inflammatory responses and organ damage might be modulated by androgen deprivation therapies. METHODS: The mRNA and tissue sections obtained from the lungs, intestines and livers of irradiated mice with or without androgen deprivation were analyzed by real-time PCR and histological analysis. Activation of NF-kappa B was examined by measuring nuclear protein levels in the intestine and lung 24 h after irradiation. We also examined the levels of cyclooxygenase-2 (COX-2), TGF-beta1 and p-AKT to elucidate the related pathway responsible to irradiation (RT) -induced fibrosis. RESULTS: We found androgen deprivation by castration significantly augmented RT-induced inflammation, associated with the increase NF-kappaB activation and COX-2 expression. However, administration of flutamide had no obvious effect on the radiation-induced inflammation response in the lung and intestine. These different responses were probably due to the increase of RT-induced NF-kappaB activation and COX-2 expression by castration or lupron treatment. In addition, our data suggest that TGF-beta1 and the induced epithelial-mesenchymal transition (EMT) via the PI3K/Akt signaling pathway may contribute to RT-induced fibrosis. CONCLUSION: When irradiation was given to patients with total androgen deprivation, the augmenting effects on the RT-induced inflammation and fibrosis should take into consideration for complications associated with radiotherapy.

The predictive role of E2-EPF ubiquitin carrier protein in esophageal squamous cell carcinoma.

The ubiquitin proteasome pathway has been implicated in carcinogenesis. However, the role of E2-EPF ubiquitin carrier protein (UCP) in esophageal cancer remains relatively unstudied. In the study, we examined the mRNA level of circulating tumor cells from 60 esophageal cancer patients by membrane arrays consisting of a panel of potential markers including UCP, compared to 40 normal populations. The predictive capacity of UCP was also assessed by immunohistochemical staining of a retrospective series of 84 biopsied esophageal squamous cell carcinomas in relation to clinical outcome. In addition, we studied in vitro biological changes including tumor growth, metastatic capacity, and the sensitivity to irradiation and cisplatin, after experimental manipulation of UCP expression in esophageal cancer cells. By the data of 25-gene membrane array analysis, UCP was the only factor significantly associated with the extent of tumor burden in esophageal cancer patients. Our immunochemistry findings further indicate that UCP positivity was linked to poor response to neoadjuvant therapy and worse survival. In cell culture, inhibited UCP significantly decrease tumor growth and the capacity for metastasis. The epithelial-mesenchymal transition (EMT) induced by VHL/HIF-1alpha-TGF-beta1 pathway might be the underlying mechanism responsible to the more aggressive tumor growth in UCP-positive esophageal cancer. Our results suggest that UCP was significantly associated with poor prognosis of esophageal cancer and may be a new molecular target for therapeutic intervention for esophageal squamous cell carcinoma.

Significance of nuclear accumulation of Foxo3a in esophageal squamous cell carcinoma.

PURPOSE: To investigate the value of Foxo3a in predicting the response to neoadjuvant treatment of, and prognosis for, esophageal squamous cell carcinoma. METHODS AND MATERIALS: Immunohistochemical staining was performed in a retrospective series of 60 biopsied esophageal squamous cell carcinomas, and the correlation between nuclear accumulation of Foxo3a and clinicopathologic features was analyzed, including patient survival. In addition, in vitro biologic changes, radiosensitivity, and in vivo tumorigenicity of esophageal carcinoma cells after experimental manipulation of Foxo3a expression levels were determined. RESULTS: Clinical findings point to a significant correlation between the nuclear accumulation of Foxo3a and the survival rate of esophageal cancer patients. In addition, Foxo3a is a significant predictor for the response to neoadjuvant therapy. In cell culture, irradiation and oxidative stress seemed to result in nuclear accumulation of Foxo3a. Down-regulation of Foxo3a significantly decreased radiosensitivity but had no obvious effect on tumor growth, as measured by a clonogenic assay in vitro and growth delay in vivo. CONCLUSIONS: Nuclear accumulation of Foxo3a in tumor cells was correlated with increased radiosensitivity and with improved patient survival. Thus, it is suggested that Foxo3a may be a potential marker for esophageal cancer.